Treatment for mild traumatic brain injury

Abstract

Disclosed are methods for alleviating one or more debilitating symptoms of mTBI in a patient diagnosed with mTBI, e.g., persistent mTBI, comprising administering an effective amount of ghrelin or a variant thereof for multiple consecutive days after diagnosis of mTBI, e.g., persistent mTBI.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Nos. 63 / 374,879, filed September 7, 2022, and 63 / 476,355, filed December 20, 2022, each of which is expressly incorporated by reference herein in its entirety for all purposes. [Background technology]

[0002] The present disclosure is directed to methods for treating mild traumatic brain injury, including, for example, concussion and other neurological disorders, which employ an effective amount of a composition comprising ghrelin or a ghrelin variant.

[0003] prior art Mild traumatic brain injury (mTBI), which typically includes concussions, "bangs to the head," etc., represents trauma to the brain that can cause long-term damage / injury to the brain. mTBI often results from a direct impact to the head, but can also result from indirect injury (e.g., whiplash injury or violent shaking of the head). Individuals who have suffered a single brain injury are at high risk for a second brain injury and are therefore more susceptible to subsequent injury. It is recognized that the damage from successive mTBIs is cumulative. (Cantu, R.C., Second-impact syndrome, Clinics in Sports Medicine, 17(I):37-44, 1998).

[0004] Long-term damage resulting from mTBI includes, for example, declines in cognitive and motor skills, such as slowed psychomotor performance, reduced concentration and attention recovery, leading to increased performance variability and overall executive dysfunction, as well as sleep disturbances and emotional / behavioral changes (Stuns, et al., 'Adult Clinical Neuropsychology: Lessons from Studies of the Frontal Lobes', Annual Review of Psychology, 53, 401-433 (2003)). Common examples of the long-term effects of mTBI are seen in soldiers, boxers, football players, and soccer players. There are many reported cases in which cumulative brain damage begins to manifest long after the occurrence of mTBI(s), with the loss of one or more cognitive and / or motor functions.

[0005] What distinguishes mTBI from other brain injuries or diseases is that, in contrast to underlying disease modalities such as neurodegenerative disorders, mTBI is caused by one or more injuries, meaning that brain damage is not attributable to an underlying pathology but rather is the result of the injury.

[0006] In some patients, the short-term symptoms of mTBI become prolonged, resulting in a condition called post-concussion syndrome (PCS). Such symptoms are recognized in the art and include, among others, headache, loss of clarity or confusion, difficulty focusing, double vision, blurred vision, sleep disturbances, emotional / behavioral changes, emotional outbursts, and memory loss. Described herein are improved treatments for the symptoms of mTBI, including persistent or poorly resolved symptoms. Summary of the Invention

[0007] Many of the symptoms of mTBI are debilitating, and most resolve spontaneously within a few days to a week after injury. However, in some cases, some or all of the symptoms may not resolve adequately. As described herein, patients who do not experience resolution of one or more of these debilitating symptoms within one week of mTBI can be classified as experiencing persistent mTBI. This is easily distinguishable from post-concussion syndrome (PCS). PCS involves a set of symptoms that persist after concussive trauma, often continuing for weeks, months, or even a year after injury. In persistent mTBI, symptoms do not persist long enough for a patient to be characterized as having PCS. Rather, patients with persistent mTBI desire resolution of their mTBI symptoms as quickly as possible.

[0008] Treatment of mTBI with ghrelin or variants thereof is described, for example, in U.S. Patent Application Publication No. 2017 / 0281732, the entire contents of which are incorporated herein by reference. For example, ghrelin can be administered within 72 hours after the injury occurs.

[0009] Surprisingly, ghrelin treatment provided by the methods described herein has been found to alleviate one or more symptoms of mTBI, for example, in subjects with persistent mTBI, even days to weeks after the initial injury. The present disclosure is directed, in part, to methods of alleviating one or more debilitating symptoms of mTBI, for example, in patients diagnosed with persistent mTBI. In particular, the present disclosure includes administering ghrelin or a variant thereof for one or multiple consecutive days after diagnosis of mTBI, for example, persistent mTBI.

[0010] The present disclosure also relates to the treatment of mTBI with multiple administrations of ghrelin or a variant thereof.

[0011] In one aspect, provided herein is a method for reducing one or more symptoms of mild traumatic brain injury (mTBI) in a patient diagnosed with persistent mTBI, the method comprising administering to the patient an effective amount of ghrelin or a variant thereof for multiple consecutive days after diagnosis, wherein within about 40 days after initiation of administration of ghrelin or a variant thereof, the one or more symptoms improve by at least 20% compared to baseline.

[0012] In some embodiments, within about 44 days after initiating administration of ghrelin or a variant thereof, one or more symptoms are improved by at least 20% compared to baseline. In some embodiments, within about 30 days after initiating administration of ghrelin or a variant thereof, one or more symptoms are improved by at least 20% compared to baseline. In some embodiments, within about 20 days after initiating administration of ghrelin or a variant thereof, one or more symptoms are improved by at least 20% compared to baseline. In some embodiments, within about 10 days after initiating administration of ghrelin or a variant thereof, one or more symptoms are improved by at least 20% compared to baseline. In some embodiments, within about 40 days after initiating administration of ghrelin or a variant thereof, one or more symptoms are improved by at least 25% compared to baseline. In some embodiments, within about 10 days after initiating administration of ghrelin or a variant thereof, one or more symptoms are improved by at least 30% compared to baseline. In some embodiments, within about 20 days after initiating administration of ghrelin or a variant thereof, one or more symptoms are improved by at least 30% compared to baseline. In some embodiments, within about 30 days after initiating administration of ghrelin or a variant thereof, one or more symptoms are improved by at least 30% compared to baseline. In some embodiments, one or more symptoms are improved by at least 30% compared to baseline within about 40 days after initiation of administration of ghrelin or a variant thereof, hi some embodiments, one or more symptoms are improved by at least 30% compared to baseline within about 44 days after initiation of administration of ghrelin or a variant thereof.

[0013] In some embodiments, improvement is measured by QOLIBRI, PCSS, PGAS, and / or Brain Check.

[0014] In some embodiments, administration of ghrelin is continued until the patient's symptoms become asymptomatic. In some embodiments, the improvement achieved by administering ghrelin according to the methods described herein continues long after ghrelin administration has ceased. Thus, in such situations, ghrelin administration is continued for a first period, followed by a second period during which ghrelin is not administered but the patient's ongoing response to ghrelin is monitored. Optionally, if the patient desires further relief from persistent mTBI symptoms, a second daily dose of ghrelin can be initiated after the second period.

[0015] In some embodiments, ghrelin or a variant thereof is administered as a pharmaceutical composition. In some further embodiments, the pharmaceutical composition is a sterile aqueous solution suitable for injection. In some further embodiments, the pharmaceutical composition is a transdermal patch.

[0016] In some embodiments, administration of ghrelin or a variant thereof continues for at least 3 days. In some embodiments, administration of ghrelin or a variant thereof continues for at least 5 days. In some embodiments, administration of ghrelin or a variant thereof continues for at least 14 days. In some embodiments, administration of ghrelin or a variant thereof continues for at least 40 days.

[0017] In some embodiments, only a single dose of ghrelin or a variant thereof is administered per day, hi some further embodiments, two or more doses of ghrelin or a variant thereof are administered per day.

[0018] In some embodiments, ghrelin or a variant thereof is administered by subcutaneous injection.

[0019] In some embodiments, administration of ghrelin is continued until the patient is able to resume normal activity.

[0020] In some embodiments, the one or more symptoms include headache, loss of clarity or confusion, difficulty focusing, double vision, blurred vision, sleep disturbances, emotional / behavioral changes, emotional outbursts, and / or memory loss. In some further embodiments, the one or more symptoms include the patient's four most bothersome symptoms (MBS).

[0021] In some embodiments, the total daily dose of ghrelin or a variant thereof is administered at a dose of about 80 μg / kg per day.

[0022] In one aspect, provided herein is a method for alleviating one or more symptoms of mild traumatic brain injury (mTBI), the method comprising: selecting a patient who has had mTBI due to injury and who has had one or more symptoms of mTBI for at least 3 days to about 30 days, preferably at least 7 days to about 30 days, after injury; and administering ghrelin or a variant thereof to the patient for a period of time, wherein the ghrelin or variant thereof is administered at a dose of about 80 μg / kg per day, wherein the one or more symptoms improve by at least 20% compared to baseline within about 40 days after initiation of administration of ghrelin or a variant thereof.

[0023] In further embodiments, ghrelin or a variant thereof is administered at about 40 μg / kg twice daily.

[0024] In some further embodiments, the first period of time is up to about 14 days, hi some further embodiments, the first period of time is about 10 days.

[0025] In some further embodiments, the patient is periodically evaluated for one or more symptoms of mTBI. In some embodiments, the patient is evaluated for one or more symptoms of mTBI before administration of ghrelin or a variant thereof. In some embodiments, the patient is evaluated for one or more symptoms of mTBI during administration of ghrelin or a variant thereof.

[0026] In some embodiments, the patient is evaluated for one or more symptoms of mTBI about 3 days, 7 days, 10 days, 14 days, 20 days, and / or 43 days after initiation of administration of ghrelin or a variant thereof.

[0027] In some embodiments, the patient is assessed using one or more of the PCSS, QOLIBRI, PGAS, and / or BrainCheck.

[0028] In some embodiments, one or more symptoms are improved by at least 20% compared to baseline within about 10 days after initiating administration of ghrelin or a variant thereof, hi some embodiments, one or more symptoms are improved by at least 30% compared to baseline within about 10 days after initiating administration of ghrelin or a variant thereof.

[0029] One embodiment provided herein is a method of treating a concussive event in a human subject by eliminating or reducing the severity of multiple symptoms associated with the concussive event, the method comprising administering ghrelin or a variant thereof to the subject daily for a first period beginning at least three days after the concussive event, wherein the severity of the subject's multiple symptoms is reduced within 45 days after the end of administration of ghrelin or a variant thereof.

[0030] Another aspect provided herein is a method for accelerating recovery from a concussive event in a human subject by eliminating or reducing the severity of multiple symptoms associated with the concussive event, the method comprising administering daily to the patient ghrelin or a variant thereof beginning at least 3 to 30 days after the concussive event, and continuing the daily administration for at least 10 days, wherein multiple symptoms associated with the concussive event in the subject are reduced.

[0031] In another aspect, provided herein is a method of accelerating recovery of one or more neurological functions in a human subject following a concussive event, the method comprising administering daily to the subject ghrelin or a variant thereof beginning at least 3 to 30 days after the concussive event, and continuing the daily administration for at least 10 days, resulting in recovery of one or more neurological functions in the subject.

[0032] In one embodiment, a kit of parts is provided that includes a set of syringes, each containing an effective amount of ghrelin in a sterile, pharmaceutically acceptable aqueous solution, with each syringe annotated with the day and time of administration. Such annotations may include, by way of example only, "Day 1 Morning," "Day 1 Evening," "Day 2 Morning," "Day 2 Evening," etc. Morning and evening injections for a particular day may be labeled together for ease of identification. [Brief explanation of the drawings]

[0033] [Figure 1] Summary of a phase 2 clinical trial of ghrelin (OXE103) for the treatment of post-acute concussion. [Figure 2] 1 is a summary of an exemplary mechanism of action of ghrelin (OXE103) in concussion. [Figure 3]A and B show a plot (A) of the mean QOLIBRI percent (PCT) change for patients treated with or without ghrelin in a phase 2 clinical trial, and a table (B) of the number of patients who responded based on QOLIBRI at each time point. For QOLIBRI, patients were considered to have responded to treatment if the percent change compared to baseline was 20% or greater. [Figure 4] A and B show a plot of the mean PCSS percent change in patients treated with or without ghrelin in a phase 2 clinical trial (A) and a table of the number of patients who responded based on PCSS at each time point (B). For PCSS, patients were considered to have responded to treatment if the percent change compared to baseline was -20% or greater. [Figure 5] A and B show a plot (A) of the mean percent change in four MBS (4MBS) in patients with and without ghrelin treatment in a phase 2 clinical trial, and a table (B) of the number of patients who responded based on the 4MBS at each time point. For the 4MBS, patients were considered to have responded to treatment if the percent change compared to baseline was -20% or greater. [Figure 6] A and B show a plot of the mean PGAS percent change (A) in patients treated with or without ghrelin in a phase 2 clinical trial, and a table of the number of patients who responded based on PGAS at each time point (B). For PGAS, patients were considered to have responded to treatment if the percent change compared to baseline was -20% or greater. [Figure 7] 7A and 7B show a plot of the percent change in mean PCSS symptom counts for patients treated with or without ghrelin in a phase 2 clinical trial (A) and a table of the number of patients who responded based on PCSS symptom counts at each time point (B). [Figure 8] A and B are plots showing the change in Braincheck scores over time in patients treated with ghrelin (A) and patients not treated with ghrelin (B) in a phase 2 clinical trial. [Figure 9]A and B are individual patient plots of percent change from baseline in PCSS scores for patients treated with ghrelin (A) and not treated with ghrelin (B) in a phase 2 clinical trial. [Figure 10] A and B are individual patient plots of percent change from baseline in symptom count scores for patients treated with ghrelin (A) and not treated with ghrelin (B) in a phase 2 clinical trial. [Figure 11] A and B are individual patient plots of percent change from baseline in PGAS scores for patients treated with ghrelin (A) and not treated with ghrelin (B) in a phase 2 clinical trial. [Figure 12] A and B are individual patient plots of percent change from baseline in 4MBS scores for patients treated with ghrelin (A) and patients not treated with ghrelin (B) in a phase 2 clinical trial. [Figure 13] A and B are individual patient plots of percent change from baseline in QOLIBRI scores for patients treated with ghrelin (A) and not treated with ghrelin (B) in a phase 2 clinical trial. [Figure 14] PCSS data are plotted showing the reduction in all symptoms in OXE-103-treated subjects from Day 1 to Day 44. PCSS data were ordered by symptom and aggregated across 11 OXE-103 treatment responders by symptom. DETAILED DESCRIPTION OF THE INVENTION

[0034] Disclosed are methods for treating mTBI, including persistent mild traumatic brain injury such as concussion. However, prior to describing the details, the following terms are defined. Unless defined, terms used herein have their generally accepted scientific meaning.

