Extended-release triamcinolone acetonide for treating osteoarthritis pain in subjects with diabetes

Abstract

Embodiments of the present disclosure relate to uses of an extended release formulation of triamcinolone acetonide extended for treating osteoarthritis pain in subjects with diabetes.

Description

PCTRX.019WO PATENT EXTENDED-RELEASE TRIAMCINOLONE ACETONIDE FOR TREATING OSTEOARTHRITIS PAIN IN SUBJECTS WITH DIABETES BACKGROUND

[0001] Osteoarthritis (OA) is a painful and debilitating musculoskeletal disease that is characterized by intra-articular (IA) inflammation, deterioration of articular cartilage, and degenerative changes to the peri-articular and subchondral bones. With 27 million Americans affected, OA is the most common join disease and arthritis is the most common cause of disability in the United States (McDonough et al. Clin Geriatr Med. 2010 August; 26(3):387–399). These numbers are expected to grow as a result of aging, obesity and sports injuries. OA commonly affects large weight-bearing joints like the knees and hips, but it can also affect the shoulders, hands, feet and spine. Subjects with OA can have joint pain, tenderness, stiffness and limited movement. As the disease progresses, it can become increasingly painful and debilitating, in many cases requiring total joint arthroplasty. The knee is the most commonly affected joint, with knee OA representing a leading cause of disability in adults (Peat et al. Ann Rheum Dis. 2001 Feb; 60(2): 91–97).

[0002] Diabetes, also known as diabetes mellitus (DM), is estimated to affect 34.2 million people in the U.S. alone, with an estimated 26.8 million people (10.2% of the population) to have an official diagnosis and approximately 7.3 million people to have yet to be diagnosed. (Centers for Disease Control [CDC’s] National Diabetes Statistics Report for 2020). The prevalence of OA is approximately 30% among subjects with type 2 diabetes, and among those approximately 17.2% have knee OA (Louati et al. RMD Open 2015;1:e000077). Accordingly, the identification of shared mechanisms that contribute to the development of inflammatory illnesses including diabetes and OA is an area of active research. For example, in one study, type 2 diabetes was found to predict joint space narrowing in men with symptomatic OA (Eymard et al. Osteoarthr. Carti.2015, 23, 851–859). Furthermore, it has been hypothesized that hyperglycemia may contribute to the progression of OA by producing advanced glycation end products, inducing oxidative stress and activating inflammatory mediators (Berenbaum, Ann. Rheum. Dis. 2011;70:1354–1356.).

[0003] There is currently no cure for OA. The major goals of current interventions are to improve pain, physical health and quality of life (QoL) while reducing opioid use and likelihood of disability. Subjects with knee OA typically receive conservative nonsurgical treatments for 50% of their lives post-diagnosis, with total knee arthroplasty generally only performed on subjects with end-stage disease.

[0004] The most common nonsurgical knee OA interventions include physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), bracing, opioids, IA corticosteroid injections and visco-supplementation. IA corticosteroids are especially recommended for short- term acute pain relief by medical organizations such as the American College of Rheumatology (ACR), the Osteoarthritis Research Society International, the European League against Rheumatism (EULAR) and the American Academy of Orthopaedic Surgeons. (American Academy of Orthopaedic Surgeons, Evidence-based Clinical Practice Guideline, August 31, 2021, https: / / www.aaos.org / oak3cpg.).

[0005] Within hours after conventional administration of corticosteroid formulations, rapid and substantial efflux of the corticosteroids from the joint can be observed, thus limiting the effectiveness of the intended pain reduction and potentially causing systemic effects in the patient. Additionally, blood glucose elevation (also known as hyperglycemia) has been observed in diabetic patients following such administration lasting for a period of up to 3 weeks (Habib and Miari, J Clin Rheumatol.2011;17:302-305). Hyperglycemia is defined by the American Diabetes Association as Level 1 (blood glucose level between 180 mg / dL and 250 mg / dL) or Level 2 (blood glucose level greater than 250 mg / dL). In one study, blood glucose levels significantly increased for 23% of subjects receiving IA triamcinolone acetonide crystalline suspension to treat knee osteoarthritis, peaking at 24-32 hours post injection, and remaining elevated for 2.5-4 days post injection. (Habib G. et al. Arthritis Rheumatol. 2014 Jan;66(1):230). Accordingly, potential loss of blood glucose control poses an important clinical challenge for patients with type 2 diabetes receiving IA corticosteroids. (Russell et al., Rheumatology 2018;57(12):2235–2241). As such, there remains a need for alternative and effective treatment of osteoarthritis pain in subjects with diabetes. SUMMARY

[0006] One aspect the present disclosure relates to a method of treating osteoarthritis (OA) pain (e.g., knee OA pain) in a diabetic subject, comprising: identifying or selecting a subject having diabetes mellitus (DM) who is at risk of suffering from hyperglycemia resulting from intra-articular injection of a corticosteroid; determining or receiving information on a baseline blood glucose level of the subject; and administering about 32 mg of an extended-release formulation of triamcinolone acetonide (TA) to the subject by a single intra-articular injection;wherein the extended-release formulation of TA is an extended-release formulation of TA comprising 75:25 molar ratio of poly(lactic-co-glycolic) acid (PLGA) microspheres (e.g., administered in a 5 mL intra-articular injection); and wherein the administration of the extended-release formulation of TA reduces the percent time above a blood glucose level of 180 mg / dL or 250 mg / dL during a period of time post administration when compared to an administration of 40 mg of an immediate- release formulation of TA to the subject.

[0007] Another aspect of the present disclosure relates to a method of treating OA pain such as knee OA pain in a diabetic subject, comprising: identifying or selecting a subject having diabetes mellitus who is at risk of suffering from hyperglycemia resulting from intra-articular injection of a corticosteroid; determining or receiving information on a baseline blood glucose level of the subject; and administering about 32 mg of an extended-release formulation of TA to the subject by a single intra-articular injection; wherein the extended-release formulation of TA is an extended-release formulation of TA comprising 75:25 molar ratio of poly (lactic-co-glycolic) acid (PLGA) microspheres (e.g., administered in a 5 mL intra-articular injection); and the administration of the extended-release formulation of TA reduces the likelihood that the subject’s blood glucose level is above 180 mg / dL or 250 mg / dL during a period of time post administration when compared to an administration of 40 mg of an immediate-release formulation of TA to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 shows the results of percent time spent in four blood glucose ranges before and after intra-articular injection of an extended-release formulation of TA (TA-ER) in comparison to an immediate-release formulation of TA (TA-IR), as described in Example 1.

[0009] FIG. 2 shows the change in glucose levels (mg / dL) measured by continuous glucose monitor (CGM) of the TA-ER treatment group in comparison to TA-IR treatment of CGM blood glucose levels for TA-ER and TA-IR from day -7 to day 14, as described in Example 1. DETAILED DESCRIPTION

[0010] Embodiments of the present disclosure relate to methods or uses of extended- release triamcinolone acetonide (TA) for osteoarthritis pain management in a diabetic subject. The method of use includes selecting or determining a diabetic subject who is at risk of developinghyperglycemia for treatment. The method or use may further include determining or receiving information on a subject’s baseline blood glucose level prior to administering TA. The method or use may further comprise continuously monitoring the blood glucose level of the subject post injection to determine the subject’s blood glucose level post administration during a period of time, such as with a continuous glucose monitoring (CGM) device. The method or use described herein provides better glucose control and lower glucose spikes as compared to immediate-release TA and improves the patient’s quality of life. Definitions

[0011] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. The use of “or” or “and” means “and / or” unless stated otherwise. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The use of the term “having” as well as other forms, such as “have”, “has,” and “had,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the above terms are to be interpreted synonymously with the phrases “having at least” or “including at least.” For example, when used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, formulation, or device, the term “comprising” means that the compound, composition, formulation, or device includes at least the recited features or components, but may also include additional features or components.

