Methods for Treating Overweight and Obesity

Abstract

To provide effective treatment of overweight and obesity in subjects at increased risk of adverse cardiovascular outcomes.SOLUTION: The present disclosure relates to compositions, kits, uses, systems and methods for treating overweight and obesity using naltrexone plus bupropion, preferably in combination with a comprehensive web-based and / or telephone-based weight management program, and preferably in subjects at increased risk of adverse cardiovascular outcomes.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application is not a provisional application and claims priority to U.S. Provisional Patent Application No. 61 / 656,451, filed June 6, 2012, which is incorporated by reference in its entirety herein where permitted.

[0002] The present disclosure relates to compositions, kits, uses, systems and methods for treating overweight and obesity, possibly in subjects at increased risk of adverse cardiovascular outcomes, using naltrexone plus bupropion, preferably in combination with a comprehensive web-based and / or telephone-based weight management program. [Background technology]

[0003] Obesity is defined by the body mass index (BMI), which is weight (kg) / [height (m)]. 2 According to guidelines from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), for adults aged 20 years and older, BMI is classified as follows: <18.5 is underweight, 18.5-24.9 is normal, 25.0-29.9 is overweight, and ≥30.0 ​​is considered obese. (World Health Organization, General Status: Use and Interpretation of Anthropometric Measurements, Geneva, Switzerland: World Health Organization, 1995, WHO Technical Report Series).

[0004] The prevalence of obesity has increased significantly over the past 30 years, with 32% of men and 36% of women considered obese. These individuals are at increased risk for a variety of chronic conditions associated with obesity, including type 2 diabetes, coronary artery disease, hypertension, stroke, dyslipidemia, gallbladder disease, sleep apnea, certain types of cancer, and osteoarthritis, as well as the risk of death from all causes (NHLBI Clinical Guidelines, 1998). Overweight and obesity are also associated with increased all-cause mortality.

[0005] Diet- and exercise-based behavior modification is the mainstay of weight management therapy. However, such interventions often have limited effectiveness and are difficult to achieve with individual adherence. Therefore, pharmacotherapy has been adopted as an adjunct to diet and exercise. Orlistat, lorcaserin, and phentermine / topiramate are the only three drugs currently approved in the United States for the long-term treatment of obesity. A weight loss of 5–10% has been determined to translate into significant medical benefit. Orlistat has a favorable safety profile, but can cause loose stools and fecal incontinence, making patient acceptance difficult. Bariatric surgery (particularly gastric banding) is now recommended for patients with at least one obesity-related comorbidity and a BMI of 30 kg / m. 2 Although effective in most cases, it is invasive and can be associated with complications including infection, death, hypoglycemia, failure to lose weight, gastrointestinal symptoms, nutritional deficiencies, depression, sexual and relationship problems, and non-compliance with behavioral suggestions.

[0006] U.S. Patent Nos. 7,375,111 and 7,462,626 disclose a combination of naltrexone and bupropion (NB) for weight loss therapy. Wadden et al. (2011) 19:110-120) discloses a combination of naltrexone and bupropion as an adjunct to an intensive behavior modification (BMOD) program for weight loss. The BMOD program described by Wadden et al. was administered to groups of 10 to 20 people. Group meetings lasted 90 minutes and were held weekly for the first 16 weeks, once every other week for the next 12 weeks, and once a month thereafter (for a total of 28 meetings). Group meetings typically began with a review of participants' eating and activity logs and other topics. Then, during the first 16 weeks, the group leader introduced new topics related to weight control, including dietary planning, stimulus control, slow eating, problem-solving, social support, and addressing high-risk conditions. Subsequent meetings will address techniques needed to maintain weight loss. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 7,375,111 [Patent Document 2] U.S. Patent No. 7,462,626 [Patent Document 3] U.S. Patent Application Publication No. 2007 / 0275970 [Patent Document 4] U.S. Patent Application Publication No. 2007 / 0270450 [Patent Document 5] U.S. Patent Application Publication No. 2007 / 0117827 [Patent Document 6] U.S. Patent Application Publication No. 2007 / 0179168 [Patent Document 7] U.S. Patent Application Publication No. 2008 / 0214592 [Patent Document 8] U.S. Patent Application Publication No. 2007 / 0128298 [Patent Document 9] U.S. Patent Application Publication No. 2007 / 0129283 [Patent Document 10] U.S. Patent Application No. 12 / 751970 [Patent Document 11] U.S. Patent Application Publication No. 61 / 167486 [Patent Document 12] U.S. Patent Application Publication No. 61 / 293844 [Patent Document 13] WO 2009 / 158114 [Patent Document 14] U.S. Patent Application Publication No. 2008 / 0113026 [Patent Document 15] U.S. Patent Application Publication No. 2007 / 0281021 [Patent Document 16] U.S. Patent Application Publication No. 2008 / 0110792 [Non-patent literature]