[0035] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0036] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs or does not occur.

[0037] The term "about," when used before specifying a numerical value including a range, e.g., temperature, time, amount, concentration, etc., indicates an approximation that may vary by (+) or (-) 10%, 5%, 1%, or any subrange or subvalue therebetween. Preferably, the term "about" used in reference to a dose means that the dose may vary by + / - 10%.

[0038] "Comprising" or "comprises" means that the compositions and methods include the recited elements, but is not intended to exclude other elements.

[0039] When used to define compositions and methods, "consisting essentially of" means excluding other elements that are of any essential importance to the combination for which it is intended. Thus, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure.

[0040] "Consisting of" means excluding more than trace elements and substantial method steps of other components. Embodiments defined by each of these transitional phrases are within the scope of this disclosure.

[0041] The term "ghrelin" refers to a naturally occurring peptide consisting of 28 amino acids containing an N-octanoyl group at position 3 of serine. The amino acid sequence of ghrelin is known.

[0042] The term "ghrelin variant" refers to any ghrelin variant, including C-terminal alkyl esters (-COOR), where R is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, N-terminal amides (R 1 C(O)NH-) (where R 1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl), a combination of a C-terminal alkyl ester and an N-terminal amide, both as defined above, and / or a peptide containing a ghrelin variant described in U.S. Patent Application Publication No. 2017 / 0281732, which is incorporated herein by reference in its entirety, including all compositions, formulations, and methods taught therein. The term "ghrelin variant" may be used interchangeably with "ghrelin agonist." A ghrelin agonist may be, for example, a peptide or molecule that binds to the ghrelin receptor or other receptor to which ghrelin can bind and induces one or more of the effects that are caused when ghrelin binds to the receptor.

[0043] The term "administration" refers to administering an effective amount of a composition containing ghrelin (or a variant thereof) to a patient. Administration may be a single dose, continuous or intermittent administration, or several subdoses that total to provide a single dose. For example, administration may continue throughout the treatment period, which may be as short as 1-2 or 3 days, or as long as 7 or more days, such as 10, 12, or 14 days. In some embodiments, treatment begins after a diagnosis of mTBI or persistent mTBI. The route of administration is selected by the attending physician and is determined based on factors such as the patient's age, weight, general health, and severity of the condition. Suitable routes of administration include parenteral, intravenous, transdermal, vaginal, nasal, sublingual, and pulmonary.

[0044] The term "asymptomatic" means that the patient reports no residual debilitating symptoms of mTBI (e.g., persistent mTBI). While some mild symptoms may persist, debilitating symptoms such as (but not limited to) debilitating headaches, double vision, blurred vision, nausea, migraines, confusion, etc. have lessened. In some cases, patients are able to resume most, if not all, of their daily and usual activities.

[0045] The term "debilitating" in relation to mTBI refers to the inability of a patient to lead a normal life due to one or more symptoms of that mTBI.

[0046] The term "mild traumatic brain injury" or "mTBI" is used herein according to its plain and ordinary meaning to refer to brain injury caused by a blow to the head or violent shaking of the head and body. In some embodiments, the terms mTBI and concussion can be used interchangeably. Clinically, traumatic brain injury can be classified as mild, moderate, or severe based on TBI variables such as duration of loss of consciousness (LOC), Glasgow Coma Score (GCS), and post-traumatic stress amnesia (PTAM) (see, e.g., Levin et al., “The Galveston Orientation and Amnesia Test: a practical scale to assess cognition after head injury,” J Nervous Mental Dis 167:675-84 (1979); Holm et al., “J Neurotrauma task force on mild traumatic brain injury of the WHO Collaborating Centre. Summary of the WHO Collaborating Centre for Neurotrauma Task Force on Mild Traumatic Brain Injury,” J Rehabil Med 37:137-41 (2005)). For example, a brain injury is classified as mild if the patient’s GCS score is 13–15, post-traumatic amnesia lasts less than 1 day, and / or LOC is 0–30 minutes.

[0047] The term "persistent mTBI" (sometimes referred to as "poorly resolved mTBI") means that one or more symptoms of mTBI do not resolve and continue to debilitate the patient days to weeks after the initial injury. In one embodiment, one or more symptoms of mTBI persist for at least seven days after injury. However, persistent mTBI should not be confused with PCS, which requires a much longer duration of symptoms than persistent mTBI (usually about 30 days or more).

[0048] As used herein, the term "concussive event" is used according to its plain and ordinary meaning to refer to an event involving excessive force to the head or neck. In embodiments, the excessive force to the head or neck occurs through a direct impact. In embodiments, the excessive force to the head or neck occurs through the transmission of force through the body and neck. In embodiments, the concussive event includes injury to the brain, central nervous system, cervical spine, and / or vestibular system. In embodiments, the concussive event includes brain injury. In embodiments, the concussive event includes central nervous system injury. In embodiments, the concussive event includes cervical spine injury. In embodiments, the concussive event includes vestibular system injury. In embodiments, the concussive event results in an mTBI. In embodiments, the concussive event results in a sustained mTBI. In embodiments, the concussive event results in a concussion. In embodiments, the concussive event results in a PCS.

[0049] As used herein, the term "plurality of symptoms" is used according to its plain and ordinary meaning to refer to more than one symptom of a disease in a subject. In embodiments, the plurality of symptoms is two symptoms. In embodiments, the plurality of symptoms is two or more symptoms. In embodiments, the plurality of symptoms is three symptoms. In embodiments, the plurality of symptoms is three or more symptoms. In embodiments, the plurality of symptoms is four symptoms. In embodiments, the plurality of symptoms is four or more symptoms. In embodiments, the plurality of symptoms is five symptoms. In embodiments, the plurality of symptoms is five or more symptoms. In embodiments, the plurality of symptoms is six symptoms. In embodiments, the plurality of symptoms is six or more symptoms. In embodiments, the plurality of symptoms is seven symptoms. In embodiments, the plurality of symptoms is seven or more symptoms. In embodiments, the plurality of symptoms is eight symptoms. In embodiments, the plurality of symptoms is eight or more symptoms. In embodiments, the plurality of symptoms is nine symptoms. In embodiments, the plurality of symptoms is nine or more symptoms. In embodiments, the plurality of symptoms is ten symptoms. In embodiments, the plurality of symptoms is 10 or more symptoms. In embodiments, the plurality of symptoms is 11 symptoms. In embodiments, the plurality of symptoms is 11 or more symptoms. In embodiments, the plurality of symptoms is 12 symptoms. In embodiments, the plurality of symptoms is 12 or more symptoms. In embodiments, the plurality of symptoms is 13 symptoms. In embodiments, the plurality of symptoms is 13 or more symptoms. In embodiments, the plurality of symptoms is 14 symptoms. In embodiments, the plurality of symptoms is 14 or more symptoms. In embodiments, the plurality of symptoms is 3 symptoms. In embodiments, the plurality of symptoms is 15 symptoms. In embodiments, the plurality of symptoms is 15 or more symptoms.

[0050] As used herein, the terms "alleviate," "alleviated," or "alleviation" are used according to their plain and ordinary meaning to refer to a decrease in amount or quantity. In embodiments, alleviation of symptoms refers to a decrease in the occurrence of disease symptoms in a subject. In embodiments, alleviation may be complete (no detectable symptoms) or partial, with milder symptoms observed than would likely occur in the absence of treatment. In embodiments, alleviation of symptoms may be gradual (e.g., symptom alleviation increases over time). In embodiments, alleviation is assessed or evaluated quantitatively and qualitatively. In embodiments, alleviation is assessed or evaluated quantitatively. In embodiments, alleviation is measured or evaluated qualitatively. In embodiments, alleviation is assessed or evaluated by a clinician. In embodiments, alleviation is assessed or evaluated by the subject.

[0051] As used herein, the term "neuronal function" is used according to its plain and ordinary meaning to refer to an activity or function performed by nerve cells in a subject. In embodiments, neuronal function includes receiving sensory input from the outside world and / or sending motor commands to muscles. In embodiments, neuronal function includes receiving, converting, and relaying electrochemical signals. In embodiments, neuronal function includes cognition. In embodiments, neuronal function includes perception, learning, memory, attention, decision-making, language, and / or motor planning.

[0052] As used herein, the term "responder" is used according to its plain and ordinary meaning to refer to a subject who experiences a clinically meaningful benefit from a prescribed treatment. In embodiments, the prescribed treatment is administration of ghrelin or a variant thereof. In embodiments, the prescribed treatment is standard of care. In embodiments, the prescribed treatment is no treatment. In embodiments, the clinically meaningful benefit is a reduction in the number and / or severity of symptoms associated with a concussive event. In embodiments, the clinically meaningful benefit is a reduction in the number of symptoms associated with a concussive event. In embodiments, the clinically meaningful benefit is a reduction in the severity of multiple symptoms associated with a concussive event. In embodiments, the clinically meaningful benefit is at least a 20% reduction in multiple symptoms associated with a concussive event. In embodiments, the clinically meaningful benefit is at least a 25% reduction in multiple symptoms associated with a concussive event. In embodiments, the clinically meaningful benefit is at least a 30% reduction in multiple symptoms associated with a concussive event. In some embodiments, the symptoms associated with a concussive event are measured using the 22-symptom PCSS. In some embodiments, the severity of the symptoms associated with a concussive event is rated by the subject on a 7-point Likert scale. In some embodiments, the reduction in the symptoms associated with a concussive event is assessed about 15 days after initiation of administration of ghrelin or a variant thereof. In some embodiments, the reduction in the symptoms associated with a concussive event is assessed about 20 days after initiation of administration of ghrelin or a variant thereof. In some embodiments, the reduction in the symptoms associated with a concussive event is assessed about 30 days after initiation of administration of ghrelin or a variant thereof. In some embodiments, the reduction in the symptoms associated with a concussive event is assessed about 40 days after initiation of administration of ghrelin or a variant thereof. In some embodiments, the reduction in the symptoms associated with a concussive event is assessed about 50 days after initiation of administration of ghrelin or a variant thereof. In some embodiments, the reduction in the symptoms associated with a concussive event is assessed about 60 days after initiation of administration of ghrelin or a variant thereof. method

[0053] The methods described herein treat patients who have been diagnosed with a concussive event, e.g., persistent mTBI, and whose symptoms do not readily resolve after the event. The diagnosis and selection or identification of such patients can be based on the persistence of debilitating symptoms of mTBI for at least 3, 4, 5, 6, or 7 days, or from about 3 days to about 29 days, following the trauma resulting from the mTBI, without a diagnosis of PCS. Many patients who suffer from mTBI do not immediately seek medical attention, seeking medical care only if the debilitating symptoms of mTBI do not resolve in a timely manner.

[0054] Unlike patients who receive treatment immediately after mTBI, patients suffering from persistent mTBI experience an unabated biological cascade of adverse events in the brain. Such events include untreated inflammation in the brain due to, for example, metabolic abnormalities, neuronal injury, or inflammation associated with excessive production of reactive oxygen species (ROS). Without being bound by theory, Figure 2 provides an example of injury resulting from an mTBI (e.g., concussion). This disclosure addresses the need to address these unabated adverse events while simultaneously alleviating patients' debilitating symptoms.

[0055] The methods described herein further relate to treating patients with mTBI by administering ghrelin or a variant thereof in multiple doses (administrations) and / or for multiple days. In some embodiments, the mTBI is acute mTBI. In some embodiments, the mTBI is persistent mTBI. In some embodiments, the mTBI is PCS. In some embodiments, the mTBI is not acute mTBI. In some embodiments, the mTBI is not PCS.