[0013] As used herein, “triamcinolone acetonide” or “TA” refers to a compound having the following structure:.

[0014] The term “immediate release” or “immediate-release” as used herein, has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non- limiting example, release of a drug from a dosage form in a relatively brief period of time after administration.

[0015] The term “extended release” or “extended-release” as used herein, each has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non- limiting example, controlled release of a drug from a dosage form over an extended period of time. For example, in some embodiments, extended-release formulations are those that have a release rate that is substantially longer than that of a comparable immediate-release form.

[0016] The term “treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition / formulation for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a patient who is not yet suffering from a disease, but who is susceptible to, or otherwise at risk of, a particular disease, whereby the treatment reduces the likelihood that the patient will develop a disease. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease.

[0017] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions or formulations is contemplated. Supplementary active ingredients can also be incorporated into the compositions or formulations. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press. Methods of Treating Diabetic Patients

[0018] Some embodiments of the present disclosure relate to a method of treating or ameliorating osteoarthritis pain (such as knee osteoarthritis pain) in a diabetic subject, including identifying or selecting a subject having diabetes mellitus (DM) who is at risk of suffering from hyperglycemia resulting from intra-articular injection of a corticosteroid; determining or receiving information on a baseline blood glucose level of the subject; and administering an amount of anextended-release formulation of triamcinolone acetonide (TA) to the subject by a single intra- articular injection. Patient selection

[0019] In some embodiments of the method described herein, the subject having diabetes mellitus (DM) who is at risk of suffering from hyperglycemia resulting from intra- articular injection of a corticosteroid may suffer from type 2 diabetes. In some other embodiments, the subject may suffer from type 1 diabetes. In some embodiments, the subject has had type 2 or type 1 diabetes for at least 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months prior to the treatment. In some embodiments, the subject has been or is being treated with one or more antidiabetic agents (e.g., insulin injectable and / or oral antidiabetic agents). In some further embodiments, the subject has been or is being treated with stable doses of the one or more antidiabetic agents for at least 1, 2, or 3 months prior to the treatment. In some embodiments, the subject being selected or identified has a hemoglobin A1c (HbA1c) level ^ 9% before or at the start of the treatment. In some further embodiments, the subject being selected or identified has a hemoglobin A1c (HbA1c) level ^ 6.5% and < 9.0% before the start of the treatment. In some embodiments, the subject has a body mass index (BMI) from about 27 to about 45 kg / m2.

[0020] In some embodiments of the method described herein, the subject has had painful symptoms associated with OA of the knee for at least 1, 2, 3, 4, 5, or 6 months prior to the treatment. In some embodiments, the subject meets American College of Rheumatology (ACR) criteria (clinical and radiological) for OA (Altman et al. Arthritis Rheum.1986 Aug;29(8):1039- 49) as follows: x Knee pain x Osteophytes x at least 1 of the following: o Age > 50 years o Stiffness < 30 minutes o Crepitus In some embodiments, the subject has had index knee pain on most days (>15 days) over the last month prior to the start of the treatment. Exclusions

[0021] In some embodiments, the subject does not have Reiter’s syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or arthritis associated with inflammatory bowel disease. In some embodiments, the subject does not have a history ofinfection in the index knee joint. In some embodiments, the subject does not have clinical signs and symptoms of active knee infection or crystal disease of the index knee within 1 month after being selected or identified or before the start of the treatment.

[0022] In some embodiments, the subject has not previously been treated with, or is being concomitantly treated with one or more of the following medications: x IA corticosteroid in any joint within 1, 2, or 3 months before the start of the treatment x IA hyaluronic acid in the index knee within 1, 2, 3, 4, 5 or 6 months before the start of the treatment x Oral, intravenous (IV) or intramuscular (IM) corticosteroids within 1, 2, or 3 months before the start of the treatment x Inhaled, intranasal or topical corticosteroids within 1, 2, 3, or weeks before the start of the treatment, such as inhaled corticosteroids (including but not limited to budesonide, fluticasone, Alvesco®, mometasone, flunisolide, fluticasone propionate / salmeterol, fluticasone propionate, mometasone / formoterol, budesonide / formoterol, and Flovent® Diskus), intranasal corticosteroids (including but not limited to azelastine / fluticasone intranasal, beclomethasone intranasal, Beconase® AQ, budesonide intranasal, ciclesonide intranasal, ClariSpray™, Dymista®, flonase allergy relief, flonase sensimist allergy relief, flunisolide intranasal, FlutiCare®, fluticasone intranasal, mometasone intranasal, Nasacort® Allergy 24HR, Nasonex™, olopatadine intranasal / mometasone intranasal, Omnaris®, QNASL®, Rhinocort® Allergy, Rhinocort® Aqua (DSC), Ryaltris®, triamcinolone intranasal, Veramyst®, Xhance®, and Zetonna™), topical corticosteroids (including but not limited to betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, fluocinonide, flurandrenolide, halobetasol, amcinonide, desoximetasone, halcinonide, fluticasone propionate, triamcinolone acetonide, desoximetasone, hydrocortisone , hydrocortisone valerate, fluocinolone acetonide, mometasone furoate, alclometasone dipropionate, desonide, and fluocinolone)

[0023] In some embodiments, the subject has not had prior arthroscopic or open surgery of the index knee within 3, 6, 9 or 12 months before the start of the treatment.

[0024] In some embodiments, the subject should not use acetaminophen, or acetaminophen containing products after the start of the treatment till at least 7, 14, 21 or 28 days after the completion of the treatment if the subject uses a continuous glucose monitoring device to monitor the blood glucose level.

[0025] In any embodiments of method described herein, the subjects who has been identified or selected is at risk of suffering from hyperglycemia resulting from intra-articular (IA) injection of an immediate-release formulation of corticosteroid, including but not limited to beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, triamcinolone acetonide, fludrocortisone, deoxycorticosterone, aldosterone, and mixtures thereof. In further embodiments, the subject may be at risk of having a glucose spike of above 180 mg / dL or 250 mg / dL for an extended period of time after IA injection (e.g., within 24, 48 or 72 hours after IA injection) of an immediate-release formulation of corticosteroid (e.g., the immediate-release formulation of TA as described herein). In further embodiments, the subject may have had a glucose spike of above 180 mg / dL or 250 mg / dL for an extended period of time after a prior IA injection (e.g., within 24, 48 or 72 hours after IA injection) of an immediate-release formulation of corticosteroid (e.g., the immediate-release formulation of TA as described herein). In some further embodiments, the subject being identified or selected may be at risk of having, or have had experienced a glucose spike of above 180 mg / dL or 250 mg / dL for at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% of time within 24, 48 or 72 hours after IA injection) of an immediate-release formulation of corticosteroid (e.g., the immediate-release formulation of TA as described herein). Extended-release formulation of triamcinolone acetonide