[0008] [Non-Patent Document 1] Obesity(2011) 19:110-120 [Non-patent document 2] "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, PA, 18th edition, 1990 [Non-patent document 3] Wadden et al. “A two-year randomized trial of obesity treatment in primary care practice” N Eng J.Med.2011, 365(21):1969~1979 [Non-patent document 4] Tsai et al. “A primary care intervention for weight loss: results of a randomized controlled pilot study” Obesity, 2010, 18(8): 1614–1618 Summary of the Invention [Problem to be solved by the invention]

[0009] Although the combination of naltrexone and bupropion, alone or in combination with an intensive BMOD program, is known to be effective in weight management for some patient populations, there is a need for an effective treatment of overweight or obesity in subjects at increased risk of adverse cardiovascular outcomes.Furthermore, there is a need for a weight management program for use in combination with naltrexone and bupropion that is easier for patients to comply with than existing BMOD programs, yet is effective, particularly in subjects at increased risk of adverse cardiovascular outcomes. [Means for solving the problem]

[0010] One embodiment of the present invention includes a method of treating a subject for overweight or obesity who is at increased risk of an adverse cardiovascular outcome, the method comprising identifying an overweight or obese subject who is at increased risk of an adverse cardiovascular outcome, and administering to the subject therapeutically effective amounts of extended-release naltrexone, or a pharmaceutically acceptable salt thereof, and extended-release bupropion, or a pharmaceutically acceptable salt thereof. In some embodiments, overweight or obese subjects are selected from the group consisting of: a) a history of myocardial infarction documented more than three months prior to identification; a history of coronary revascularization, including coronary artery bypass graft surgery, stent placement, percutaneous transluminal coronary angioplasty, or laser atherectomy; a history of carotid or peripheral revascularization, including carotid endarterectomy, atherectomy for lower extremity atherosclerotic disease, abdominal aortic aneurysm repair, or femoral or popliteal bypass; angina pectoris with ischemic changes on graded exercise stress test or positive cardiac imaging study, ECG changes; ankle-brachial index less than 0.9 assessed by simple palpation within two years prior to identification; a history of coronary, carotid, or other arterial hyperplasia within two years prior to identification; A subject is identified as being at increased risk for adverse cardiovascular outcomes if they have been diagnosed with cardiovascular disease with at least one risk factor selected from the group consisting of: a) 50% or greater stenosis of the arteries of the lower extremities; and / or b) type 2 diabetes with at least two risk factors selected from the group consisting of: high blood pressure controlled with or without medication to less than 145 / 95 mmHg; dyslipidemia requiring medication; low HDL cholesterol documented to be less than 50 mg / dL for women and less than 40 mg / mL for men within 12 months prior to identification; and current tobacco smoker.