[0056] One embodiment provided herein is a method of treating a concussive event in a human subject by eliminating or reducing the severity of multiple symptoms associated with the concussive event, the method comprising administering ghrelin or a variant thereof to the subject daily for a first period beginning at least three days after the concussive event, wherein the severity of the subject's multiple symptoms is reduced within 45 days after the end of administration of ghrelin or a variant thereof.

[0057] In some embodiments, the method further comprises administering ghrelin or a variant thereof to the subject daily for a second period of time beginning after the first period of time, further reducing the severity of the symptoms in the subject.

[0058] In embodiments, the plurality of symptoms includes at least three concussion symptoms. In embodiments, the plurality of symptoms includes at least four concussion symptoms. In embodiments, the plurality of symptoms includes at least five concussion symptoms. In embodiments, the plurality of symptoms includes at least six concussion symptoms. In embodiments, the plurality of symptoms includes at least seven concussion symptoms. In embodiments, the plurality of symptoms includes at least eight concussion symptoms. In embodiments, the plurality of symptoms includes at least nine concussion symptoms. In embodiments, the plurality of symptoms includes at least ten concussion symptoms.

[0059] In some embodiments, the severity of each of the plurality of symptoms is reduced by at least 20%. In some embodiments, the severity of each of the plurality of symptoms is reduced by at least 30%. In some embodiments, the plurality of symptoms are selected from neck pain, double vision, blurred vision, visual disturbances, memory loss, difficulty understanding or concentrating, difficulty focusing or paying attention, loss of clarity or confusion, temporary blackouts, feeling slowed down, numbness or tingling, emotional outbursts, anxiety, sad or depressed mood, irritability, tinnitus, sensitivity to light, sensitivity to noise, drowsiness, sleeping more than usual, sleeping less than usual, difficulty falling asleep, trouble sleeping, fatigue, dizziness or unsteadiness, problems with balance, vomiting, nausea, and / or headache.

[0060] In embodiments, the reduction in symptoms is measured by QOLIBRI, PCSS, PGAS, or Brain Check. In embodiments, the reduction in symptoms is measured by QOLIBRI. In embodiments, the reduction in symptoms is measured by PCSS. In embodiments, the reduction in symptoms is measured by PGAS. In embodiments, the reduction in symptoms is measured by Brain Check.

[0061] In some embodiments, the severity of the symptoms in the subject is reduced within one day after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within two days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within three days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within four days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within five days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within ten days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 15 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 20 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 25 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 30 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 35 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 40 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 45 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 50 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 55 days after the end of administration of ghrelin or a variant thereof. In some embodiments, the severity of the symptoms in the subject is reduced within 60 days after the end of administration of ghrelin or a variant thereof.

[0062] Another aspect provided herein is a method for accelerating recovery from a concussive event in a human subject by eliminating or reducing the severity of multiple symptoms associated with the concussive event, the method comprising administering daily to the patient ghrelin or a variant thereof beginning at least 3 to 30 days after the concussive event, and continuing the daily administration for at least 10 days, wherein multiple symptoms associated with the concussive event in the subject are reduced.

[0063] In embodiments, the plurality of symptoms associated with a concussive event includes at least three concussion symptoms. In embodiments, the plurality of symptoms associated with a concussive event includes at least four concussion symptoms. In embodiments, the plurality of symptoms associated with a concussive event includes at least five concussion symptoms. In embodiments, the plurality of symptoms associated with a concussive event includes at least six concussion symptoms. In embodiments, the plurality of symptoms associated with a concussive event includes at least seven concussion symptoms. In embodiments, the plurality of symptoms associated with a concussive event includes at least eight concussion symptoms. In embodiments, the plurality of symptoms associated with a concussive event includes at least nine concussion symptoms. In embodiments, the plurality of symptoms associated with a concussive event includes at least ten concussion symptoms.

[0064] In embodiments, the symptoms associated with the concussive event are reduced by at least 20%. In embodiments, the symptoms associated with the concussive event are reduced by at least 30%. In embodiments, the symptoms associated with the concussive event are selected from neck pain, double vision, blurred vision, visual disturbances, memory loss, difficulty remembering, difficulty understanding or concentrating, difficulty focusing or paying attention, loss of clarity or confusion, feeling like you're in a fog, temporary loss of consciousness, feeling slowed down, numbness or tingling, emotional outbursts, tension or anxiety, sad or depressed mood, irritability, tinnitus, sensitivity to light, sensitivity to noise, drowsiness, sleeping more than usual, sleeping less than usual, difficulty falling asleep, trouble sleeping, fatigue, dizziness or unsteadiness, balance problems, vomiting, nausea, and / or headache. In embodiments, the symptoms associated with the concussive event include neck pain. In embodiments, the symptoms associated with the concussive event include double vision. In embodiments, the symptoms associated with a concussive event include blurred vision. In embodiments, the symptoms associated with a concussive event include visual impairment. In embodiments, the symptoms associated with a concussive event include memory loss or difficulty remembering. In embodiments, the symptoms associated with a concussive event include difficulty understanding or concentrating. In embodiments, the symptoms associated with a concussive event include difficulty concentrating or paying attention. In embodiments, the symptoms associated with a concussive event include loss of clarity or confusion. In embodiments, the symptoms associated with a concussive event include feeling like you're in a fog. In embodiments, the symptoms associated with a concussive event include temporary loss of consciousness. In embodiments, the symptoms associated with a concussive event include feeling sluggish. In embodiments, the symptoms associated with a concussive event include numbness or tingling. In embodiments, the symptoms associated with a concussive event include feeling emotional. In embodiments, the symptoms associated with a concussive event include emotional outbursts.In embodiments, the plurality of symptoms associated with a concussive event include tension or anxiety. In embodiments, the plurality of symptoms associated with a concussive event include sadness or depressed mood. In embodiments, the plurality of symptoms associated with a concussive event include irritability. In embodiments, the plurality of symptoms associated with a concussive event include tinnitus. In embodiments, the plurality of symptoms associated with a concussive event include sensitivity to light. In embodiments, the plurality of symptoms associated with a concussive event include sensitivity to noise. In embodiments, the plurality of symptoms associated with a concussive event include drowsiness. In embodiments, the plurality of symptoms associated with a concussive event include sleeping more than usual. In embodiments, the plurality of symptoms associated with a concussive event include sleeping less than usual. In embodiments, the plurality of symptoms associated with a concussive event include difficulty falling asleep. In embodiments, the plurality of symptoms associated with a concussive event include sleep disturbances. In embodiments, the plurality of symptoms associated with a concussive event include fatigue. In embodiments, the plurality of symptoms associated with a concussive event include dizziness or unsteadiness. In embodiments, the symptoms associated with a concussive event include balance problems. In embodiments, the symptoms associated with a concussive event include vomiting. In embodiments, the symptoms associated with a concussive event include nausea. In embodiments, the symptoms associated with a concussive event include headache.

[0065] Without being limited to any theory, after a concussion occurs, damaged cells, neurons, or organs enter an injury mode that includes at least one of oxygen deficiency due to reduced blood flow, energy deficiency due to reduced glucose levels, and / or the release of pro-inflammatory compounds such as reactive oxygen species. In subjects with delayed recovery, damaged cells, neurons, or organs remain in the injury mode for a long period of time, delaying recovery.

[0066] Again, without being limited to any theory, the methods described herein utilize administration of ghrelin or a variant thereof to promote the transition of injured cells, neurons, or organs from a trauma mode to a recovery mode, initiating the return of the cells, neurons, or organs to their pre-concussion quiescent state. The use of ghrelin or a variant thereof helps accelerate this transition, significantly shortening the time to onset of recovery compared to a control (without administration of ghrelin or a variant thereof).

[0067] In another aspect, provided herein is a method of accelerating recovery of one or more neurological functions in a human subject following a concussive event, the method comprising administering daily to the subject ghrelin or a variant thereof beginning at least 3 to 30 days after the concussive event, and continuing the daily administration for at least 10 days, resulting in recovery of one or more neurological functions in the subject.

[0068] In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 3 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 4 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 5 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 6 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 7 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 8 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 9 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 10 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 11 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 12 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 13 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 14 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 15 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 16 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 17 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 18 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 19 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 20 days after the concussive event. In embodiments, daily administration of ghrelin or a variant thereof begins at least 21 days after the concussive event.In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 22 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 23 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 24 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 25 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 26 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 27 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 28 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated at least 29 days after the concussive event. In some embodiments, daily administration of ghrelin or a variant thereof is initiated within 3 days and 30 days after the concussive event. The start time may be any value or subrange within the listed ranges, including the endpoints.

[0069] Ghrelin or a variant thereof may be administered in a single dose or multiple doses over one or more days. In embodiments, the daily administration is for at least one day. In embodiments, the daily administration is for at least two days. In embodiments, the daily administration is for between three and thirty days. In embodiments, the daily administration is for at least three days. In embodiments, the daily administration is for at least four days. In embodiments, the daily administration is for at least five days. In embodiments, the daily administration is for at least six days. In embodiments, the daily administration is for at least seven days. In embodiments, the daily administration is for at least eight days. In embodiments, the daily administration is for at least nine days. In embodiments, the daily administration is for at least ten days. In embodiments, the daily administration is for at least eleven days. In embodiments, the daily administration is for at least twelve days. In embodiments, the daily administration is for at least thirteen days. In embodiments, the daily administration is for at least fourteen days. In embodiments, the daily administration is for at least fifteen days. In some embodiments, the daily administration is for at least 16 days. In some embodiments, the daily administration is for at least 17 days. In some embodiments, the daily administration is for at least 18 days. In some embodiments, the daily administration is for at least 19 days. In some embodiments, the daily administration is for at least 20 days. In some embodiments, the daily administration is for at least 21 days. In some embodiments, the daily administration is for at least 22 days. In some embodiments, the daily administration is for at least 23 days. In some embodiments, the daily administration is for at least 41 days. In some embodiments, the daily administration is for at least 51 days. In some embodiments, the daily administration is for at least 26 days. In some embodiments, the daily administration is for at least 27 days. In some embodiments, the daily administration is for at least 28 days. In some embodiments, the daily administration is for at least 29 days. In some embodiments, the daily administration is for at least 30 days. The administration time may be any value or subrange within the recited ranges, including the endpoints.

[0070] In some embodiments, ghrelin or a variant thereof may be administered for more than 14 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 15 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 20 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 25 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 30 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 35 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 40 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 45 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 50 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 55 days. In some embodiments, daily administration of ghrelin or a variant thereof continues for up to 60 days. In one embodiment, ghrelin or a variant thereof can be administered until one or more symptoms of mTBI (or persistent mTBI or PCS) have resolved. In one embodiment, ghrelin or a variant thereof can be administered continuously (e.g., using a transdermal patch) for 1 to 14 days or more, for example, up to 40 days or more.

[0071] In some embodiments, the first administration of ghrelin or a variant thereof is formulated to occur about 1-2 hours after breakfast, and the second administration of ghrelin or a variant thereof is formulated to occur about 1-2 hours after dinner. In some embodiments, the first administration of ghrelin or a variant thereof is formulated to occur about 1.25-2 hours after breakfast, and the second administration of ghrelin or a variant thereof is formulated to occur about 1.25-2 hours after dinner. In some embodiments, the first administration of ghrelin or a variant thereof is formulated to occur about 1.5-2 hours after breakfast, and the second administration of ghrelin or a variant thereof is formulated to occur about 1.5-2 hours after dinner. In some embodiments, the first administration of ghrelin or a variant thereof is formulated to occur about 1.75-2 hours after breakfast, and the second administration of ghrelin or a variant thereof is formulated to occur about 1.75-2 hours after dinner. The times may be any value or subrange within the recited ranges, including the endpoints.

[0072] In some embodiments, daily administration of ghrelin or a variant thereof is formulated to occur within about 1-2 hours after a meal. In some embodiments, daily administration of ghrelin or a variant thereof is formulated to occur within about 1.25-2 hours after a meal. In some embodiments, daily administration of ghrelin or a variant thereof is formulated to occur within about 1.5-2 hours after a meal. In some embodiments, daily administration of ghrelin or a variant thereof is formulated to occur within about 1.75-2 hours after a meal. The time period may be any value or subrange within the recited range, including the endpoint.

[0073] In some embodiments, daily administration of ghrelin or a variant thereof is formulated to occur within about 1-2 hours after food ingestion. In some embodiments, daily administration of ghrelin or a variant thereof is formulated to occur within about 1.25-2 hours after food ingestion. In some embodiments, daily administration of ghrelin or a variant thereof is formulated to occur within about 1.5-2 hours after food ingestion. In some embodiments, daily administration of ghrelin or a variant thereof is formulated to occur within about 1.75-2 hours after food ingestion. The time may be any value or subrange within the recited range, including the endpoint. In certain embodiments, daily administration of ghrelin is administered twice, after breakfast and after dinner, as directed.