[0026] In some embodiments, the extended-release formulation of TA can be microsphere based. In some further embodiments, the microsphere-based formulation can be TA in a 75:25 molar ratio poly(lactic-co-glycolic) acid (PLGA) microspheres (e.g., Zilretta®). Zilretta® is formulated in PLGA microspheres comprising a 75:25 molar ratio of lactic acid to glycolic acid with a nominal drug load of 25% (w / w) and is provided as a sterile white to off- white powder. Zilretta® is prepared with a supplied diluent containing an isotonic, sterile, aqueous solution of sodium chloride (NaCl; 0.9% w / w), sodium carboxymethylcellulose (CMC; 0.5% w / w) and polysorbate-80 (0.1% w / w) to form a 5 mL sterile suspension intended for intra-articular injection. In some embodiments, the extended-release formulation of TA is administered as a single intra-articular injection. In some such embodiments, it is supplied as a single-dose kit containing one vial of 75:25 poly(lactic-co-glycolic) acid (PLGA) microsphere powder, one vial of 5 mL diluent, and one sterile vial adapter. In some embodiments, the amount of the extended- release formulation of TA administered is about 20 mg, 25 mg, 30 mg, 35 mg or 40 mg, or a range defined by any of the two preceding values. For example, the amount of extended-release formulation of TA can be from about 20 mg to about 25 mg, from about 20 mg to about 40 mg,from about 30 mg to about 35 mg, from about 25 mg to about 35 mg, etc. In some embodiments, the amount of the extended-release formulation of TA is about 30 mg, 31 mg, 32 mg, 33 mg, 34 mg or 35 mg, or a range defined by any of the two preceding values. In one embodiment, the amount of the extended-release formulation of TA is about 32 mg. In some embodiments, the extended-release formulation of TA can be administered as an intra-articular injection with a volume of about 1 mL, 2 mL 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL or 10 mL. In some embodiments, the extended-release formulation of TA is 32 mg TA administered as a 5 mL intra- articular injection.

[0027] In some embodiments, the index knee is aspirated prior to the administration of the medication. Following aspiration, either the TA-ER medication or the TA-IR control medication will be injected into the synovial space. The same needle used for IA injection of the TA medication may also be used for synovial fluid aspiration, thereby allowing for a single injection with syringe replacement. In some embodiments, a 21-gauge needle or larger may be used for injection and aspiration of fluid.

[0028] In some embodiments of the method described herein, the administration of the extended-release formulation of TA can reduce the percent time above a blood glucose level of 180 mg / dL or 250 mg / dL during a period of time post administration when compared to an administration of an immediate-release formulation of TA during the same period of time. In some such embodiments, a baseline blood glucose level is first established or measured shortly prior to the IA administration of the TA medicament and monitored for at least 24 hours, 48 hours or 72 hours right after the administration of TA. Percent time above a blood glucose level is calculated by dividing the amount of time during which the subject’s blood glucose level is above 180 mg / dL or 250 mg / dL by the period of time in which the subject’s blood glucose level is being monitored. In some further embodiments, the percent time above a blood glucose level of 180 mg / dL or 250 mg / dL is reduced by at least about 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45% or 50% during the period of time post TA administration, compared to the administration of the immediate-release formulation of TA during the same period of time (e.g., 24 hours, 48 hours or 72 hours). In some further embodiments, the subject spends equal or less than about 25%, 20%, 15%, 10% or 5% of time above the blood glucose level of 180 mg / dL during the period of time post administration. In some further embodiments, the subject spends equal or less than about 25%, 20%, 15%, 10% or 5% of time above the blood glucose level of 250 mg / dL during the period of time post administration.

[0029] In some embodiments of the method described herein, the administration of the extended-release formulation of TA can reduce the likelihood that the subject’s blood glucose level is above 180 mg / dL or 250 mg / dL during a period of time post administration whencompared to an administration of an immediate-release formulation of TA. In some such embodiments, a baseline blood glucose level is first established or measured shortly prior to the IA administration of the TA medicament and monitored for at least 24 hours, 48 hours or 72 hours right after the administration of TA to determine whether the subject’s blood glucose level changes from baseline to above 180 mg / dL or 250 mg / dL within the period of time in which the subject’s blood glucose level is being monitored. In some further embodiments, the likelihood that the subject’s blood glucose level is above 180 mg / dL or 250 mg / dL is reduced by at least about 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50% , 60%, 70%, 80%, 90%, 95%, 98% or 99% during the period of time post administration, when compared to the administration of the immediate-release formulation of TA during the same period of time (e.g., 24 hours, 48 hours or 72 hours).

[0030] In some embodiments of the method described herein, the administration of the extended-release formulation of TA can increase the time to reach the blood glucose level of 180 mg / dL or 250 mg / dL during a period of time post administration when compared to the administration of an immediate-release formulation of TA. In some such embodiments, a baseline blood glucose level is first established or measured shortly prior to the IA administration of the TA medicament and monitored for at least 24 hours, 48 hours or 72 hours right after the administration of TA to determine whether the subject’s blood glucose level changes from baseline to above 180 mg / dL or 250 mg / dL within the period of time in which the subject’s blood glucose level is being monitored. In some further embodiments, the time to reach the blood glucose level of 180 mg / dL or 250 mg / dL is increased by at least about 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70% 75%, 80%, 85%, 90%, 95%, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold or 5-fold during the period of time post administration, when compared to the administration of the immediate-release formulation of TA during the same period of time (e.g., 24 hours, 48 hours or 72 hours). In some further embodiments, the time to reach the blood glucose level of 180 mg / dL or 250 mg / dL can be increased by at least about 25%, 50%, 75%, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 4-fold or 5-fold during the period of time post administration, when compared to the administration of the immediate-release formulation of TA during the same period of time (e.g., 24 hours, 48 hours or 72 hours).

[0031] In some embodiments, the administration of the extended-release formulation of TA can also increase the time to reach maximum blood glucose level during the period of time post administration when compared to the administration of an immediate-release formulation of TA. In some such embodiments, a baseline blood glucose level is first established or measured shortly prior to the IA administration of the TA medicament and monitored for at least 24 hours, 48 hours or 72 hours right after the administration of TA to determine whether the subject’s bloodglucose level changes from baseline to maximum blood glucose level within the period of time in which the subject’s blood glucose level is being monitored. In some further embodiments, the time to reach maximum blood glucose level is increased by at least about 25%, 30%, 35%, 40%, 45% 50%, 55%, 60%, 65%, 70% 75%, 80%, 85%, 90%, 95%, 1-fold, 1.5-fold, 2-fold, or 2.5-fold during the period of time post administration, when compared to the administration of the immediate-release formulation of TA during the same period of time (e.g., 24 hours, 48 hours or 72 hours). In some further embodiments, the time to reach maximum blood glucose level is increased by at least about 25%, 50%, 75%, 1-fold, 1.5-fold, 2-fold, or 2.5-fold during the period of time post administration, when compared to the administration of the immediate-release formulation of TA during the same period of time (e.g., 24 hours, 48 hours or 72 hours).

[0032] In some embodiments of the method described herein, the administration of the extended-release formulation of TA can also increase the percent time within a target blood glucose range of ^ 70 mg / dL and ^ 180 mg / dL during the period of time post administration when compared to an administration of an immediate-release formulation of TA. In some such embodiments, a baseline blood glucose level is first established or measured shortly prior to the IA administration of the TA medicament and monitored for at least 24 hours, 48 hours or 72 hours right after the administration of TA to determine the time the subject’s blood glucose level is within the target blood glucose range within the period of time in which the subject’s blood glucose level is being monitored. In some further embodiments, the percent time within the target blood glucose range is increased by at least about 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% 75%, 80%, 85%, 90%, 95%, 1-fold, 1.5-fold, 2-fold, or 2.5-fold during the period of time post administration, when compared to the administration of the immediate-release formulation of TA during the same period of time (e.g., 24 hours, 48 hours or 72 hours).

[0033] In some embodiments of the method described herein, the subject’s antidiabetic agent consumption (e.g., insulin consumption) post administration of the extended-release formulation of TA is less than the antidiabetic agent consumption (e.g., insulin consumption) post administration of 40 mg of the immediate-release formulation of TA during a period of time post administration. In some further embodiments, the antidiabetic agent consumption is decreased by at least about 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% during the period of time post administration, when compared to the same period of time post administration of the immediate-release formulation of TA. The period of time may be up to 2 weeks (e.g., 1 day, 2 day, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days). In some such embodiments, the subject’s antidiabetic agent consumption (e.g., insulin consumption) is increased from base line (72 hours prior to dosing) but such increase is less thanthe increase of the antidiabetic agent consumption (e.g., insulin consumption) post administration of 40 mg of the immediate-release formulation of TA.