[0011] In some embodiments, the method further includes a two-week run-in period during which the subject is treated with one of two sequences: a test active agent comprising sustained-release naltrexone, or a pharmaceutically acceptable salt thereof, and sustained-release bupropion, or a pharmaceutically acceptable salt thereof, once daily for one week, followed by a placebo once daily for one week; or a placebo for one week, followed by one week of a test active agent comprising sustained-release naltrexone, or a pharmaceutically acceptable salt thereof, and sustained-release bupropion, or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the subject is diagnosed with myocardial infarction within three months prior to identification; angina pectoris, grade III or IV according to the Canadian Cardiovascular Society classification; a clinical history of cerebrovascular disease, including stroke; a history of tachyarrhythmia other than sinus tachycardia; a blood pressure equal to or greater than 145 / 95 mmHg despite treatment with antihypertensive medications; weight instability within three months prior to identification; planned bariatric surgery, cardiac surgery, or coronary angioplasty; severe renal impairment defined as a predicted GFR of less than 30 mL / min; a clinical history of liver failure or documented ALT or AST greater than three times the upper limit of normal; known infection with HIV or hepatitis; long-term opioid use or a positive opioid screen; recent drug or alcohol abuse or dependence within six months prior to identification other than nicotine dependence; a history of seizures, including febrile convulsions, cranial trauma, or other conditions that predispose the subject to seizures; a history of mania, or a recent diagnosis of active psychosis, active binge eating disorder, or anorexia nervosa; risk of suicide attempts; acute depressive illness, including new onset of depression or acute exacerbation of symptoms, in subjects not stable on long-term treatment for depression; any condition with an expected life expectancy of less than 4 years, including congestive heart failure NYHA class 3 or 4; history of malignancy within the past 5 years, excluding non-melanoma skin cancer or surgically treated cervical cancer; recent use of other bupropion- or naltrexone-containing products; history of hypersensitivity or intolerance to naltrexone or bupropion; use of a monoamine oxidase inhibitor within 14 days prior to identification; use of any investigational drug, device, or procedure within 30 days prior to identification; pregnant or lactating women, or women recently trying to become pregnant, or women of childbearing potential, including perimenopausal women who have had a menstrual cycle within the past year and who do not consent to birth control practices; and lack of consistent access to broadband internet.

[0013] In some embodiments, the method further comprises providing the subject with a web-based weight management program, a phone-based weight management program, or a combination thereof.

[0014] One embodiment of the present invention includes a method of treating a subject for overweight or obesity comprising identifying an overweight or obese subject and administering to the subject a therapeutically effective amount of sustained-release naltrexone or a pharmaceutically acceptable salt thereof and sustained-release bupropion or a pharmaceutically acceptable salt thereof in combination with a web-based weight management program, a telephone-based weight management program, or a combination thereof.

[0015] In some embodiments, the identified subject has a blood pressure of 30 to 45 kg / m 2 In some embodiments, the identified subject has a BMI of 27 to 45 kg / m 2 and have a BMI below 18.5 and are associated with dyslipidemia and / or controlled hypertension. In some embodiments, the subject is treated for at least 26 weeks. In some embodiments, the telephone-based weight management program includes one or more coaching calls to the subject. In some embodiments, the telephone-based weight management program optionally includes one or more web-based coaching tools. In some embodiments, the web-based or telephone-based weight management program provides one or more behavioral, nutritional, or fitness education sessions to the subject.

[0016] In some embodiments, education is provided by trained health or fitness instructors and / or certified dietitians.In some embodiments, trained health or fitness instructors and / or certified dietitians provide advice to subjects via telephone or through websites for subjects, and provide one or more of the following topics selected from the group consisting of tips and motivational messages; guidance through Q&A; weekly consultation time for subject's immediate response via websites for questions; weekly educational materials; video lessons; weight, exercise or diet tracking with badge awarding; goal setting; progress tracking; and communication to encourage subjects to engage in weight management program.

[0017] In some embodiments, the subject is administered 32 mg of sustained-release naltrexone or a pharmaceutically acceptable salt thereof per day and 360 mg of sustained-release bupropion or a pharmaceutically acceptable salt thereof per day. In some embodiments, the subject is administered sustained-release naltrexone or a pharmaceutically acceptable salt thereof and sustained-release bupropion or a pharmaceutically acceptable salt thereof as a tablet containing 8 mg of sustained-release naltrexone and 90 mg of sustained-release bupropion.