[0074] In embodiments where the daily administration of ghrelin or a variant thereof is in a single dose, the administration is formulated to occur within about 1-2 hours after ingestion of a meal. In embodiments where the daily administration of ghrelin or a variant thereof is in a single dose, the administration is formulated to occur within about 1.25-2 hours after ingestion of a meal. In embodiments where the daily administration of ghrelin or a variant thereof is in a single dose, the administration is formulated to occur within about 1.5-2 hours after ingestion of a meal. In embodiments where the daily administration of ghrelin or a variant thereof is in a single dose, the administration is formulated to occur within about 1.75-2 hours after ingestion of a meal. The time period can be any value or subrange within the recited range, including the endpoint.

[0075] In embodiments where the daily administration of ghrelin or a variant thereof is in a single dose, the administration is formulated to occur within about 1-2 hours after food ingestion. In embodiments where the daily administration of ghrelin or a variant thereof is in a single dose, the administration is formulated to occur within about 1.25-2 hours after food ingestion. In embodiments where the daily administration of ghrelin or a variant thereof is in a single dose, the administration is formulated to occur within about 1.5-2 hours after food ingestion. In embodiments where the daily administration of ghrelin or a variant thereof is in a single dose, the administration is formulated to occur within about 1.75-2 hours after food ingestion. The time may be any value or subrange within the recited range, including the endpoint.

[0076] In the methods described herein, ghrelin or a variant thereof is administered as a one-day treatment and / or daily for multiple consecutive days following diagnosis.

[0077] In some embodiments, ghrelin or a composition comprising ghrelin is administered. In some embodiments, a ghrelin variant or a composition comprising ghrelin variant is administered. In some embodiments, the ghrelin variant comprises one or more ghrelin agonists, such as macimorelin (EP1572), LY444711, LY426410, capromorelin (CP-424391), CP464709, anamorelin (RC-1291), urimorelin, tabimorelin (NN703, NNC-26-703), ibutamoren (MK-0677), G-7203, G7502, SM-130686, L-692429, L-692587, L-739943, L-1 63255, L-163540, L-163833, L-166446, EP-51389, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187, NNC-26-1291, L-692,429, L-252,564, S-37435, EX-1314, PF-5190457, AMX-213.

[0078] In one embodiment, ghrelin or a variant thereof can be administered at least once daily. In one embodiment, ghrelin or a variant thereof can be administered at least twice daily. In one embodiment, ghrelin or a variant thereof can be administered at least three times daily. In one embodiment, ghrelin or a variant thereof can be administered at least four times daily. In one embodiment, ghrelin or a variant thereof can be administered at least five times daily. In one embodiment, ghrelin or a variant thereof can be administered once daily. In one embodiment, ghrelin or a variant thereof can be administered twice daily. In one embodiment, ghrelin or a variant thereof can be administered three times daily. In one embodiment, ghrelin or a variant thereof can be administered four times daily. In one embodiment, ghrelin or a variant thereof can be administered five times daily.

[0079] Currently, patients with acute mTBI are discharged home once clinicians determine that the mTBI poses no immediate risk. In contrast, patients with persistent mTBI, whose symptoms do not resolve days, weeks, or months after the initial injury, are treated based on the symptoms they present with. In one embodiment, treatments for persistent mTBI, e.g., treatments that occur significantly after the acute injury and when the underlying adverse events in the brain continue unabated, are provided. These methods may be based on a dosing schedule requiring daily administration of ghrelin for one or several days to alleviate the debilitating symptoms of mTBI and address its adverse effects on the brain.

[0080] In one embodiment, patients with persistent mTBI are selected for treatment. In one embodiment, patients are selected who have one or more symptoms of mTBI (e.g., debilitating symptoms) at least 3 days after injury. In one embodiment, patients are selected who have one or more symptoms of mTBI (e.g., debilitating symptoms) at least 4 days after injury. In one embodiment, patients are selected who have one or more symptoms of mTBI (e.g., debilitating symptoms) at least 5 days after injury. In one embodiment, patients are selected who have one or more symptoms of mTBI (e.g., debilitating symptoms) at least 6 days after injury. In one embodiment, patients are selected who have one or more symptoms of mTBI (e.g., debilitating symptoms) at least 7 days after injury. In one embodiment, patients are selected who have one or more symptoms of mTBI (e.g., debilitating symptoms) at least 10 days after injury. In one embodiment, patients are selected who have one or more symptoms of mTBI (e.g., debilitating symptoms) at least 14 days after injury. In one embodiment, patients are selected who have one or more symptoms of mTBI (e.g., debilitating symptoms) at least 3-29 days after injury.

[0081] In some embodiments, patients with acute mTBI are selected. In some embodiments, patients not suffering from acute mTBI (e.g., at least 3 days, at least 7 days, up to 29 days after injury) are selected. In some embodiments, patients with PCS are selected. In some embodiments, patients not diagnosed with PCS are selected.

[0082] In one embodiment, ghrelin levels are varied at least twice during the treatment period. Examples of ghrelin level variations are shown in Table 1. [Table 1]

[0083] In one embodiment, mTBI is diagnosed using one or more diagnostic devices or protocols. In one embodiment, the methods provided herein are used in combination with one or more recovery protocols. For example, potential brain injury can be diagnosed and / or monitored using the BTrackS™ System (balancetrackingsystems.com / ; Balance Tracking Systems Inc.), utilizing the NFL Concussion Tool, "sports concussion assessment tool" ("SCAT-2;" static.nfl.com / static / content / public / photo / 2014 / 02 / 20 / 0ap2000000327062.pdf, incorporated herein by reference in its entirety), or other similar tools used by the NHL, NBA, FIFA, rugby league and union, boxing organizations, etc. Examples include SCAT-3, ImPACT, ICD-10, nPITEST, Acute Concussion Assessment ("ACE"), King-Devick, etc. Other diagnostic or assessment methods may utilize serum biomarkers (glial fibrillary acidic protein (GFAP), see, e.g., Mannix et al., "Serum Biomarkers Predict Acute Symptom Burden in Children after Concussion: A Preliminary Study," J Neurotrauma 31:1072-1075 (Jun. 1, 2014), which is incorporated herein by reference in its entirety), radiological imaging, self-reporting, accelerometers (e.g., in helmets), and the like.

[0084] In one embodiment, a subject administered ghrelin or a variant thereof described herein may exhibit improvement in one or more assessment tools when assessed before, during, and / or after administration. As will be appreciated by those of skill in the art, any suitable tool may be used. In one embodiment, the subject exhibits improvement in the number and / or severity of subacute concussion symptoms. In one embodiment, the subject exhibits improvement in the Post-Concussion Symptom Score Questionnaire (PCSS) (available at hawaiiconcussion.com / downloads / Post-Concussion-Symptom-Scale.pdf, incorporated herein by reference in its entirety). The PCSS can be used as an overall measure of symptom burden. Symptom number and severity may be important indicators at any time point before, during, or after treatment.

[0085] In one embodiment, the subject exhibits an improvement in quality of life. In one embodiment, the subject demonstrates an improvement in quality of life after brain injury (QOLIBRI) (available at Qolibri.Quality of Life Assessment for TBI.qolibrinet.com, which is incorporated herein by reference in its entirety). QOLIBRI is a 37-item tool specifically developed to assess an individual's health-related quality of life (HRQoL) after traumatic brain injury.

[0086] In one embodiment, subjects demonstrate improvement on the Patient Global Assessment of Symptoms (PGAS), a tool that utilizes a visual analog scale (VAS) to briefly assess a patient's overall assessment of their symptoms through the question, "How would you rate the impact of your symptoms on your mood and functioning today?"

[0087] In one embodiment, the subject shows improvement in cognitive function. In one embodiment, the subject shows improvement on BrainCheck. See Yang, S., et al., Diagnostic accuracy of tablet-based software for the detection of concussion. PLoS One, 2017. 12(7):p.e0179352, incorporated herein by reference in its entirety. In one embodiment, the subject shows improvement on one or more tests measured by BrainCheck. BrainCheck is a validated digital assessment tool to aid in the diagnosis of mild cognitive impairment. The tool administers a battery of seven tests to measure cognitive ability, response time, and balance. BrainCheck is a Class II medical device under the FDA. BrainCheck assessments include the Coordination Balance Test, which measures static and dynamic balance using the Ebbinghaus illusion; the Digit Symbol Substitution Test, which measures general cognitive ability; the Flanker Test, which measures visual attention; the Stroop Effect, which measures response time; Trails A&B, which measures visual attention and task switching; and the Recall Test, which measures immediate and delayed memory. All scoring algorithms compare test results to a normative age-matched dataset.

[0088] In one embodiment, the subject shows at least about a 10% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 15% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 20% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 25% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 30% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 35% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 40% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 45% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 50% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 60% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 70% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about an 80% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 90% improvement in any one or more of the assessments. In one embodiment, the subject shows at least about a 100% improvement in any one or more of the assessments. The percent improvement can be any value or subrange within the recited range, including the endpoint. The improvement can occur between any two time points, e.g., before, during, and / or after administration of ghrelin or a variant thereof. In several embodiments, the improvement is compared to baseline (e.g., assessment before administration of ghrelin or a variant thereof).

[0089] In one embodiment, the subject exhibits improvement within about 50 days after the first administration of ghrelin (e.g., within 50 days from the first day ghrelin is administered). In one embodiment, the subject exhibits improvement within about 44 days. In one embodiment, the subject exhibits improvement within about 40 days. In one embodiment, the subject exhibits improvement within about 30 days. In one embodiment, the subject exhibits improvement within about 21 days. In one embodiment, the subject exhibits improvement within about 20 days. In one embodiment, the subject exhibits improvement within about 15 days. In one embodiment, the subject exhibits improvement within about 14 days. In one embodiment, the subject exhibits improvement within about 13 days. In one embodiment, the subject exhibits improvement within about 12 days. In one embodiment, the subject exhibits improvement within about 11 days. In one embodiment, the subject exhibits improvement within about 10 days. In one embodiment, the subject exhibits improvement within about 9 days. In one embodiment, the subject exhibits improvement within about 8 days. In one embodiment, the subject exhibits improvement within about 7 days. In one embodiment, the subject exhibits improvement within about 6 days. In one embodiment, the subject exhibits improvement within about 5 days. In one embodiment, the subject exhibits improvement within about 4 days. In one embodiment, the subject exhibits improvement within about 4 to about 40 days. The time may be any value or subrange within the recited ranges, including the endpoints.

[0090] Pharmaceutical Composition Ghrelin or its variants are administered in therapeutically effective amounts. For example, administration of ghrelin or peptide ghrelin variants can be by any recognized administration method suitable for delivering peptides. The actual amount of ghrelin or its variants will depend on the severity of the disease being treated, the age and other relative health of the subject, the route and form of administration, and other factors well known to those skilled in the art.

[0091] An effective or therapeutically effective amount or dosage of ghrelin or a variant thereof refers to an amount that results in an improvement in the patient's debilitating symptoms. Specific dosages may vary within this range depending on the dosage form employed and / or the route of administration used. The exact formulation, route of administration, dosage, and administration interval should be selected in light of the specifics of the subject's condition, according to methods known in the art.

[0092] In one embodiment, the effective amount of ghrelin or a variant thereof is in the range of about 10 ng / kg to about 10 mg / kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof is in the range of about 1 μg / kg to about 10 mg / kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof is in the range of about 1 μg / kg to about 1 mg / kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof is in the range of about 10 μg / kg to about 1 mg / kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof is in the range of about 20 μg / kg to about 1 mg / kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof is in the range of about 30 μg / kg to about 1 mg / kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof is in the range of about 40 μg / kg to about 1 mg / kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof is in the range of about 50 μg / kg to about 1 mg / kg per day. In one embodiment, an effective amount of ghrelin or a variant thereof ranges from about 60 μg / kg to about 1 mg / kg per day. In one embodiment, an effective amount of ghrelin or a variant thereof ranges from about 70 μg / kg to about 1 mg / kg per day. In one embodiment, an effective amount of ghrelin or a variant thereof ranges from about 80 μg / kg to about 1 mg / kg per day. In one embodiment, an effective amount of ghrelin or a variant thereof ranges from about 90 μg / kg to about 1 mg / kg per day. In one embodiment, an effective amount of ghrelin or a variant thereof ranges from about 100 μg / kg to about 1 mg / kg per day. In one embodiment, an effective amount of ghrelin or a variant thereof ranges from about 10 μg / kg to about 0.1 mg / kg per day. The effective amount may be any value or subrange within the recited range, including the endpoint.

[0093] In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 72 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 74 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 76 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 78 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 80 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 82 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 84 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 86 μg / kg to about 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 88 μg / kg to about 90 μg / kg per day. The amount can be any value or subrange within the recited range, including the endpoints.