[0034] In some embodiments of the method described herein, the subject’s average daily knee pain intensity score (in the index knee which received the administration) during the period of time post administration of the extended-release formulation of TA is less than the average daily knee pain intensity score during the period of time post administration of 40 mg of the immediate-release formulation of TA.

[0035] In any of the embodiments of the method described herein, the subject’s baseline blood glucose level is measured or the information on the subject’s baseline blood glucose level is received within about 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours before the injection.

[0036] In any of the embodiments of the method described herein, the period of time post administration can be about or at least about 24 hours (1 day), about 48 hours (2 days), about 72 hours (3 days), about 96 hours (4 days), about 120 hours (5 days), about 144 hours (6 days), 168 hours (7 days), 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days. In one embodiment, the period of time post administration is about 72 hours. In further embodiments, the subject is being continuously monitored after the TA treatment for the whole period of time. In one embodiment, the continuous monitoring is done by a CGM device (e.g., Dexcom Professional CGM device). Immediate-release formulation of triamcinolone acetonide

[0037] In any embodiments of the method described herein, the immediate-release formulation of TA (TA-IR) as comparison is for administration as an intra-articular injection. In some embodiments, the amount of the immediate-release formulation of TA for comparison is about 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg or 45 mg. In one embodiment, the amount of the immediate-release formulation of TA for comparison with the extended-release formulation of TA described herein is about 40 mg. In further embodiments, the immediate-release formulation of TA for comparison is for administration in a volume of about 1 mL, 2 mL 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL or 10 mL at a concentration of about 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, or 60 mg / mL. In one embodiment, the immediate-release formulation of TA is administered as a 1 mL intra-articular injection. In some embodiments, the immediate-release formulation of TA is a 40 mg / mL injectable suspension (Kenalog®-40) administered in a 1 mL intra-articular injection. Each mL of the sterile aqueous suspension ofKenalog®-40 includes 40 mg triamcinolone acetonide, with sodium chloride for isotonicity, carboxymethylcellulose sodium, and polysorbate 80. A preservative, benzyl alcohol may also be present. Sodium hydroxide or hydrochloric acid may be present to adjust pH to 5.0 to 7.5.

[0038] In any of the embodiments described herein, the subject having DM may have been managed with one or more antidiabetic agents prior to the treatment, such as injectable or oral antidiabetic agents or both. In some further embodiments, the method can also include adjusting the dosage of the one or more antidiabetic agents when the subject’s blood glucose level is above the target blood glucose range of ^ 70 mg / dL and ^ 180 mg / dL. EXAMPLES

[0039] The examples below are non-limiting and are merely representative of various aspects of the present disclosure. Example 1

[0040] In this example, a double-blind, a phase 2 study (NCT02762370) of randomized, parallel group comparison of the effects of triamcinolone acetonide extended-release (TA-ER) and triamcinolone acetonide immediate-release (TA-IR) on blood glucose (BG) in subjects with osteoarthritis of the knee and type 2 diabetes mellitus and the analysis of the clinical study results are summarized here. Study Design

[0041] Eligible participants at screening had symptomatic knee OA for at least 6 months, had type 2 diabetes for at least 1 year, met American College of Rheumatology clinical and radiological criteria for OA, and had hemoglobin A1c levels (HbA1c) ^6.5% and <9.0%. Participants were randomized to either receive an IA injection of TA-ER or TA-IR. A continuous glucose monitor (CGM) provided an ambulatory glucose profile (AGP) that summarized BG levels before and throughout the 14 days after IA injection for each participant.

[0042] Patients were randomized to receive IA administration of TA-ER 32mg (Zilretta® 5 ml) or TAcs 40mg (Kenalog®-40; Bristol-Myers Squibb Company, Princeton, NJ, USA; 1ml). 18 people were treated with TA-ER and 15 people were treated with TA-IR. TA-ER and TA-IR were not identical in appearance at the time of administration. For that reason, treatments were prepared and administered by designated unblinded site personnel who had no other contact with participants or study personnel, and the injection syringe was concealed from study participants. Following screening (days -21 to -7), CGMG data (Dexcom G4 PlatinumProfessional CGM) were collected, as described above, from pre-treatment (days -7 to 0) through 2 weeks post injection (days 0-14). Day 0 was the injection day.

[0043] In this post-hoc analysis, data from participants were categorized by the internationally recognized threshold for severe (Level 2) hyperglycemia (i.e., BG level greater than 250 mg / dL). Changes in average daily glucose levels from baseline, average time in or above the target range of 70 to 180 mg / dL, and glycemic variability at multiple time points were also examined. Time above range (TAR) between groups was compared across 4 study periods: pre- injection days о7 to 0 and о3 to 0, and post injection days 1 to 3 and 4 to 14. Kaplan–Meier analysis was performed to determine the time required to reach 250 mg / dL and time to reach maximum glucose level. The glucose management indicator (GMI) was used to estimate HbA1c levels from the CGM data according to a published validated algorithm. Results

[0044] FIG. 1 shows the results of percent time spent in four blood glucose ranges before and after intra-articular injection of an extended-release formulation of TA (TA-ER) in comparison to an immediate-release formulation of TA (TA-IR). From top to bottom of each column in the chart, ranges are defined as BG level > 250 mg / dL; 250 mg / dL ^ BG level > 180 mg / dL; 180 mg / dL ^ BG level > 70 mg / dL; BG level < 70 mg / dL. During the study period of post injection days 1 to 3, the average percentage of TAR > 250 mg / dL for the TA-ER group (12%) was reduced 2-fold compared with the TA-IR group (26%), and the percentage of time in target range (70 mg / dL to 180 mg / dL) was larger for the TA-ER group (62%) compared with the TA- IR group (48%) (See FIG. 1). The TA-ER group also had a markedly smaller proportion of subjects who developed maximum CGM glucose levels greater than 250 mg / dL (50%) compared with the TA-IR group (93%) for days 1 to 3.

[0045] FIG. 2 shows the change in glucose levels (mg / dL) measured by continuous glucose monitor (CGM) of the TA-ER treatment group in comparison to TA-IR treatment of CGM blood glucose levels for TA-ER and TA-IR from day -7 to day 14. Median glucose levels are represented as thick lines, median glucose levels ± mean absolute deviation (MAD) are represented as thin lines, target range limits are represented as dashed lines, and injection day is indicated as shading. The dashed line at 250 mg / dL indicates sever hyperglycemia threshold. The dashed lines between 180 mg / dL and 70 mg / dL indicates the target blood glucose thresholds. The AGP analyses showed more consistent glucose levels and lower glucose level spikes throughout the course of the study in the TA-ER group (See FIG. 2). Similar trends were observed for the additional AGP output conducted for 7:00 AM fasting glucose. Median time to 250 mg / dL (TA- ER, 44 hours; TA-IR, 6 hours; P=0.003) and time to maximum glucose level (TA-ER, 34 hours;range of maximum glucose level, 154-390 mg / dL; TA-IR, 13 hours; range of maximum glucose level, 206-401 mg / dL; P=0.007) significantly favored TA-ER compared with TA-IR. The estimated mean GMI values were lower numerically, though not statistically, with TA-ER versus TA-IR across 0-14 days (7.1 vs 7.5).