[0018] In some embodiments, treatment with naltrexone and bupropion does not increase the risk of adverse cardiovascular outcomes in patients. In some embodiments, treatment with naltrexone and bupropion reduces the risk of adverse cardiovascular outcomes in patients. In some embodiments, the adverse cardiovascular outcomes are cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. In some embodiments, the subject achieves a weight loss rate of at least 5%, at least 10%, or at least 15%. In some embodiments, the weight management program is conducted for at least 52 weeks or at least 78 weeks.

[0019] In some embodiments, the subject does not receive face-to-face counseling as part of the weight management program. In some embodiments, the subject does not receive more than five face-to-face counseling sessions as part of the weight management program. In some embodiments, the subject does not receive an intensive behavior modification (BMOD) program for weight loss. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure relates to compositions, kits, uses, systems, and methods for treating overweight and obesity using naltrexone and bupropion, preferably in combination with a comprehensive lifestyle intervention (CLI) program, including web-based weight management programs, telephone-based weight management programs, and combinations thereof. In some embodiments, the subject being treated for overweight and obesity is a subject at increased risk of adverse cardiovascular outcomes. In preferred embodiments, treatment of subjects at increased risk of adverse cardiovascular outcomes with naltrexone and bupropion in combination with a web-based and / or telephone-based comprehensive weight management program does not result in serious adverse cardiovascular outcomes, as does treatment with a web-based and / or telephone-based weight management program alone. In some embodiments, treatment of subjects at increased risk of adverse cardiovascular outcomes with naltrexone and bupropion in combination with a web-based and / or telephone-based comprehensive weight management program surprisingly results in fewer serious adverse cardiovascular outcomes than treatment with a web-based and / or telephone-based weight management program alone. Serious adverse cardiovascular outcomes are cardiovascular death (including fatal myocardial infarction and fatal stroke), nonfatal myocardial infarction, nonfatal stroke, or nonfatal unstable angina requiring hospitalization.

[0021] In some embodiments, subjects treated with the methods disclosed herein are at increased risk for adverse cardiovascular outcomes. Subjects at increased risk for adverse cardiovascular outcomes include those with: a) a history of myocardial infarction documented more than 3 months prior to screening; a history of coronary revascularization (i.e., coronary artery bypass graft surgery, stent placement, percutaneous transluminal coronary angioplasty, or laser atherectomy); a history of carotid or peripheral revascularization (i.e., carotid endarterectomy, atherectomy for lower extremity atherosclerotic disease, abdominal aortic aneurysm repair, femoral or popliteal bypass); ischemic changes (resting ECG) based on a graded exercise stress test (GXT) or positive cardiac imaging study, angina pectoris with ECG changes; or a history of angina pectoris within the past 2 years. Subjects with a) ankle-brachial index of less than 9 (assessed by simple palpation); cardiovascular disease (definite or probable diagnosis of cardiovascular disease) with at least one of the following within the past two years: coronary, carotid, or lower extremity artery stenosis of 50% or more; and / or b) hypertension (controlled with or without medication to less than 145 / 95 mmHg); dyslipidemia requiring medication; low HDL cholesterol (less than 50 mg / dL for women, less than 40 mg / dL for men) recorded within the past 12 months; and type 2 diabetes with at least two of the following among current tobacco smokers.

[0022] In some such embodiments, the subject being treated is not complicated with obesity. In some other embodiments, the subject being treated is overweight and has dyslipidemia and / or controlled hypertension. In some embodiments, the subject being treated by the methods disclosed herein is not at increased risk of adverse cardiovascular outcomes.

[0023] In some embodiments, treatment with naltrexone and bupropion is combined with a weight management program. In some embodiments, the weight management program is a web-based program. In some other embodiments, the weight management program is a telephone-based program. In some other embodiments, the weight management program is a combination of both web-based and telephone-based programs. In some embodiments, the subject does not receive more than 15, 10, 5, 4, 3, 2, or 1 face-to-face counseling session as part of the weight management program. In some embodiments, the subject does not receive more than 1 face-to-face counseling session as part of the weight management program.