[0094] In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 88 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 86 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 84 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 82 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 80 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 78 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 76 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 74 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of about 70 μg / kg to about 72 μg / kg per day. The amount can be any value or subrange within the recited range, including the endpoints.

[0095] In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 72 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 74 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 76 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 78 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 80 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 82 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 84 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 86 μg / kg to 90 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 88 μg / kg to 90 μg / kg per day. The amount may be any value or subrange within the recited range, including the endpoints.

[0096] In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 88 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 86 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 84 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 82 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 80 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 78 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 76 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 74 μg / kg per day. In some embodiments, ghrelin or a variant thereof is administered in an amount of 70 μg / kg to 72 μg / kg per day. The amount may be any value or subrange within the recited range, including the endpoints.

[0097] The present invention is not limited to any particular composition or pharmaceutical carrier, as these may vary. Generally, ghrelin or a variant thereof is administered as a pharmaceutical composition by either oral, systemic (e.g., transdermal, intranasal, or suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. In some embodiments, administration is parenteral, using a dosing regimen that can be adjusted as described above. Other pharmaceutical compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable compositions.

[0098] Pharmaceutical dosage forms of the compounds of the present invention can be prepared by any method well known in the art, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, levigating, emulsifying, (nano- / micro-)encapsulating, entrapping, or lyophilizing processes. As noted above, the compositions of the present invention can contain one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into pharmaceutical preparations.

[0099] As described above, one pharmaceutical composition for use in the methods described herein is a sterile aqueous composition suitable for intravenous or intramuscular injection. In one embodiment, such a composition is pre-loaded into a syringe for use by a clinician or patient. In one embodiment, the syringe is loaded into a container and labeled, marked, or otherwise identified for use on a specific day. For example, in a 7-day treatment plan, the identification of each syringe indicates whether it is for day 1, day 2, etc.

[0100] Alternatively, the pharmaceutical composition can be in the form of a transdermal patch that continuously releases ghrelin or a variant thereof in such an amount that the total amount delivered on a given day is the effective amount defined above. Because ghrelin has a serum half-life of approximately 30 minutes, continuous release allows it to be present not only in the serum but also in the brain.

[0101] When ghrelin is administered via a transdermal patch, one or more patches can be used. In a preferred embodiment, multiple patches are used, each identified for use on a particular treatment day. Each patch can contain the same dose of ghrelin or its variant, or, as described above, the dose can be tapered.

[0102] If a single patch is used, the patch can be formulated to provide the same daily dose of ghrelin or its variants, or the patch can be formulated to provide a tapered dose of ghrelin or its variants over the course of treatment.

[0103] In some embodiments, ghrelin or a variant thereof is administered as a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a sterile aqueous solution suitable for injection. In some embodiments, the pharmaceutical composition is a transdermal patch.

[0104] Timing of administration In one embodiment, ghrelin is administered when the natural abundance of ghrelin in the body is low. In addition to the benefits described herein, ghrelin is known to stimulate appetite, and ghrelin concentrations in the body typically peak immediately before a meal. Following the ingestion of such a meal, ghrelin concentrations in the body decrease, typically reaching their lowest levels for the day within 1 to 2 hours. See, e.g., Adamska-Patruno, et al., "The Differences in Postprandial Serum Concentrations of Peptides that Regulate Satiety / Hunger and Metabolism after Various Meal Intake," in Men with Normal vs. Excessive BMI, Nutrients, 11(3):493 et ​​seq. (2019), the entire text of which is incorporated herein by reference. Therefore, according to the present invention, ghrelin is best administered at least about 1 hour after a meal, preferably about 1 to 2 hours after a meal. Without being limited to any theory, administration of ghrelin as described above offsets the natural decline in ghrelin levels that occurs after a meal, thereby maintaining elevated ghrelin levels and promoting therapeutic efficacy. In another embodiment, twice-daily administration of ghrelin or a variant thereof is timed as follows: [Table 2] [Example]

[0105] The following examples illustrate how the present invention can be used.

[0106] Example 1 - Protocol for a Phase 2 Study of Treatment of Persistent mTBI The drug product will be a sterile, lyophilized white powder or cake equivalent to 14 mg of OXE-103 (active ingredient) and sucrose (inactive ingredient) packaged in 5 mL clear borosilicate glass vials with butyl rubber stoppers (fluoropolymer film laminate). A matching placebo and diluent will be used.

[0107] OXE-103 drug product, placebo, and diluent are stored refrigerated at 2°C to 8°C (35.6°F to 46.4°F). 14 mg of OXE-103 (in a 5 mL multi-use vial) reconstituted for subcutaneous administration is stable for up to 14 days at 10°C or up to 3 days when stored at 25°C / 1000 Lux. Reconstituted drug product (and placebo) are stored refrigerated at 2°C to 8°C (35.6°F to 46.4°F).

[0108] We will conduct a pilot study evaluating ghrelin (OXE-103) to treat subacute concussion. The treatment group (OXE-103) will be compared to a placebo group in a randomized, double-blind fashion using self-reported symptom scores, quality-of-life questionnaires, computerized cognitive tests assessing executive function, memory, and processing speed, and accelerometer-based balance scoring. Due to the exploratory nature of this study, it will not yield statistically significant outcomes, but it will detect within- and between-subject trends, support comparisons with standardized tests of neurocognitive function, and provide a sample size estimate for future studies in people with persistent concussion-related symptoms.

[0109] This study is of great clinical importance as it is the first to test ghrelin as a treatment for subacute concussion.

[0110] Specific purposes:

[0111] This study describes the change in symptom burden in subacute concussion patients across two groups. A maximum of 50 subjects will be enrolled, with recruitment ending once each group has 20 participants who are diagnosed with persistent concussion symptoms ≤28 days post-injury and complete the study. Patients will be randomized 1:1 to placebo or OXE-103. The Post-Concussion Symptom Score Questionnaire (PCSS) will be used as an overall measure of symptom burden. Symptom count and severity at each time point will also be measures of interest. Additionally, subjects will be asked to identify and rank their four most bothersome symptoms. Without being bound by theory, it is hypothesized that changes in these most bothersome symptoms are highly correlated with improvements in quality of life. Changes between the two groups will be compared visually. A 20% change is considered clinically meaningful. The primary objective is to describe symptom change from days 1 to 14.

[0112] To describe the change in quality of life between the two groups. This objective defines one of the secondary objectives. To assess this, the Quality of Life After Brain Injury (QOLIBRI) and Patient Summary Assessment of Symptoms (PGAS) will be administered. A change of 20% is considered clinically meaningful. The primary aim of this objective is to assess the change from days 1 to 14.

[0113] Describe the correlation between change in symptom burden and quality of life. This is an exploratory objective. Without being bound by theory, it is hypothesized that improvement in symptom burden will correlate with improvement in quality of life indicators. This may be more evident in the correlation between change in the four most bothersome symptoms and quality of life indicators. This objective describes the correlation between days 1 and 14.

[0114] Changes in symptom burden and quality of life at various time points will be described. This is an exploratory objective. Data will be collected at days 21 and 45 to allow for comparison at later time points. This can be used to describe changes in these measures at time points after administration of OXE-103. It is hypothesized that the effects of OXE-103 are long-lasting and will not worsen after administration. Data will compare day 14 with days 21 and 45.

[0115] The goal is to describe changes in cognitive performance between the two groups. This objective defines a secondary aim: cognitive improvement may correlate with underlying improvements in neurological function. Cognitive function will be assessed at specified intervals using BrainCheck, a digital assessment tool. This tool is administered via iPad and can be administered in the clinic under the supervision of study personnel or by subjects at home.

[0116] Benefits / risks of research

[0117] Benefits: Currently, the initial treatment for concussion is rest. Later treatments (there is no consensus on when to begin, often ranging from weeks to months after injury) include physical therapy and vestibular therapy (which can be time-consuming and initially cause symptoms), and medications to treat symptoms. It is unclear whether these medications have a potential therapeutic effect on underlying neurometabolic changes or a purely symptomatic effect. Furthermore, each medication has the potential for adverse events. Providing a safe treatment that reduces symptoms, improves quality of life, and is effective in potentially treating the underlying neurometabolic dysfunction would be revolutionary and would change the current paradigm of concussion care.

[0118] Risks: Previous studies have shown that OXE-103 is very safe. This study helps confirm its safety profile in this clinical population. Long-term use of ghrelin can lead to increased appetite, weight gain, and obesity.

[16] However, short-term use of OXE-103 mitigates this risk, and patients will be weighed weekly during drug treatment.

[0119] Inclusion / Exclusion:

[0120] Subjects were men and women aged 18-55 years with a concussion caused by a direct or indirect blow, rotational, or whiplash injury to the head or body. Subjects were enrolled within 28 days of injury. Subjects were screened for 7 days to ensure symptom stability before treatment. To mitigate the expected degree of spontaneous symptom resolution (number and severity) before study completion, subjects were required to have a symptom severity score of ≥ 20 at randomization (end of screening). During screening, subjects were excluded if 1) two consecutive screening assessments showed improvement in symptom severity or number of symptoms, or 2) symptom severity or number decreased by ≥ 20%.

[0121] Subjects with pre-existing neurological conditions (including cognitive impairment) other than mTBI will be excluded. Subjects who have been treated with donepezil (Aricept) and / or memantine (Namenda) after TBI will be excluded.

[0122] Subjects receiving other concomitant medications, physical therapy, or other treatments related to their current TBI will be eligible if they: 1) meet the inclusion criteria related to lack of improvement during the screening period and 2) such treatment was initiated at least 7 days prior to enrollment and screening. Subjects unable to self-inject will be excluded. Ultimately, subject participation will be at the discretion of the study investigator.

[0123] Test procedure:

[0124] General study design:

[0125] Described here is a randomized, double-blind, placebo-controlled study design in which 40 subjects will be randomly assigned to either the placebo cohort or the OXE-103 treatment cohort. Randomization will be performed using the RedCap database, which is configured to share randomization assignments exclusively with the study pharmacy. All subjects will consent and begin a screening period within 28 days after injury. A 7-day screening period will be conducted prior to randomization and the start of study treatment to assess the stability of symptom burden. This screening period must begin within 28 days after injury. Starting on Day 1 (the end of the screening period), the treatment cohort will self-administer 40 μg / kg of OXE-103 subcutaneously twice daily, while the placebo group will receive placebo injections subcutaneously twice daily. Study drug and placebo will be administered and dispensed by the study pharmacy. Subjects will receive an 8-day supply of pre-filled syringes with either OXE-103 or placebo. Each cohort will receive a second set of syringes containing either OXE-103 or placebo at their Day 7 visit. Neither cohort will receive any other treatments other than OXE-103 during the 14-day treatment period. After completing 14 days of treatment with either placebo or OXE-103, either cohort can begin other medications or treatments, if needed, starting at their Day 14 visit.

[0126] Subject training

[0127] Subjects will be provided with instructions for self-administration of OXE-103 and placebo subcutaneously. Subjects will be trained to inject themselves and must demonstrate competence by self-administering the first dose of study drug at the study site. Alternatively, if the subject is accompanied by a trusted and supportive family member, that person must be trained to administer study drug to the subject and must demonstrate competence at the study site. If self-administration or family administration is not possible, the subject will be deemed ineligible for participation. Subjects will be instructed to store the drug / placebo according to parameters. A study team member will record the storage location for each enrolled subject. Subjects will be asked to inject the first dose of the day in the morning after a meal. The second dose will be administered in the evening after a meal.

[0128] Recruitment:

[0129] Patients who meet the study's inclusion / exclusion criteria will be identified and invited to participate in the study. If interested, a member of the research team will meet with the patient to discuss the study in further detail. Informed consent will be sought and, if obtained, subjects will be screened for study risks and other exclusion criteria.

[0130] Dropouts: This is a pilot study, and there are no historical data on which to base an estimate of dropouts for this study. Study participants who withdraw consent during the 28-day study period, are dropped from the study, or fail to complete the required 14-day protocol may be replaced until there are 40 subjects completing the protocol.

[0131] Target duration: The target duration of OXE-103 treatment is 2 weeks. The total duration of study participation, including screening and follow-up assessments, is 8 weeks.

[0132] Outcomes and Research Tools:

[0133] Symptom Reduction (Objective 1): The primary goal is to describe the change in the number and / or severity of subacute concussion symptoms following OXE-103 treatment using the PCSS at days 1 and 15. Data will also be collected at days 21 and 44 to describe long-term changes and potential lasting effects (Objective 4).