[0046] This analysis suggests TA-ER was associated with a clinically meaningful reduction in hyperglycemia compared with TA-IR. The reduced spikes in glucose levels observed in the TA-ER group suggest that TA-ER may lead to fewer short-term hyperglycemia-related adverse events. The increased duration in the 70 mg / dL to 180 mg / dL target range is expected to improve glucose management following the IA injection, especially in subjects requiring repeat corticosteroid injections for OA knee pain management. Reduced time spent with glucose levels greater than 250 mg / dL is expected to improve subjects’ well-being and reduce healthcare resource utilization. Since HbA1c is the primary measurement for estimating glucose control and long-term complications, the reduction in GMI seen in the TA-ER group compared with TA-IR group suggests TA-ER may help reduce risk of these complications. Example 2

[0047] In this example, a phase 4 randomized, double blind, active-controlled study to evaluate the effects of Zilretta® (triamcinolone acetonide extended-release; TA-ER) and TA-IR (triamcinolone acetonide immediate-release) on blood glucose in subjects with osteoarthritis of the knee and diabetes mellitus is summarized here. The purpose of this phase 4 study is to assess CGM patterns for TAR > 250 mg / dL from baseline to 0-3 days following a single IA injection of 32 mg of TA-ER relative to 40 mg of TA-IR. The study is also intended to address the following objectives: (1) to characterize fasting blood glucose (FBG) variability for the full study period using CGM derived AGP analysis, for the single IA injection of 32 mg TA-ER relative to 40 mg TA-IR; (2) to evaluate differences in time-dependent maximum hyperglycemic distance travelled following a single IA injection of 32 mg TA-ER relative to 40 mg TA-IR; (3) to assess the safety and general tolerability of a single IA injection of 32 mg TA-ER relative to 40 mg TA-IR; (4) to characterize hyperglycemic patterns for the study period using CGM derived AGP analysis for single IA injections of 32 mg TA-ER relative to 40 mg TA-IR; (5) to assess the acute effects of hyperglycemia on quality of life (QoL) for treatments of 32 mg TA-ER relative to 40 mg TA-IR; and (5) to quantify GMI index for 32 mg TA-IR relative to 40 mg TA-IR using 14-day CGM blood glucose study data.Study Design

[0048] Eligible participants are at least 40 years old with symptomatic OA of the knee and diabetes mellitus who are being managed with either injectable or oral antidiabetic agents or both. About 20% of the subject population comprise type 1 diabetes. Subjects are to be on stable doses of injectable or oral agents for at least 2 months prior to the study screening and have HbA1c levels between 6.5% and 9.0% at screening. Approximately 140 subjects are to be randomized into one of two treatment groups (1:1) and treated with either 32 mg of TA-ER or 40 mg TA-IR. BG levels in each subject are to be collected and evaluated for a total of 3 weeks spanning one week pre-injection and 2 weeks post injection.

[0049] After a screening visit, subjects’ BG levels will be measured using a Dexcom G6 Pro “masked” CGM device, set to blinded mode, for up to one week pre-injection and 2 weeks post injection. The analyses of co-primary endpoints are to be conducted based on 72-hour post treatment CGM-derived BG data. Secondary and exploratory endpoint analyses are to be based on CGM-derived FBG-AGP analysis for the complete study period. Treatment Arms

[0050] Treatment arms include the following: 32 mg extended-release formulation of triamcinolone acetonide in 75:25 PLGA (poly(lactic-co-glycolic acid)) microspheres administered as a 5 mL IA knee injection. 40 mg immediate-release formulation of triamcinolone acetonide injectable suspension administered as a 1 mL IA knee injection. Inclusion Criteria

[0051] During the Screening Period (except as noted below), each subject must meet all of the following criteria to be enrolled in this study: 1. Male or female at least 40 years of age. 2. Type 1 or type 2 diabetes for at least 1 year prior to screening. 3. Currently being treated with injectable and / or oral antidiabetic agents with stable doses for at least 2 months prior to screening. 4. HbA1c ^ 6.5% and < 9.0% at screening. 5. Painful symptoms associated with OA of the knee for at least 6 months prior to screening. 6. Currently meets American College of Rheumatology criteria (clinical and radiological) for OA (Altman et al, 1986): ^ Knee pain^ at least 1 of the following: x Age > 50 years x Stiffness < 30 minutes x Crepitus ^ Osteophytes. 7. Index knee pain on most days (>15) over the last month (as reported by the subject). 8. Body mass index (BMI) 27 to 45 kg / m2. Exclusion Criteria

[0052] Subjects meeting any of the following criteria (during the Screening Period, except as noted below) will be excluded from the study: 1. Reiter’s syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or arthritis associated with inflammatory bowel disease. 2. History of infection in the index knee joint. 3. Clinical signs and symptoms of active knee infection or crystal disease of the index knee within 1 month of Screening. 4. Presence of surgical hardware or other foreign body in the index knee. 5. Unstable joint (such as a torn anterior cruciate ligament) within 12 months of screening. 6. IA corticosteroid (investigational or marketed) in any joint within 3 months of screening. 7. IA hyaluronic acid (investigational or marketed) in the index knee within 6 months of screening. 8. IV or IM corticosteroids (investigational or marketed) within 3 months of screening. 9. Oral corticosteroids (investigational or marketed) within 1 month of screening. 10. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks of screening. 11. Any other IA investigational drug / biologic within 6 months of screening or 5 half-lives (whichever is longer). 12. Prior arthroscopic or open surgery of the index knee within 12 months of screening. 13. Planned / anticipated surgery of the index knee or any other surgery during the study period. 14. Use of acetaminophen, or acetaminophen containing products, from screening through Day 14 (completion of post treatment BG monitoring). 15. Known hypersensitivity to any form of triamcinolone. 16. History of sarcoidosis or amyloidosis.Active or history of malignancy within the last 3 years with the exception of resected basal cell carcinoma, squamous cell carcinoma of the skin, or effectively managed cervical carcinoma. Known active or quiescent systemic fungal, bacterial (including tuberculosis), viral or parasitic infections, or ocular herpes simplex. Any infection requiring intravenous IV antibiotics within 4 weeks of screening or infection requiring oral antibiotics within 2 weeks of screening. History of osteomyelitis. Known or clinically suspected infection with human immunodeficiency virus (HIV) or), hepatitis B or C viruses. Any clinically significant electrocardiogram (ECG) abnormality as judged by the Principal Investigator. Subjects requiring or likely to require treatment with corticosteroids during the study period based on subject medical history. History of or active Cushing’s syndrome. Active psychiatric disorder including psychosis (e.g., schizophrenia), bipolar disorder, uncontrolled anxiety disorder and major depressive disorder. Active substance abuse (drugs or alcohol), history of chronic substance abuse within the last year, or prior chronic substance abuse judged by the investigator likely to recur during the study. Skin breakdown at the knee where the injection would take place. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 3 years of screening. Has received a live or live attenuated vaccine within 3 months of screening. Use of any other investigational drug or device within 30 days of screening or within 5 half-lives (whichever is longer) or an investigational biologic within 60 days of screening or within 5 half-lives (whichever is longer). Any other clinically significant acute or chronic medical conditions that, in the judgment of the Investigator, would preclude the use of an IA corticosteroid or nonsteroidal anti- inflammatory drugs (NSAIDs) or that could compromise subject safety, limit the subject’s ability to complete the study, and / or compromise the objectives of the study. Has a positive pregnancy test at any visit, lactates or intends to become pregnant during the time period from screening through end of study.Injection Administration Procedure