[0024] <Web-based weight management program> Preferably, the web-based program provides a progressive nutrition and fitness program with goal setting and tracking tools. Each subject is assigned a health and fitness professional who will provide online guidance throughout the program. Additional educational tools include web-based weekly information, education, and motivational strategies, supplemented by video lessons (Table 1) provided at regular intervals. Program content consisted of a weekly email informing participants of the week's goals, providing motivation, and encouraging continued participation; weekly goals (from the email) listing each week's theme (Table 1) along with detailed explanations and strategies for achieving these goals placed on the MyWeightMate.com subject page; three additional pieces of content (tips and educational information) posted each week to help participants reach their weekly goals; motivational messages posted to the participant's page throughout the week; motivating emails sent to users based on behavior (i.e., non-participation in program activities, successful implementation records); video lessons provided on the MyWeightMate.com site for participants to view and archived for future access; and two update invitations, including weekly for the first 16 weeks, biweekly for the next 12 weeks, monthly for the remainder of the study, and once every four weeks during each of the third and fourth trial years. The video lessons focused on relevant topics and were developed by subject matter experts.

[0025] [Table 1]

[0026] The web-based weight management program provides behavioral, nutritional, and fitness education delivered by trained health and fitness instructors. The website offers a "WeightMate Coach" who counsels participants via their individual web pages and provides one or more of: tips and motivational messages; coaching via Q&A; weekly consultation hours for immediate response via the website; weekly educational materials; content developed by subject matter experts; video lessons to complement the weekly themes; weight, exercise, and diet tracking with badge awards; activity suggestions and coaching tips; communication to encourage engagement; and a fun, intuitive, and modern website.

[0027] In one embodiment, a new theme and goal is introduced each Monday, and two to three goals for the week are provided along with related content and / or video lessons (Table 1), and motivational messages are provided one or more days of the week. Optionally, additional tips are provided one or more days during the week. In some embodiments, the video lessons supplement the weekly educational theme. Produced video content ensures quality and uniformity of messages to the subject, and a Q&A feature allows patients to ask questions with a turnaround time of less than 24 hours.

[0028] In some embodiments, web-based individual counseling is provided by a trainer, and preferably, the subject does not have limited access to the trainer. Preferably, the trainer provides the subject with a schedule including weekly "consultation times" for instant Q&A responses. The program emphasizes daily food and activity tracking along with weekly weigh-ins. Preferably, the website uses a computer database of calories for specific foods and / or meals to track calories for each meal and can control preferred foods and meals. Four reference menus are provided based on calorie needs and food preferences. In some embodiments, subjects are awarded badges upon meeting individual goals (e.g., 7-day activity log; 7-day food log; 3-week weight log; first 15 lb weight loss; 12 weeks of program participation; 26 weeks of program participation; 52 weeks of program participation; 78 weeks of program participation; 5% weight loss; 10% weight loss; 15% weight loss). In a preferred embodiment, subjects regularly set weight loss goals that are recorded as part of the program. The subject's progress toward the goal can be provided to the subject via the subject's webpage. The weight loss goal can be for a period of one week, two weeks, one month, two months, six months, one year, or longer. The program provides the participating subject with the option to set a specific weight loss goal at the time of program initiation. The program also provides the option to track and record weight loss and progress toward achieving the specific goal on a daily or weekly basis. Optionally, a graphical display of weight loss progress is provided to the subject via the subject's webpage. Periodic encouraging messages (e.g., badges and award notes) can be provided. Preferably, automated messages from a behavior-based trainer are provided to increase motivation and participation.

[0029] In some embodiments, the exercise portion of the web-based weight management program encourages five days of activity and two days of rest, preferably non-consecutive days (e.g., Monday and Friday). In some embodiments, the exercise program provides instructions for stretching, walking, and other light cardio activities. Short videos can provide educational demonstrations of stretching and exercise movements. The website can track calories burned by the subject through exercise and activity logging.