[0134] Subjects complete the PCSS upon signing the consent form (score must be ≥20) (Day -7), midway through the screening period (Day -3), before treatment cohort assignment (score must be ≥20) (Day 1), and on Days 4, 8, 11, 15, 21, and 44

[17] . Subjects are instructed to record their symptoms at the same time at each assessment time point. In each case, there may be a 2-hour window (e.g., 12:00 PM + / - 2 hours). The PCSS is recorded via RedCap survey. The PCSS is a self-reported assessment of 22 symptoms using a Likert-type scale ranging from 0 to 6, with 0 indicating no difficulty with the outlined symptoms and a rating of 1 to 6 representing mild to severe difficulty with the symptoms. The reliability and validity of the PCSS have been well documented [18-20]. Subjects are also asked to rank their four most bothersome symptoms (4MBS) on Day 1, which are analyzed separately. As stated in the specific objectives, the purpose of this study is to further refine clinical endpoints that can be used in larger Phase 2 studies and to collect data that may lead to the establishment of key endpoints for Phase 3 registration trials. The PCSS assessment of 22 symptoms is designed to cover the full range of concussion-related symptoms across cognitive, emotional, and physical domains. In that respect, the PCSS is particularly useful for diagnosing patients and monitoring their recovery after injury. However, due to the number of symptoms across cognitive, emotional, and physical domains, the resolution of some mild symptoms may result in changes in overall symptom scores, despite relatively little clinical impact on the patient's health status. Pre-IND feedback already obtained from the FDA indicates that effective treatment for concussion must affect the patient's mood and function. Including specific analysis of the patient-perceived 4MBS may increase the likelihood of correlating symptom scores with improvements in the quality of life tools used in this study. Completing the PCSS is estimated to take approximately 5 minutes.

[0135] Quality of Life (Aim 2): The secondary objective is to examine changes in quality of life with treatment of subacute concussion. Without being bound by theory, it is hypothesized that OXE-103 will reduce symptoms when comparing days 1 and 15, thereby improving quality of life as assessed by 1) the Quality of Life After Brain Injury Scale (QOLIBRI) and 2) the PGAS.

[0136] The QOLIBRI is a 37-item tool specifically developed to assess individuals' health-related quality of life (HRQoL) after traumatic brain injury

[21] . It is incorporated into an online RedCap survey. Because it was developed as a disease- or condition-specific HRQoL measurement tool for TBI, it is expected to be more sensitive than general quality-of-life tools. The QOLIBRI was developed by an international task force in two multilingual studies involving more than 2,000 people after TBI. Using a TBI-specific HRQoL assessment can detect the effects of interventions by measuring physical, psychological, daily living, and psychosocial changes typical of TBI. A 20% increase / decrease in the QOLIBRI is considered to represent an improvement.

[0137] Additionally, this study will utilize the PGAS. This tool utilizes a visual analog scale (VAS) to briefly assess patients' overall symptom assessment through the question, "How would you rate the impact your symptoms have on your mood and functioning today?" Patients are instructed to use a slider tool within RedCap to rate the impact of their symptoms from 0 to 10 (0 being no impact and 10 being the worst impact). A 20% increase / decrease in the PGAS is considered to indicate improvement.

[0138] QOL measurements will be taken on days 1, 4, 8, 11, 15, 21, and 44. They are estimated to take approximately 15 minutes to complete.

[0139] Cognitive testing (Aim 5): The secondary outcome measure will be to summarize the change in cognitive function in the two groups. Without being bound by theory, it is speculated that the mechanism of action of OXE-103 may improve cognitive function.

[0140] Subjects complete computerized neurocognitive testing on an iPad using BrainCheck

[22] , a validated digital assessment tool to aid in the diagnosis of mild cognitive decline. This tool administers a battery of seven tests to measure cognitive ability, response time, and balance. BrainCheck is a Class II medical device under the FDA. BrainCheck assessments include the Coordination Balance Test, which measures static and dynamic balance using the Ebbinghaus illusion; the Digit-Symbol Substitution Test, which measures general cognitive ability; the Flanker Test, which measures visual attention; the Stroop Effect, which measures response time; Trails A&B, which measures visual attention and task switching; and the Recall Test, which measures immediate and delayed memory. All scoring algorithms compare test results to a normative age-matched dataset. All tests are simple video games that require no special skills and are not expected to induce stress. The total time required to complete the battery of tests is estimated to be 15 minutes. BrainCheck is administered in the clinic on days 1, 7, 14, and 45, and by subjects at home on days 3, 10, and 21. The iPad will be given to the subject as compensation for their time upon completion of all study procedures. If the subject withdraws from the study, they will be asked to return the iPad to the research team.

[0141] Electronic PHI data is stored on HIPAA-compliant servers. All computers are password protected. Access to the servers is restricted to the research team and IT personnel. Access to study-specific data and communications related to the study is limited to the PI and PI's staff, study personnel, responsible parties at the study sponsor, and appropriate regulatory agencies. Study data is added to the subject's medical record.

[0142] Amazon Works (AWS) has an established information security organization managed by the AWS Security Team and led by the AWS Chief Information Security Officer (CISO).

[0143] AWS meets the American Institute of Certified Public Accountants (AICPA) TSP Section 100, Trusted Services Principles, and standards for security, availability, processing, integrity, confidentiality, and privacy.

[0144] BrainCheck uses AWS HIPAA-compliant services and has been third-party verified to certify that: AWS complies with ISO 27017 implementation guidance for cloud-specific information security controls, which complements ISO 27002 guidance and ISO 27001 compliance. AWS adheres to ISO 27001, the internationally recognized standard for best practices in security management, and comprehensive security controls that follow ISO 27002 best practice guidance. AWS complies with the implementation guidance for ISO 27018 controls applicable to the protection of personally identifiable information (PII) in the public cloud, which supplements the ISO 27002 guidance and ISO 27001 compliance.

[0145] The information sent by the app is limited to subject code, survey responses, and timestamps of survey responses. No location data is sent. Vendors are not allowed to re-identify subjects.

[0146] Statistical analysis:

[0147] This pilot study describes changes observed in the two groups receiving OXE-103 versus placebo. Because this study is exploratory, analyses focused on descriptive comparative statistics rather than a pre-specified statistically significant primary endpoint. Data will be used to enable power calculations and the definition of appropriate clinical endpoints for further clinical development. Data will be analyzed from baseline and study days 1, 4, 8, 11, 15, 21, and 44.

[0148] The primary objective was to determine the proportion of subjects (responders) who experienced a clinically meaningful benefit, defined as a 20% reduction in both the number and severity of concussion-related symptoms. Concussion-related symptoms were measured using the 22-symptom PCSS. The severity of each of the 22 symptoms was rated by the patient on a 7-point Likert scale. This scale is widely used in the evaluation of patients with concussion / mTBI [18,19].

[0149] Additionally, to control for the impact of clinically minor changes in symptoms on the overall number and severity of PCSS, data are analyzed based on the change in each subject's 4MBS. This type of analysis has been used to evaluate patient-reported outcome measures for migraine and is described in FDA guidance documents (Dodick et al. 2018, Migraine 2018 FDA).

[0150] The FDA's pre-IND guidance for the clinical development of OXE-103 advises that "outcome measures should be constructed so that changes in scores indicate meaningful improvements in patient mood and function due to treatment effects specific to mild TBI." Two quality assessment tools, QOLIBRI and PGAS, will be used to correlate changes in symptom count / severity to impact on quality of life. Improvements in these measures will be compared with the responder definition to assess meaningful clinical improvement in response to treatment with OXE-103.

[0151] Furthermore, patient-reported outcomes of the PCSS scales have been correlated with objective digital measures of cognition and balance / stability using BrainCheck, a Class II FDA-approved device.

[0152] Medical history and test results are stored in REDCap.

[0153] Plans for ensuring subject privacy and confidentiality

[0154] Signed consent forms and data forms are stored in a designated file cabinet with limited access owned by a member of the research team. Outcome data are entered into the aforementioned REDCap database, with access restricted to authorized staff only. All analyzed data is anonymized before submission to sponsors, scientific journals, etc., in accordance with HIPAA guidelines. Each participant is assigned a unique study number to enable information tracking over time. Once a study number is assigned, personally identifiable information is removed from the initial data and from subsequent data when new data is matched to an existing study number. Participant identities and their associated study numbers are stored in the Velos system and are accessible only to authorized research team members.

[0155] Follow-up

[0156] Patients will continue standard of care after completing or withdrawing from the study. The study design is shown in Table 2. [Table 3-1] [Table 3-2]

[0157] Example 2 - Interim Status Report of a Phase 2 Study - Treatment of Persistent Symptoms of Concussion A phase 2 study of ghrelin (OXE-103) for the treatment of persistently symptomatic concussion patients was conducted at the University of Kansas Medical Center, generally as described in Example 1. Interim results are reported here (Figure 1).

[0158] Intermediate Research Group

[0159] A study was conducted to treat patients with subacute concussion using a pharmaceutical formulation of ghrelin (OXE-103). Completed results from a treatment group of 10 patients were compared with a placebo group of three patients receiving standard of care (SoC). Additionally, at the time of the interim report, two other patients were currently receiving treatment in the study's treatment arm. The study was randomized, double-blind, and compared self-reported symptom scores, quality-of-life questionnaires, computerized cognitive tests assessing executive function, memory, and processing speed, and accelerometer-based balance scoring.

[0160] This study was the first to test ghrelin as a treatment for subacute concussion.

[0161] Demographic and Baseline Data: The demographic and baseline data of the subjects are shown in Table 3. [Table 4]

[0162] Subjects who completed the study were diagnosed with persistent concussion symptoms ≤28 days post-injury. The treatment group was split 3:7 (male:female), with a mean age of 46 years and 21 days post-injury. 50% of the group had no history of concussion, 30% had a history of 2-4 previous concussions, and 20% had a history of 5 or more previous concussions. The standard care group was all female, with a mean age of 38 years and 23 days post-injury. 67% of this group had no prior concussion, and 33% had a history of 2-4 previous concussions.

[0163] Dropouts: The interim study initially enrolled 15 subjects in the treatment group and 4 in the no-treatment or standard-care groups. One subject was randomized before the study became open-label. Two subjects (#007 and #009) withdrew before completing the study.

[0164] Interim analysis: Primary efficacy endpoint

[0165] Interim study efficacy endpoints were PCSS (22-symptom concussion scoring scale), QOLIBRI (WHO TBI-specific quality of life after brain injury), and BRAIN CHECK (digital assessment of cognition, balance, and visual changes (510K FDA approved)).

[0166] Clinician feedback indicated that a 20% reduction in concussion symptoms was considered a clinically meaningful improvement. The 20% change from baseline is indicated by a black line on the graphs for QOLIBRI (Figure 3A), PCSS-Total Severity Score (Figure 4A), PGAS (Figure 5A), 4MBS (Figure 6A), and PCSS Symptom Count (Figure 7A). The graphs in Figures 3A, 4A, 5A, 6A, and 7A show the mean scores for each endpoint at days 1, 4, 8, 11, 15, 21, and 44 for both the treatment and control groups (SoC). For PCSS, Symptom Count, PGAS, and 4MBS, patients were considered to have responded to treatment if the percent change compared to baseline was -20% or less. For QOLIBRI, patients were considered to have responded to treatment if the percent change compared to baseline was 20% or greater.

[0167] BRAIN CHECK scores are plotted only if there is a significant abnormality at baseline (Figures 8A and 8B). A BRAIN CHECK score of 0 indicates no cognitive impairment, a range of -1 to 0 indicates possible cognitive impairment, and a score below -1 indicates significant cognitive impairment.

[0168] At the midpoint of the study, improvements of greater than 20% were observed within 8 to 10 days of starting treatment. OXE103 demonstrated an 80% response rate (RR) for both endpoints by 40 days after starting treatment.

[0169] Endpoint Conclusions

[0170] Strong treatment effects were observed across the full range of study endpoints. Treatment effects were sustained for at least 44 days. A rapid onset of treatment effect (8-10 days) was observed in this persistently affected population. The efficacy of OXE-103 treatment in reducing symptoms and improving quality of life assessments was consistent across all endpoints, with improvements observed in objective measures of quality of life, individual symptoms, and cognition, consistent with FDA guidance.

[0171] The reduction in concussion symptoms in OXE-103-treated subjects is shown in Table 4. [Table 5]

[0172] Response rates for subjects who received ghrelin treatment (treated) or did not receive treatment (untreated) are shown in Tables 5 through 8, based on an improvement of at least 20% or 30% on the indicated assessment. [Table 6] [Table 7] [Table 8] [Table 9]

[0173] P embodiment Embodiment P1. A method of alleviating one or more symptoms of mild traumatic brain injury (mTBI) in a patient diagnosed with persistent mTBI, said method comprising administering to said patient an effective amount of ghrelin or a variant thereof for multiple consecutive days after diagnosis, wherein said one or more symptoms are improved by at least 20% compared to baseline within about 40 days after initiation of administration of said ghrelin or variant thereof.

[0174] Embodiment P2. The method of embodiment P1 wherein said one or more symptoms are improved by at least 20% compared to baseline within about 30 days after initiation of administration of said ghrelin or variant thereof.