[0053] IA injections will be administered by the assigned unblinded injector, who has significant experience in the administration of IA injections and has been trained on study administration procedures. The injector may choose the position of the knee (e.g., extended or bent), the approach for the injection (e.g., medial or lateral), and the numbing agent to be used (e.g., ethyl chloride or subcutaneous lidocaine; IA anesthetics are not allowed) based on standard of care. Following aspiration, 5 mL of the reconstituted TA-ER or 5 mL of TA-IR (1 mL) and normal saline (4 mL) will be injected into the synovial space. The same needle used for IA injection of the study medication may also be used for synovial fluid aspiration, thereby allowing for a single injection with syringe replacement. The injector will use a 21-gauge needle or larger for injection and aspiration of fluid. Study Endpoints

[0054] The primary endpoints of the study include the percentage of time spent above 250 mg / dL (Time Above Range, TAR) from post baseline to 72 hours (0-3 days) for TA-ER relative to TA-IR and the proportion of subjects who reach TAR > 250 mg / dL from post baseline to 72 hours (0-3 days) for TA-ER relative to TA-IR. The secondary and exploratory endpoints include (1) group difference comparison of FBG levels for median, 75thpercentile and 90thpercentile levels during post baseline study period (0-14 days) per AGP analysis for TA-ER relative to TA-IR; (2) median time to maximum hourly average BG value during post baseline to 72 hours (0-3 days) per Kaplan-Meier Analysis for TA-ER relative to TA-IR; (3) mean total change in DSC-R (Diabetes Symptom Checklist-Revised) score for domains of psychological fatigue, psychological cognition and hyperglycemia from baseline to time periods of 0-24 hours (0-1 days), 0-48 hours (0-2 days), and 0-72 hours (0-3 days) for TA-ER relative to TA-IR; (4) BG study group comparisons from baseline (-7 to 0 days) to 0-14 days for median, 75thpercentile and 90thpercentile levels of CGM derived AGP analysis for TA-ER relative to TA-IR; (5) comparison of study mean GMI for TA-ER relative to TA-IR, quantified using CGM derived BG values over the study period, per validated formula (Bergenstal et al. Diabetes Care.2018 Nov; 41(11): 2275– 2280) as follows: GMI (%) = 3.31 + 0.02392 * [mean glucose in mg / dL]; and (6) incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs) post baseline (0-14 days).

[0055] Percentage of time spent at BG > 250 mg / dL from post baseline to 72 hours (0- 3 days): To compute this endpoint, first average hourly blood glucose is calculated from timepoints for each hour. Each hour is categorized as BG > 250 mg / dL or not. The number of hours at BG > 250 mg / dL is summed from post baseline to 72 hours (0-3 days) and divided by the total number of hours during the same period within each subject. The resulting endpoint isanalyzed with a linear model with a fixed effect for treatment group along with covariates of the mean of the pre-treatment BG values and the hour of the day at which the subject received a drug injection.

[0056] Proportion of subjects who reach BG > 250 mg / dL from post baseline to 72 hours (0-3 days): To compute this endpoint, the following binary variable is created for each subject: whether BG levels reach > 250 mg / dL within the first 72 hours post baseline. This endpoint is analyzed with a generalized linear model with a binomial family and the logit link function (i.e., a logistic regression model). This model includes the same fixed effect and covariates as the above model.

[0057] Percentiles of Fasting Ambulatory Glucose Profile (AGP): Fasting AGPs are computed and analyzed as follows. BG levels collected in the last hour before first meal of the day are flagged and retained in the dataset as FBG readings. Average BG levels are computed for each half-hour block (7:00-7:30, 7:31-7:59) at each day throughout the post baseline period (i.e., days 0-14). The resulting fasting AGPs are analyzed with a mixed quantile regression model for repeated measures (MQRMRM) with fixed effects for treatment group, day, and group-by-day interaction along with covariates of the mean of the pre-treatment BG values and the hour of the day at which the subject received a drug injection. This model includes a subject random effect. This model estimates the fixed effect on 50th (i.e., the median), 75th and 90th percentiles of the fasting AGP. (Analysis assumes to use an R package, since no mixed-effects version of quantile regression is available in SAS.)

[0058] Median time to the maximum hourly average BG value during hours 1-72 (Days 0-3): This time-to-event endpoint is analyzed with the Kaplan-Meier estimator with the time to reach the maximum BG as the outcome and treatment groups as the strata.

[0059] For all analyses, baseline covariates not mentioned above (e.g., age, gender, BMI, body weight at baseline) may be considered for inclusion in the models. Example 2

[0060] In this example, a double-blind, a phase 2 study of randomized, parallel group comparison of the effects of triamcinolone acetonide extended-release (TA-ER) and triamcinolone acetonide immediate-release (TA-IR) on blood glucose (BG) in subjects with osteoarthritis of the knee and type 2 diabetes mellitus and the analysis of the clinical study results are summarized here. Study Design

[0061] Eligible participants are at least 40 years old with symptomatic OA of the knee and type 2 diabetes mellitus who are being managed with either injectable or oral antidiabeticagents or both. Subjects are to be on stable doses of injectable or oral agents for at least 1 month prior to the study screening and have HbA1c levels ^9.0% at screening. Approximately 120 subjects are to be randomized into one of two treatment groups and treated with either 32 mg of TA-ER or 40 mg of TA-IR. BG levels in each subject are to be collected and evaluated for a total of 3 weeks spanning one week pre-injection and 2 weeks post injection.

[0062] After a screening visit, subjects’ BG levels are to be measured using a CGM device for up to one week pre-injection and 2 weeks post-injection. Subjects are blinded to treatment assignments but not to the glucose readings. Subjects are to use a 6-point self- monitoring BG (SMBG) profile measured with a downloadable glucometer starting the day prior to dosing and continuing 72 hours post-dosing. Treatment Arms

[0063] Treatment arms include the following: 32 mg extended-release formulation of triamcinolone acetonide in 75:25 PLGA (poly(lactic-co-glycolic acid)) microspheres administered as a 5 mL IA knee injection. 40 mg immediate-release formulation of triamcinolone acetonide injectable suspension administered as a 1 mL IA knee injection. Inclusion Criteria

[0064] During the Screening Period (except as noted below), each subject must meet all of the following criteria to be enrolled in this study: 1. Male or female at least 40 years of age. 2. Type 2 diabetes mellitus for at least 1 year prior to screening. 3. Currently being treated with injectable (except insulin) and / or oral antidiabetic agents with stable doses for at least 1 month prior to screening. 4. HbA1c ^ 9.0% at screening. 5. Estimated glomerular filtration rate (eGFR) ^ 50 mL / min / 1.73 m2. 6. Triglycerides < 500 mg / dL. 7. Painful symptoms associated with OA of the knee for at least 6 months prior to screening. 8. Currently meets modified American College of Rheumatology criteria (clinical and radiological) for OA (Altman et al, 1986): a. Knee pain b. at least 1 of the following: Stiffness < 30 minutes Crepitusc. steophytes. 9. Index knee pain on most days (>15) over the last month (as reported by the subject). 10. Kellgren-Lawrence Grade of Knee X-ray of 2 or 3. Exclusion Criteria