[0030] In a preferred embodiment, the web-based weight management program does not involve any face-to-face therapy or group meetings.

[0031] <Phone-based weight management program> In some embodiments, the telephone-based program includes personalized instruction via one or more phone calls. In one embodiment, the calls to the treated subject are conducted by a dedicated instructor. In another embodiment, the calls to the treated subject are conducted by a registered dietitian. In some such embodiments, the telephone-based program includes 6 to 15, preferably 12, scheduled calls over the first 3 to 8 months, preferably 6 months, of treatment. Topics for the scheduled calls can include cognitive-behavioral instruction and nutritional instruction (see, e.g., Table 2). In some such embodiments, the telephone-based program includes 6 to 15, preferably 12, additional calls over the next 3 to 8 months, preferably 6 months, of treatment.

[0032] In some embodiments, the telephone-based program optionally includes online coaching tools, such as an integrated web support for web-based coaching, including the web-based program. The web-based coaching can include essential practices for weight loss and weight loss maintenance, progress tracking, and / or virtual coaching. Non-limiting examples of essential practices can include e-lessons, videos, podcasts, articles, and games related to topics such as healthy cooking, realistic goal setting, and stress management. Non-limiting examples of items that the progress tracking tool can track include weight, nutritional intake, activity, stress, biometrics, coaching calls, etc. Non-limiting examples of virtual coaching can include creating and updating to-do lists, sending emails, etc. for subjects participating in the program.

[0033] In some embodiments, the phone-based program can also optionally include one or more electronic devices for wireless activity monitoring. A non-limiting example of such an electronic device is the FitLinxx® ActiPed, which is intended to be used with a USB access point to track steps, distance, calories, and active minutes. The electronic device can be wirelessly synchronized with web assistance. In one embodiment, the phone-based program is the Weight Talk® Program available from Alere™.

[0034] Subjects receiving naltrexone and bupropion therapy can enroll in the telephone-based program through a variety of methods, including both web-based and telephone enrollment. In some embodiments, the telephone-based program also includes front-line assistance to identify patients eligible for the clinical study, discuss the benefits of the telephone-based program, set realistic expectations, assist with enrollment, and ask specific questions of instructors.

[0035] [Table 2]

[0036] In preferred embodiments, treatment with a sustained-release (SR) naltrexone / sustained-release bupropion combination (NB), alone or in combination with a web-based and / or telephone-based weight management program, does not increase, or more preferably reduces, the incidence of major adverse cardiac events defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in overweight and obese subjects compared to placebo or a web-based and / or telephone-based weight management program alone. In some embodiments, treatment with NB, alone or in combination with a web-based and / or telephone-based weight management program, does not increase, or more preferably reduces, the incidence of one or more of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or non-fatal unstable angina requiring hospitalization in overweight and obese subjects compared to placebo or a web-based and / or telephone-based weight management program alone. In some embodiments, treatment with NB alone or in combination with a web-based and / or telephone-based weight management program does not increase or more preferably reduces one or more of the following: incidence of all-cause mortality; incidence of unstable angina requiring hospitalization; and incidence of coronary revascularization procedures compared to placebo or a web-based and / or telephone-based weight management program alone. In some embodiments, treatment with NB alone or in combination with a web-based and / or telephone-based weight management program reduces weight or improves systolic and / or diastolic blood pressure compared to placebo or a web-based and / or telephone-based weight management program alone. In some embodiments, the individual being treated is overweight or obese and is at increased risk of adverse cardiovascular outcomes.