[0175] Embodiment P3. The method of embodiment P1 wherein said one or more symptoms are improved by at least 20% compared to baseline within about 20 days after initiation of administration of said ghrelin or variant thereof.

[0176] Embodiment P4. The method of embodiment P1 wherein said one or more symptoms are improved by at least 20% compared to baseline within about 10 days after initiation of administration of said ghrelin or variant thereof.

[0177] Embodiment P5. The method of any one of Embodiments P1-P4, wherein said one or more symptoms are improved by at least 25% compared to baseline within about 40 days after initiation of administration of said ghrelin or variant thereof.

[0178] Embodiment P6. The method of any one of embodiments P1-P5, wherein said improvement is measured by QOLIBRI, PCSS, PGAS, and / or Brain Check.

[0179] Embodiment P7. The method of any one of Embodiments P1-P6, wherein the administration of ghrelin is continued until the patient's condition becomes asymptomatic.

[0180] Embodiment P8. The method of any one of Embodiments P1 to P7, wherein the ghrelin or variant thereof is administered as a pharmaceutical composition.

[0181] Embodiment P9. The method of any one of Embodiments P1-P8, wherein the pharmaceutical composition is a sterile aqueous solution suitable for injection.

[0182] Embodiment P10. The method of any one of Embodiments P1 to P8, wherein the pharmaceutical composition is a transdermal patch.

[0183] Embodiment P11. The method of any one of Embodiments P1 to P10, wherein administration of said ghrelin or variant thereof is continued for at least 3 days.

[0184] Embodiment P12. The method of any one of Embodiments P1 to P10, wherein administration of said ghrelin or variant thereof is continued for at least 5 days.

[0185] Embodiment P13. The method of any one of Embodiments P1 to P10, wherein administration of said ghrelin or variant thereof is continued for at least 40 days.

[0186] Embodiment P14. The method of any one of Embodiments P1 to P13, wherein only a single administration of said ghrelin or variant thereof is administered per day.

[0187] Embodiment P15. The method of any one of Embodiments P1 to P13, wherein more than one administration of said ghrelin or variant thereof is administered per day.

[0188] Embodiment P16. The method of any one of Embodiments P1 to P15, wherein said ghrelin or variant thereof is administered by subcutaneous injection.

[0189] Embodiment P17. The method of any one of Embodiments P1 to P16, wherein administration of said ghrelin is continued until said patient is able to resume normal activity.

[0190] Embodiment P18. The method of any one of embodiments P1-P17, wherein said one or more symptoms include headache, loss of clarity or confusion, difficulty focusing, double vision, blurred vision, sleep disturbances, emotional / behavioral changes, emotional outbursts, and / or memory loss.

[0191] Embodiment P19. The method of any one of embodiments P1 to P18, wherein said one or more symptoms comprise said patient's four most bothersome symptoms (MBS).

[0192] Embodiment P20. The method of any one of Embodiments P1 to P19, wherein said ghrelin or variant thereof is administered at a dose of about 80 μg / kg per day.

[0193] Embodiment P21. A method of alleviating one or more symptoms of mild traumatic brain injury (mTBI), comprising: a. selecting a patient who has mTBI due to injury and who has said one or more symptoms of mTBI at least 7 days after said injury; b. administering ghrelin or a variant thereof to the patient for a period of time, wherein the ghrelin or variant thereof is administered at a dose of about 80 μg / kg per day; The method, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 40 days after initiation of administration of the ghrelin or variant thereof.

[0194] Embodiment P22. The method of embodiment P21, wherein said ghrelin or variant thereof is administered at about 40 μg / kg twice daily.

[0195] Embodiment P23. The method of embodiment P21 or P22, wherein said period of time is up to about 14 days.

[0196] Embodiment P24. The method of embodiment P23, wherein the period of time is about 14 days.

[0197] Embodiment P25. The method of any one of embodiments P21-P24, wherein said patient is periodically evaluated for said one or more symptoms of mTBI.

[0198] Embodiment P26. The method of any one of embodiments P21 to P25, wherein said patient is assessed for said one or more symptoms of mTBI prior to administration of said ghrelin or variant thereof.

[0199] Embodiment P27. The method of any of embodiments P21-P26, wherein the patient is evaluated for said one or more symptoms of mTBI during administration of said ghrelin or variant thereof.

[0200] Embodiment P28. The method of any one of Embodiments P21 to P27, wherein the patient is assessed for said one or more symptoms of mTBI at about 3, 7, 10, 14, 20, and / or 43 days after initiation of administration of said ghrelin or variant thereof.

[0201] Embodiment P29. The method of any one of embodiments P21 to P28, wherein said patient is assessed using one or more of the PCSS, QOLIBRI, PGAS, and / or BrainCheck.

[0202] Embodiment P30. The method of embodiments P21-P29, wherein said one or more symptoms are improved by at least 20% compared to baseline within about 10 days after initiation of administration of said ghrelin or variant thereof.

[0203] Embodiment P31. The method of any one of embodiments P1 to P30, wherein said one or more symptoms are improved by at least 30%. Embodiment

[0204] Embodiment 1. A method of alleviating one or more symptoms of mild traumatic brain injury (mTBI) in a patient diagnosed with persistent mTBI, said method comprising administering to said patient an effective amount of ghrelin or a variant thereof for multiple consecutive days after diagnosis, wherein said one or more symptoms improve by at least 20% compared to baseline within about 40 days after initiation of administration of said ghrelin or variant thereof.

[0205] Embodiment 2. The method of embodiment 1, wherein said one or more symptoms are improved by at least 20% compared to baseline within about 30 days after initiation of administration of said ghrelin or variant thereof.

[0206] Embodiment 3 The method of embodiment 1, wherein said one or more symptoms are improved by at least 20% compared to baseline within about 20 days after initiation of administration of said ghrelin or variant thereof.

[0207] Embodiment 4 The method of embodiment 1, wherein said one or more symptoms are improved by at least 20% compared to baseline within about 10 days after initiation of administration of said ghrelin or variant thereof.

[0208] Embodiment 5. The method of any one of embodiments 1-4, wherein the one or more symptoms are improved by at least 25% compared to baseline within about 40 days after initiation of administration of the ghrelin or variant thereof.

[0209] Embodiment 6. The method of any one of embodiments 1 to 5, wherein said improvement is measured by QOLIBRI, PCSS, PGAS, and / or Brain Check.

[0210] Embodiment 7 The method of any one of embodiments 1-6, wherein the administration of ghrelin is continued until the patient's condition becomes asymptomatic.

[0211] Embodiment 8 The method of any one of Embodiments 1 to 7, wherein the ghrelin or variant thereof is administered as a pharmaceutical composition.

[0212] Embodiment 9. The method of any one of embodiments 1 to 8, wherein the pharmaceutical composition is a sterile aqueous solution suitable for injection.

[0213] Embodiment 10. The method of any one of Embodiments 1 to 8, wherein the pharmaceutical composition is a transdermal patch.

[0214] Embodiment 11 The method of any one of embodiments 1 to 10, wherein administration of said ghrelin or variant thereof continues for at least 3 days.

[0215] Embodiment 12 The method of any one of embodiments 1 to 10, wherein the administration of ghrelin or a variant thereof continues for at least 5 days.

[0216] Embodiment 13 The method of any one of embodiments 1 to 10, wherein administration of said ghrelin or variant thereof continues for at least 40 days.

[0217] Embodiment 14. The method of any one of embodiments 1 to 13, wherein only a single administration of said ghrelin or variant thereof is administered per day.

[0218] Embodiment 15. The method of any one of embodiments 1 to 13, wherein two or more doses of said ghrelin or variant thereof are administered per day.

[0219] Embodiment 16 The method of any one of embodiments 1 to 15, wherein the ghrelin or variant thereof is administered by subcutaneous injection.

[0220] Embodiment 17 The method of any one of embodiments 1 to 16, wherein administration of the ghrelin is continued until the patient is able to resume normal activity.

[0221] Embodiment 18. The method of any one of embodiments 1-17, wherein the one or more symptoms include headache, loss of clarity or confusion, difficulty focusing, double vision, blurred vision, sleep disturbances, emotional / behavioral changes, emotional outbursts, and / or memory loss.

[0222] Embodiment 19. The method of any one of embodiments 1-18, wherein said one or more symptoms comprise said patient's four most bothersome symptoms (MBS).

[0223] Embodiment 20 The method of any one of embodiments 1 to 19, wherein the ghrelin or variant thereof is administered at a dose of about 80 μg / kg per day.

[0224] Embodiment 21. A method for alleviating one or more symptoms of mild traumatic brain injury (mTBI), the method comprising: a. selecting a patient having mTBI due to injury, wherein the patient has one or more symptoms of mTBI at least 7 days after the injury; and b. administering to the patient ghrelin or a variant thereof for a period of time, wherein the ghrelin or variant thereof is administered at a dose of about 80 μg / kg per day, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 40 days after initiation of administration of the ghrelin or variant thereof.

[0225] Embodiment 22 The method of embodiment 21, wherein the ghrelin or variant thereof is administered at about 40 μg / kg twice daily.

[0226] Embodiment 23. The method of embodiment 21 or 22, wherein the period of time is up to about 14 days.

[0227] Embodiment 24. The method of embodiment 23, wherein the period of time is about 14 days.

[0228] Embodiment 25. The method of any one of embodiments 21-24, wherein the patient is periodically evaluated for said one or more symptoms of mTBI.

[0229] Embodiment 26 The method of any one of embodiments 21 to 25, wherein the patient is evaluated for said one or more symptoms of mTBI prior to administration of said ghrelin or variant thereof.

[0230] Embodiment 27 The method of any one of embodiments 21-26, wherein the patient is assessed for said one or more symptoms of mTBI during administration of said ghrelin or variant thereof.

[0231] Embodiment 28. The method of any one of embodiments 21-27, wherein the patient is evaluated for said one or more symptoms of mTBI about 3 days, 7 days, 10 days, 14 days, 20 days, and / or 43 days after initiation of administration of the ghrelin or variant thereof.

[0232] Embodiment 29. The method of any one of embodiments 21 to 28, wherein the patient is assessed using one or more of the PCSS, QOLIBRI, PGAS, and / or BrainCheck.

[0233] Embodiment 30. The method of any one of embodiments 21 to 29, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 10 days after initiating administration of the ghrelin or variant thereof.

[0234] Embodiment 31. A method of treating a concussive event in a human subject by eliminating or reducing the severity of multiple symptoms associated with the concussive event, the method comprising administering to the subject ghrelin or a variant thereof daily for a first period beginning at least 3 days after the concussive event, wherein the severity of the multiple symptoms in the subject is reduced within 45 days after the end of administration of the ghrelin or variant thereof.

[0235] Embodiment 32 The method of embodiment 31, further comprising administering to the subject daily ghrelin or a variant thereof for a second period of time beginning after the first period of time, wherein the severity of the plurality of symptoms in the subject is further reduced.

[0236] Embodiment 33. The method of embodiment 31 or 32, wherein said plurality of symptoms comprises at least three concussion symptoms.

[0237] Embodiment 34. The method of any one of embodiments 31-33, wherein the plurality of symptoms comprises at least five concussion symptoms.

[0238] Embodiment 35. The method of embodiments 31-34, wherein the plurality of symptoms comprises at least 10 concussion symptoms.

[0239] Embodiment 36. The method of any one of embodiments 31-35, wherein the severity of each of said symptoms is reduced by at least 20%.

[0240] Embodiment 37. The method of any one of embodiments 31-36, wherein the plurality of symptoms are selected from neck pain, double vision, blurred vision, visual disturbances, memory loss or difficulty remembering, difficulty understanding or concentrating, difficulty focusing or paying attention, loss of clarity or confusion, feeling like you're in a fog, temporary loss of consciousness, feeling slowed down, numbness or tingling, emotional outbursts, tension or anxiety, sad or depressed mood, irritability, tinnitus, sensitivity to light, sensitivity to noise, drowsiness, sleeping more than usual, sleeping less than usual, difficulty falling asleep, trouble sleeping, fatigue, dizziness or unsteadiness, problems with balance, vomiting, nausea, and / or headache.

[0241] Embodiment 38. The method of any one of embodiments 31 to 37, wherein the first period begins within about 28 days after the concussive event.

[0242] Embodiment 39. The method of any one of embodiments 31 to 38, wherein the first period of time is at least 10 days.

[0243] Embodiment 40. The method of any one of embodiments 31 to 39, wherein the first period of time is at least 14 days.

[0244] Embodiment 41. The method of any one of embodiments 31 to 40, wherein the first period of time is 20 days or less.

[0245] Embodiment 42. The method of any one of embodiments 31-41, wherein the reduction in said plurality of symptoms is measured by QOLIBRI, PCSS, PGAS, or Brain Check.