[0065] Subjects meeting any of the following criteria (during the Screening Period, except as noted below) will be excluded from the study: 1. Reiter’s syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or arthritis associated with inflammatory bowel disease. 2. History of infection in the index knee joint. 3. Clinical signs and symptoms of active knee infection or crystal disease of the index knee within 1 month of Screening. 4. Presence of surgical hardware or other foreign body in the index knee. 5. Unstable joint (such as a torn anterior cruciate ligament) within 12 months of screening. 6. IA corticosteroid (investigational or marketed) in any joint within 3 months of screening. 7. IA hyaluronic acid (investigational or marketed) in the index knee within 6 months of screening. 8. IV or IM corticosteroids (investigational or marketed) within 3 months of screening. 9. Oral corticosteroids (investigational or marketed) within 1 month of screening. 10. Inhaled, intranasal or topical corticosteroids (investigational or marketed) within 2 weeks of screening. 11. Any other IA investigational device / drug / biologic within 6 months of screening or 5 half- lives (whichever is longer). 12. Prior arthroscopic or open surgery of the index knee within 12 months of screening. 13. Planned / anticipated surgery of the index knee or any other surgery during the study period. 14. Use of acetaminophen, or acetaminophen containing products, from screening through Day 14 (completion of post-treatment BG monitoring). 15. Subjects on Coumadins with INR ^ 5. 16. Known hypersensitivity to any form of triamcinolone. 17. History of sarcoidosis or amyloidosis. 18. Active or history of malignancy within the last 3 years with the exception of resected basal cell carcinoma, squamous cell carcinoma of the skin, or effectively managed cervical carcinoma. 19. Known active or quiescent systemic fungal, bacterial (including tuberculosis), viral or parasitic infections, or ocular herpes simplex.20. Any infection requiring intravenous IV antibiotics within 4 weeks of screening or infection requiring oral antibiotics within 2 weeks of screening. 21. History of osteomyelitis. 22. Known or clinically suspected infection with human immunodeficiency virus (HIV) or hepatitis B or C viruses. 23. Any clinically significant cardiac abnormality or clinically significant abnormal electrocardiogram (ECG) reading that will prevent IA steroid treatment as judged by the Principal Investigator. 24. Subjects requiring or likely to require treatment with corticosteroids during the study period based on subject medical history. 25. History of or active Cushing’s syndrome. 26. Active substance abuse (drugs or alcohol), history of chronic substance abuse within the last year, or prior chronic substance abuse judged by the investigator likely to recur during the study. 27. Skin breakdown at the knee where the injection would take place. 28. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 2 years of screening. 29. Has received a live or live attenuated vaccine within 3 months of screening. 30. Any other clinically significant acute or chronic psychiatric and / or medical conditions that, in the judgment of the Investigator, would preclude the use of an IA corticosteroid or nonsteroidal anti-inflammatory drugs (NSAIDs) or that could compromise subject safety, limit the subject’s ability to complete the study, and / or compromise the objectives of the study. 31. Has a positive pregnancy test at any visit, lactates or intends to become pregnant during the time period from screening through end of study. Injection Administration Procedure

[0066] IA injections will be administered by the assigned unblinded injector, who has significant experience in the administration of IA injections and has been trained on study administration procedures. The injector may choose the position of the knee (e.g., extended or bent), the approach for the injection (e.g., medial or lateral), and the numbing agent to be used (e.g., ethyl chloride or subcutaneous lidocaine; IA anesthetics are not allowed) based on standard of care. Following aspiration, 5 mL of the reconstituted TA-ER or 5 mL of TA-IR (1 mL) and normal saline (4 mL) will be injected into the synovial space. The same needle used for IA injection of the study medication may also be used for synovial fluid aspiration, thereby allowingfor a single injection with syringe replacement. The injector will use a 21-gauge needle or larger for injection and aspiration of fluid. Injection into the knee joint will be performed with ultrasound guidance. Study Endpoints

[0067] The primary endpoints of the study include the number of subjects who spend >25% of time in TAR > 180 mg / dL from baseline to post-baseline (0-3 days) for TA-ER relative to TA-IR. The secondary and exploratory endpoints include (1) number of subjects and percentage of time spent > 180 mg / dL from baseline throughout the 72 hours comparing TA-ER and TA-IR; (2) number of peaks ^250 mg / dL per subject from baseline throughout the 72 hours comparing TA-ER and TA-IR; (3) number of subjects whose insulin consumption has been increased from baseline throughout the 2 weeks after dosing by comparing TA-ER effect on BG vs. TA-IR; (4) Area under the curve (AUC) for cortisol levels after ACTH stimulation test from baseline until end-of-study comparing TA-ER vs. TA-IR (day 30); (5) group difference comparison of FBG levels prior to breakfast (confirmed by glucometer) for TA-ER relative to TA-IR; (5) comparison of study mean GMI for TA-ER relative to TA-IR, quantified using CGM derived BG values over the study period post-baseline days 1 to 15, per validated formula (Bergenstal et al., Diabetes Care 2018 Nov; 41(11): 2275–2280) as follows: GMI (%) = 3.31 + 0.02392 * [mean glucose in mg / dL]; (6) average weekly and total consumption of rescue medications over 30 days for TA-ER relative to TA-IR; (7) AUC of the change from baseline on the worst daily knee pain mean score at week 4 for TA-ER relative to TA-IR; (8) change from baseline on the average daily pain mean score at each week for TA-ER relative to TA-IR; (9) mean total change in DSC-R score for domains of psychological fatigue, psychological cognitive, and hyperglycemia, from baseline to time periods of 0 to 24 hours (days 1-2), 0 to 48 hours (days 1-3), and 0 to 72 hours (days 1-4) for TA-ER relative to TA-IR; and (10) incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs) from baseline to day 30.

[0068] Number of subjects who spend >25% of time in TAR > 180 mg / dL from baseline to post-baseline (0-3 days): To compute this endpoint, first average hourly average CGM level is calculated by taking the mean of 5 min CGM levels for each of the post-baseline 72 hours. Second, the number of hours with the hourly average levels reaching over 180 mg / dL will be counted and divided by the number of valid hours (percentage of hours > 180). Finally, the number of subjects with the percentage of hours > 180 being greater than 25% will be counted. This endpoint is analyzed with a generalized linear model with a binomial family and the logit link function (i.e., a logistic regression model) with the number of subjects in each treatmentcondition as the denominator. This model includes the fixed effect of treatment condition and relevant covariates including HbA1c.

[0069] Number of subjects and percentage of time spent > 180 mg / dL from baseline throughout 72 hours (0-3 days): This endpoint is analyzed with a generalized linear model (GLM) with a beta family and the logit link function.

[0070] Number of peaks ^250 mg / dL per subject from baseline throughout the 72 hours comparing TA-ER and TA-IR: To compute this endpoint, number of peaks for each subject is calculated by counting the number of hourly average CGM levels above 250 mg / dL that were preceded and followed by levels below 250. This endpoint is analyzed with a GLM with Poisson family with the log link function.

[0071] Number of subjects whose insulin consumption has been increased from baseline throughout the 2 weeks after dosing by comparing TA-ER effect on BG vs. TA-IR: This endpoint is analyzed as follows: (1) the change in insulin consumption from baseline to day 14 is computed, (2) those who consumed more insulin at day 15 will be flagged as such, and (3) the binary endpoint will be analyzed with Fisher’s exact test.

[0072] AUC for cortisol levels after ACTH stimulation test from baseline until end- of-study comparing TA-ER vs. TA-IR (day 30): This endpoint is analyzed by a linear model and is log or square-root transformed to approximate a normal distribution.

[0073] Change from baseline on the average daily pain mean score at each week for TA-ER relative to TA-IR: This endpoint is calculated by subtracting the baseline value from the subsequent week. The endpoint is analyzed by submitting to a longitudinal mixed-model with a random effect of subject IDS and a fixed effect of time.

[0074] Mean total change in DSC-R score for domains of psychological fatigue, psychological cognitive, and hyperglycemia: Each of these endpoints are analyzed with a linear model with the endpoint appropriately transformed if necessary.

[0075] Incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs) from baseline to day 30: This endpoint is analyzed with a GLM with a Poisson family and the log link function.

[0076] For all analyses, baseline covariates not mentioned above (e.g., age, gender, BMI, body weight at baseline) may be considered for inclusion in the models. It is expected that the TA-ER treatment meets one or more of the endpoints described herein compared to the TA- IR treatment.