[0037] In some embodiments, treatment with the extended-release (SR) naltrexone / extended-release bupropion combination (NB), alone or in conjunction with a web-based and / or telephone-based weight management program, increases one or more of the following compared to usual care (no study drug and minimal lifestyle intervention program): percent change from baseline in body weight; proportion of subjects achieving a weight loss of at least 5%, 10%, and 15% of baseline body weight; and absolute change from baseline in body weight. In some embodiments, NB treatment alone or in combination with a web-based and / or telephone-based weight management program improves one or more of the following compared to usual care (no study drug and minimal lifestyle intervention program): cardiovascular risk factors (one or more of waist circumference, fasting triglycerides, fasting LDL cholesterol, and fasting HDL cholesterol); vital signs (one or more of systolic and / or diastolic blood pressure, heart rate); glucose metabolism measures (one or more of fasting glucose, fasting insulin, and HOMA-IR); and patient-reported outcome measures (one or more of eating behavior (e.g., BES), sexual function (e.g., ASEX scale), and weight-related quality of life (e.g., IWQOL-Lite)). In some embodiments, the increase or improvement is measured relative to baseline at 26 weeks of treatment, and in some embodiments, measurements are made relative to baseline at 52 or 78 weeks of treatment. In some embodiments, the individual being treated has a BMI of 30 or greater than 45 kg / m in subjects with uncomplicated obesity. 2 Subjects who are overweight or obese and have dyslipidemia and / or controlled hypertension, and a BMI of 27 to 45 kg / m 2 The individual being treated is a woman or a man between the ages of 18 and 60 (inclusive). In some embodiments, the individual being treated is overweight or obese and at increased risk of adverse cardiovascular outcomes. In some embodiments, the individual being treated is not overweight or obese and at increased risk of adverse cardiovascular outcomes.

[0038] In some embodiments, treatment with a sustained-release (SR) naltrexone / sustained-release bupropion combination (NB) in combination with a web-based and / or telephone-based weight management program results in a comparable or greater increase in one or more of the following: percent change from baseline in body weight; proportion of subjects achieving a weight loss of at least 5%, 10%, and 15% of baseline body weight; and absolute change from baseline in body weight, compared to NB in ​​combination with a face-to-face delivered intensive behavior modification (BMOD) program for weight loss. In some embodiments, NB treatment alone or in combination with a web-based and / or telephone-based weight management program improves one or more of the following: cardiovascular risk factors (one or more of waist circumference, fasting triglycerides, fasting LDL cholesterol, and fasting HDL cholesterol); vital signs (one or more of systolic and / or diastolic blood pressure and heart rate); glucose metabolism measures (one or more of fasting glucose, fasting insulin, and HOMA-IR); and patient-reported outcome measures (e.g., eating behavior (e.g., BES), sexual function (e.g., ASEX scale), and weight-related quality of life (e.g., IWQOL-Light)) to a similar or greater extent than NB in ​​combination with an intensive behavior modification (BMOD) program delivered in-person for weight loss. In some embodiments, the increase or improvement is measured relative to baseline at 26 weeks of treatment, and in some embodiments, the measurement is measured relative to baseline at 52 or 78 weeks of treatment. In some embodiments, the individual being treated has a BMI of 30 or greater than 45 kg / m in subjects with uncomplicated obesity. 2 The following are overweight or obese individuals with dyslipidemia and / or controlled hypertension: BMI 27 to 45 kg / m 2The individual being treated is a woman or a man between the ages of 18 and 60 (inclusive). In some embodiments, the individual being treated is overweight or obese and at increased risk for adverse cardiovascular outcomes. In some embodiments, the individual being treated is not overweight or obese and at increased risk for adverse cardiovascular outcomes.

[0039] In some embodiments, the individual has a body weight of at least 25 kg / m 2 In some embodiments, the individual has a body mass index (BMI) of at least 30 kg / m 2 In some embodiments, the individual has a body mass index (BMI) of at least 40 kg / m 2 In some embodiments, the individual has a body mass index (BMI) of 25 kg / m 2 Have a body mass index (BMI) of less than or equal to 25 kg / m during the course of naltrexone and bupropion administration 2 In these embodiments, for health or cosmetic purposes, it may be beneficial to further reduce BMI by reducing subsequent weight gain or promoting weight loss. In some embodiments, the individual has been diagnosed by a doctor as being overweight or obese. In some embodiments, the individual is identified as being overweight or obese, for example, self-identified, or identified as being diagnosed as being overweight or obese. In some embodiments, the individual, in addition to being overweight or obese, suffers from dyslipidemia and / or controlled hypertension.