[0246] Embodiment 43. A method of accelerating recovery from a concussive event in a human subject by eliminating or reducing the severity of multiple symptoms associated with the concussive event, the method comprising administering daily to a patient ghrelin or a variant thereof beginning at least 3 to 30 days after the concussive event, and continuing the daily administration for at least 10 days, wherein multiple symptoms associated with the concussive event in the subject are reduced.

[0247] Embodiment 44. The method of embodiment 43, wherein the plurality of symptoms associated with the concussive event comprises at least three concussive symptoms.

[0248] Embodiment 45. The method of embodiment 43 or 44, wherein the plurality of symptoms associated with the concussive event includes at least five concussive symptoms.

[0249] Embodiment 46. The method of any one of embodiments 43-45, wherein the plurality of symptoms associated with a concussive event comprises at least 10 concussive symptoms.

[0250] Embodiment 47. The method of any one of embodiments 43-46, wherein the symptoms associated with the concussive event are reduced by at least 20%.

[0251] Embodiment 48. The method of any one of embodiments 43-47, wherein the plurality of symptoms associated with the concussive event are selected from neck pain, double vision, blurred vision, visual disturbances, memory loss or difficulty remembering, difficulty understanding or concentrating, difficulty focusing or paying attention, loss of clarity or confusion, feeling like you're in a fog, temporary loss of consciousness, feeling slowed down, numbness or tingling, emotional outbursts, tension or anxiety, sad or depressed mood, irritability, tinnitus, sensitivity to light, sensitivity to noise, drowsiness, sleeping more than usual, sleeping less than usual, difficulty falling asleep, trouble sleeping, fatigue, dizziness or unsteadiness, problems with balance, vomiting, nausea, and / or headache.

[0252] Embodiment 49. The method of any one of embodiments 43 to 48, wherein said daily administration is for at least 14 days.

[0253] Embodiment 50. A method of accelerating recovery of one or more neurological functions in a human subject following a concussive event, said method comprising administering daily to said subject ghrelin or a variant thereof beginning at least 3 to 30 days after said concussive event, and continuing said daily administration for at least 10 days, wherein said method results in recovery of said one or more neurological functions in said subject.

[0254] Embodiment 51. The method of embodiment 50, wherein said daily administration is for at least 14 days.

[0255] Embodiment 52 The method of any one of embodiments 31 to 51, wherein the ghrelin or variant thereof is administered twice daily.

[0256] Embodiment 53 The method of any one of embodiments 31-52, wherein the ghrelin or variant thereof is administered in an amount of about 70 μg / kg to about 90 μg / kg per day.

[0257] Embodiment 54. The method of any one of embodiments 31-53, wherein a first administration of the ghrelin or variant thereof is formulated to occur at least one hour after breakfast, and a second administration of the ghrelin or variant thereof is formulated to occur within one hour after dinner.

[0258] Embodiment 55 The method of any one of embodiments 31 to 54, wherein the ghrelin or variant thereof is administered as a pharmaceutical composition.

[0259] Embodiment 56. The method of embodiment 55, wherein the pharmaceutical composition is a sterile aqueous solution suitable for injection.

[0260] Embodiment 57. The method of embodiment 55, wherein the pharmaceutical composition is a transdermal patch.

[0261] Embodiment 58. The method of any one of embodiments 1 to 57, wherein the symptoms associated with the concussive event are reduced by at least 30%.

Claims

1. 1. A method for alleviating one or more symptoms of mild traumatic brain injury (mTBI) in a patient diagnosed with persistent mTBI, the method comprising administering to the patient an effective amount of ghrelin or a variant thereof for multiple consecutive days after diagnosis, wherein the one or more symptoms improve by at least 20% compared to baseline within about 40 days after initiation of administration of the ghrelin or variant thereof.

2. 2. The method of claim 1, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 30 days after initiation of administration of the ghrelin or variant thereof.

3. 2. The method of claim 1, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 20 days after initiation of administration of the ghrelin or variant thereof.

4. The method of claim 1, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 10 days after initiation of administration of the ghrelin or variant thereof.

5. The method of any one of claims 1 to 4, wherein the one or more symptoms are improved by at least 25% compared to baseline within about 40 days after initiation of administration of the ghrelin or variant thereof.

6. 6. The method of any one of claims 1 to 5, wherein the improvement is measured by QOLIBRI, PCSS, PGAS, and / or Brain Check.

7. The method of any one of claims 1 to 6, wherein the administration of ghrelin is continued until the patient's condition becomes asymptomatic.

8. The method of any one of claims 1 to 7, wherein the ghrelin or variant thereof is administered as a pharmaceutical composition.

9. The method of any one of claims 1 to 8, wherein the pharmaceutical composition is a sterile aqueous solution suitable for injection.

10. The method of any one of claims 1 to 8, wherein the pharmaceutical composition is a transdermal patch.

11. The method of any one of claims 1 to 10, wherein the administration of ghrelin or a variant thereof continues for at least 3 days.

12. The method of any one of claims 1 to 10, wherein the administration of ghrelin or a variant thereof continues for at least 5 days.

13. The method of any one of claims 1 to 10, wherein the administration of ghrelin or a variant thereof continues for at least 40 days.

14. The method of any one of claims 1 to 13, wherein only a single administration of said ghrelin or variant thereof is administered per day.

15. The method of any one of claims 1 to 13, wherein two or more doses of ghrelin or a variant thereof are administered per day.

16. The method of any one of claims 1 to 15, wherein the ghrelin or variant thereof is administered by subcutaneous injection.

17. 17. The method of any one of claims 1 to 16, wherein the administration of ghrelin is continued until the patient is able to resume normal activity.

18. 18. The method of any one of claims 1-17, wherein the one or more symptoms include headache, loss of clarity or confusion, difficulty focusing, double vision, blurred vision, sleep disturbances, emotional / behavioral changes, emotional outbursts, and / or memory loss.

19. 19. The method of any one of claims 1 to 18, wherein said one or more symptoms comprise said patient's four most bothersome symptoms (MBS).

20. 20. The method of any one of claims 1 to 19, wherein the ghrelin or variant thereof is administered at a dose of about 80 μg / kg per day.

21. 1. A method for reducing one or more symptoms of mild traumatic brain injury (mTBI), comprising: a. selecting a patient who has mTBI due to injury and who has said one or more symptoms of mTBI at least 7 days after said injury; b. administering ghrelin or a variant thereof to the patient for a period of time, wherein the ghrelin or variant thereof is administered at a dose of about 80 μg / kg per day; The method, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 40 days after initiation of administration of the ghrelin or variant thereof.

22. 22. The method of claim 21, wherein the ghrelin or variant thereof is administered at about 40 μg / kg twice daily.

23. 23. The method of claim 21 or 22, wherein the period of time is up to about 14 days.

24. 24. The method of claim 23, wherein the period of time is about 14 days.

25. 25. The method of any one of claims 21 to 24, wherein the patient is periodically evaluated for said one or more symptoms of mTBI.

26. 26. The method of any one of claims 21 to 25, wherein the patient is evaluated for said one or more symptoms of mTBI prior to administration of said ghrelin or variant thereof.

27. 27. The method of any one of claims 21 to 26, wherein the patient is evaluated for the one or more symptoms of mTBI during the period during which the ghrelin or variant thereof is administered.

28. 28. The method of any one of claims 21-27, wherein the patient is evaluated for said one or more symptoms of mTBI at about 3, 7, 10, 14, 20, and / or 43 days after initiation of administration of the ghrelin or variant thereof.

29. 29. The method of any one of claims 21 to 28, wherein the patient is assessed using one or more of the PCSS, QOLIBRI, PGAS, and / or BrainCheck.

30. 30. The method of any one of claims 21 to 29, wherein the one or more symptoms are improved by at least 20% compared to baseline within about 10 days after initiation of administration of the ghrelin or variant thereof.

31. 1. A method of treating a concussive event in a human subject by eliminating or reducing the severity of multiple symptoms associated with the concussive event, the method comprising administering ghrelin or a variant thereof to the subject daily for a first period beginning at least three days after the concussive event, wherein the severity of the multiple symptoms in the subject is reduced within 45 days after the end of administration of the ghrelin or variant thereof.

32. 32. The method of claim 31, further comprising administering to the subject daily the ghrelin or variant thereof for a second time period beginning after the first time period, wherein the severity of the plurality of symptoms in the subject is further reduced.

33. 33. The method of claim 31 or 32, wherein the plurality of symptoms comprises at least three concussion symptoms.

34. 34. The method of any one of claims 31 to 33, wherein the plurality of symptoms comprises at least five concussion symptoms.

35. 35. The method of any one of claims 31 to 34, wherein the plurality of symptoms comprises at least 10 concussion symptoms.

36. 36. The method of any one of claims 31-35, wherein the severity of each of said symptoms is reduced by at least 20%.

37. 37. The method of any one of claims 31 to 36, wherein the plurality of symptoms are selected from neck pain, double vision, blurred vision, visual disturbances, memory loss or difficulty remembering, difficulty understanding or concentrating, difficulty focusing or paying attention, loss of clarity or confusion, feeling like you're in a fog, temporary blackouts, feeling slowed down, numbness or tingling, becoming emotional, emotional outbursts, tension or anxiety, sad or depressed mood, irritability, tinnitus, sensitivity to light, sensitivity to noise, drowsiness, sleeping more than usual, sleeping less than usual, difficulty falling asleep, trouble sleeping, fatigue, dizziness or unsteadiness, problems with balance, vomiting, nausea, and / or headache.

38. 38. The method of any one of claims 31-37, wherein the first period of time begins within about 28 days after the concussive event.

39. 39. The method of any one of claims 31 to 38, wherein the first period of time is at least 10 days.

40. 40. The method of any one of claims 31 to 39, wherein the first period of time is at least 14 days.

41. 41. The method of any one of claims 31 to 40, wherein the first period of time is 20 days or less.

42. 42. The method of any one of claims 31-41, wherein the reduction in the plurality of symptoms is measured by QOLIBRI, PCSS, PGAS, or Brain Check.

43. 1. A method for accelerating recovery from a concussive event in a human subject by eliminating or reducing the severity of symptoms associated with the concussive event, the method comprising administering daily to a patient ghrelin or a variant thereof beginning at least 3 to 30 days after the concussive event, and continuing the daily administration for at least 10 days, wherein the subject experiences a reduction in symptoms associated with the concussive event.

44. 44. The method of claim 43, wherein the plurality of symptoms associated with the concussive event comprises at least three concussion symptoms.

45. 45. The method of claim 43 or 44, wherein the plurality of symptoms associated with a concussive event comprises at least five concussion symptoms.

46. 46. ​​The method of any one of claims 43 to 45, wherein the plurality of symptoms associated with a concussive event comprises at least 10 concussive symptoms.

47. 47. The method of any one of claims 43-46, wherein symptoms associated with the concussive event are reduced by at least 20%.

48. 48. The method of any one of claims 43-47, wherein the plurality of symptoms associated with the concussive event are selected from neck pain, double vision, blurred vision, visual disturbances, memory loss or difficulty remembering, difficulty understanding or concentrating, difficulty focusing or paying attention, loss of clarity or confusion, feeling like you're in a fog, temporary loss of consciousness, feeling slowed down, numbness or tingling, becoming emotional, emotional outbursts, tension or anxiety, sad or depressed mood, irritability, tinnitus, sensitivity to light, sensitivity to noise, drowsiness, sleeping more than usual, sleeping less than usual, difficulty falling asleep, trouble sleeping, fatigue, dizziness or unsteadiness, problems with balance, vomiting, nausea, and / or headache.

49. 49. The method of any one of claims 43 to 48, wherein said daily administration is for at least 14 days.

50. 1. A method of accelerating recovery of one or more neurological functions in a human subject following a concussive event, the method comprising administering to the subject daily ghrelin or a variant thereof beginning at least 3 to 30 days after the concussive event, and continuing the daily administration for at least 10 days, resulting in recovery of the one or more neurological functions in the subject.

51. 51. The method of claim 50, wherein said daily administration is for at least 14 days.

52. 52. The method of any one of claims 31 to 51, wherein the ghrelin or variant thereof is administered twice daily.

53. 53. The method of any one of claims 31 to 52, wherein the ghrelin or variant thereof is administered in an amount of about 70 μg / kg to about 90 μg / kg per day.

54. 54. The method of any one of claims 31 to 53, wherein a first administration of the ghrelin or variant thereof is formulated to occur at least one hour after breakfast and a second administration of the ghrelin or variant thereof is formulated to occur within one hour after dinner.

55. 55. The method of any one of claims 31 to 54, wherein the ghrelin or variant thereof is administered as a pharmaceutical composition.

56. 56. The method of claim 55, wherein the pharmaceutical composition is a sterile aqueous solution suitable for injection.

57. 56. The method of claim 55, wherein the pharmaceutical composition is a transdermal patch.

58. 58. The method of any one of claims 1-57, wherein symptoms associated with the concussive event are reduced by at least 20%.

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