Claims

WHAT IS CLAIMED IS:

1. A method of treating knee osteoarthritis pain in a diabetic subject, comprising: identifying or selecting a subject having diabetes mellitus (DM) who is at risk of suffering from hyperglycemia resulting from intra-articular injection of a corticosteroid; determining or receiving information on a baseline blood glucose level of the subject; and administering about 32 mg of an extended-release formulation of triamcinolone acetonide (TA) to the subject by a single intra-articular injection; wherein the extended-release formulation of TA is an extended-release formulation of TA comprising 75:25 molar ratio of poly (lactic-co-glycolic) acid (PLGA) microspheres; and wherein the administration of the extended-release formulation of TA reduces the percent time above a blood glucose level of 180 mg / dL during a period of time post administration when compared to an administration of 40 mg of an immediate-release formulation of TA.

2. The method of claim 1, wherein the percent time above the blood glucose level of 180 mg / dL is reduced by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

3. The method of claim 1 or 2, wherein the subject spends equal or less than about 25% of time above the blood glucose level of 180 mg / dL during the period of time post administration.

4. The method of any one of claims 1 to 3, wherein the administration of the extended- release formulation of TA also reduces the likelihood that the subject’s blood glucose level is above 180 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

5. The method of claim 4, wherein the likelihood that the subject’s blood glucose level is above 180 mg / dL is reduced by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

6. The method of any one of claims 1 to 5, wherein the administration of the extended- release formulation of TA also increases the time to reach the blood glucose level of 180 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

7. The method of claim 6, wherein the time to reach the blood glucose level of 180 mg / dL is increased by at least about 25%, 50%, 75%, 1-fold, 1.5-fold, 2-fold, 2.5 fold, 3-fold, 4-fold or 5-fold during the period of time post administration.

8. The method of any one of claims 1 to 7, wherein the administration of the extended- release formulation of TA reduces the percent time above a blood glucose level of 250 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

9. The method of claim 8, wherein the percent time above the blood glucose level of 250 mg / dL is reduced by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

10. The method of claim 8 or 9, wherein the administration of the extended-release formulation of TA also reduces the likelihood that the subject’s blood glucose level is above 250 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

11. The method of claim 10, wherein the likelihood that the subject’s blood glucose level is above 250 mg / dL is reduced by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

12. The method of any one of claims 8 to 11, wherein the administration of the extended- release formulation of TA also increases the time to reach the blood glucose level of 250 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

13. The method of claim 12, wherein the time to reach the blood glucose level of 250 mg / dL is increased by at least about 25%, 50%, 75%, 1-fold, 1.5-fold, 2-fold, 2.5 fold, 3-fold, 4- fold or 5-fold during the period of time post administration.

14. A method of treating knee osteoarthritis pain in a diabetic subject, comprising: identifying or selecting a subject having diabetes mellitus who is at risk of suffering from hyperglycemia resulting from intra-articular injection of a corticosteroid; determining or receiving information on a baseline blood glucose level of the subject; andadministering about 32 mg of an extended-release formulation of triamcinolone acetonide (TA) to the subject by a single intra-articular injection; wherein the extended-release formulation of TA is an extended-release formulation of TA comprising 75:25 molar ratio of poly (lactic-co-glycolic) acid (PLGA) microspheres; and wherein the administration of the extended-release formulation of TA reduces the likelihood that the subject’s blood glucose level is above 180 mg / dL during a period of time post administration when compared to an administration of 40 mg of an immediate- release formulation of TA.

15. The method of claim 14, wherein the likelihood that the subject’s blood glucose level is above 180 mg / dL is reduced by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

16. The method of claim 14 or 15, wherein the administration of the extended-release formulation of TA also reduces the percent time above the blood glucose level of 180 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

17. The method of claim 16, wherein the percent time above the blood glucose level of 180 mg / dL is reduced by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

18. The method of claim 16 or 17, wherein the administration of the extended-release formulation of TA also increases the time to reach the blood glucose level of 180 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

19. The method of claim 18, wherein the time to reach the blood glucose level of 180 mg / dL is increased by at least about 25%, 50%, 75%, 1-fold, 1.5-fold, 2-fold, 2.5 fold, 3-fold, 4- fold or 5-fold during the period of time post administration.

20. The method of any one of claims 14 to 19, wherein the administration of the extended- release formulation of TA reduces the likelihood that the subject’s blood glucose level is above 250 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

21. The method of claim 20, wherein the likelihood that the subject’s blood glucose level is above 250 mg / dL is reduced by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

22. The method of claim 20 or 21, wherein the administration of the extended-release formulation of TA also reduces the percent time above the blood glucose level of 250 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

23. The method of claim 22, wherein the percent time above the blood glucose level of 250 mg / dL is reduced by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

24. The method of any one of claims 20 to 23, wherein the administration of the extended- release formulation of TA also increases the time to reach the blood glucose level of 250 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

25. The method of claim 24, wherein the time to reach the blood glucose level of 250 mg / dL is increased by at least about 25%, 50%, 75%, 1-fold, 1.5-fold, 2-fold, 2.5 fold, 3-fold, 4- fold or 5-fold during the period of time post administration.

26. The method of any one of claims 1 to 25, wherein the administration of the extended- release formulation of TA increases the time to reach maximum blood glucose level during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

27. The method of claim 26, wherein the time to reach maximum blood glucose level is increased by at least about 25%, 50%, 75%, 1-fold, 1.5-fold, 2-fold, or 2.5 fold during the period of time post administration.

28. The method of any one of claims 1 to 27, wherein the administration of the extended- release formulation of TA increases the percent time within a target blood glucose range of ^ 70 mg / dL and ^ 180 mg / dL during the period of time post administration when compared to the administration of 40 mg of the immediate-release formulation of TA.

29. The method of claim 28, wherein the percent time within the target blood glucose range is increased by at least about 10%, 20%, 30%, 40% or 50% during the period of time post administration.

30. The method of any one of claims 1 to 29, wherein the subject’s insulin consumption post administration of the extended-release formulation of TA is less than the insulin consumption post administration of 40 mg of the immediate-release formulation of TA for up to 2 weeks.

31. The method of any one of claims 1 to 30, wherein the subject’s average daily knee pain intensity score during the period of time post administration of the extended-release formulation of TA is less than the average daily knee pain intensity score during the period of time post administration of 40 mg of the immediate-release formulation of TA.

32. The method of any one of claims 1 to 31, further comprising continuously monitoring the blood glucose level of the subject post injection to determine the subject’s blood glucose level during the period of time post administration.

33. The method of claim 32, wherein the continuous monitoring is conducted with a continuous glucose monitoring (CGM) device.

34. The method of any one of claim 1 to 33, wherein the period of time post administration is about or at least about 24 hours, about 48 hours, or about 72 hours.

35. The method of any one of claims 1 to 34, wherein the immediate-release formulation of TA is a 40 mg / mL injectable suspension, administered in a 1 mL intra-articular injection.

36. The method of any one of claims 1 to 35, wherein the subject having DM is being managed with one or more antidiabetic agents prior to the treatment.

37. The method of claim 36, further comprising adjusting the dosage of the one or more antidiabetic agents when the subject’s blood glucose level is above the target blood glucose range of ^ 70 mg / dL and ^ 180 mg / dL.

38. The method of any one of claims 1 to 37, wherein the subject has had type 1 DM for at least 1 year prior to the treatment.

39. The method of any one of claims 1 to 37, wherein the subject has had type 2 DM for at least 1 year prior to the treatment.

40. The method of any one of claims 1 to 39, wherein the subject having DM has a hemoglobin A1c (HbA1c) level ^ 9.0% before the start of the treatment.

41. The method of claim 40, wherein the subject having DM has a hemoglobin A1c (HbA1c) level ^ 6.5% and <9.0% before the start of the treatment.

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