[0040] In some embodiments, the promotion of weight loss is measured by a percentage change from baseline weight. In some of these embodiments, the amount of weight loss is 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15% or more, about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15% or more, or at least any of the values ​​above is 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15% or more, at least about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15% or more, or a range defined by any two of the foregoing values. In some embodiments, the promotion of weight loss is measured as a reduction in weight gain compared to the amount of weight gain experienced by a relevant control, and the amount of reduction in weight gain is about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 105%, 110%, 115%, 120%, or greater. 110%, 115%, 120% or more; at least 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 105%, 110%, 115%, 120% or more; at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 105%, 110%, 115%, 120% or more; or a range defined by any two of the foregoing values.

[0041] In some embodiments, the dose is adjusted so that the patient loses weight at a rate of about 3% of baseline weight every six months, although the rate of the patient's weight loss can be adjusted by the treating physician based on the patient's particular needs.

[0042] In some embodiments, reducing weight gain or promoting weight loss occurs by increasing satiety in the individual. In some embodiments, reducing weight gain or promoting weight loss occurs by suppressing the appetite of the individual. In some embodiments, treatment involves formulating a dietary regimen and / or increasing activity.

[0043] In some embodiments, the combination therapy, such as naltrexone or naltrexone in combination with bupropion or fluoxetine, is in an amount sufficient to affect weight loss, reduce cardiovascular risk factors, increase insulin sensitivity, reduce food cravings, treat visceral fat symptoms, reduce weight gain or promote weight loss during smoking cessation, or provide weight loss therapy in patients with major depression. Non-limiting examples of such methods of treatment are described in U.S. Patent Nos. 7,375,111 and 7,462,626; U.S. Patent Application Publication Nos. 2007 / 0275970, 2007 / 0270450, 2007 / 0117827, 2007 / 0179168, 2008 / 0214592, 2007 / 0128298, 2007 / 0129283; U.S. Patent Application Nos. 12 / 751970, 61 / 167486 and 61 / 293844; and WO No. 2009 / 158114, each of which is incorporated herein by reference in its entirety and for all purposes, including but not limited to, describing methods for affecting weight loss, reducing cardiovascular risk factors, increasing insulin sensitivity, reducing food cravings, treating visceral fat symptoms, reducing weight gain or promoting weight loss during smoking cessation, and providing weight loss therapy in patients with major depression. In some embodiments, the cardiovascular risk factors include one or more of the following: total cholesterol level, LDL cholesterol level, HDL cholesterol level, triglyceride level, glucose level, and insulin level. In some embodiments, the cardiovascular risk factors include one or more of the following: total cholesterol level, HDL cholesterol level, and triglyceride level.

[0044] In some embodiments, increased efficacy of a weight loss treatment described herein includes an improvement in an outcome measure. For example, in some embodiments, increased efficacy increases the amount of weight loss. In some embodiments, increased efficacy reduces the frequency or severity of adverse events, such as, but not limited to, nausea, constipation, vomiting, dizziness, dry mouth, headache, and insomnia. In some embodiments, increased efficacy improves another secondary endpoint, such as, but not limited to, waist circumference, high-sensitivity C-reactive protein (hs-CRP) levels, triglyceride levels, HDL cholesterol levels, or the ratio of LDL / HDL cholesterol levels. As one of ordinary skill in the art will recognize, in some circumstances, it is desirable to decrease waist circumference, hs-CRP levels, triglyceride levels, and the ratio of LDL / HDL cholesterol levels, and increase HDL cholesterol levels. In some embodiments, the improvement in the outcome measure is about, at least, or at least about 1, 2, 3, 4, 5, 7, 10, 12, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or within a range defined by any two of these values, compared to baseline or a relevant control.

[0045] In some embodiments, naltrexone or naltrexone and bupropion are each administered once a day.In some embodiments, naltrexone and bupropion are each divided into equal doses and administered twice or more times a day.In some embodiments, naltrexone and bupropion are each divided into unequal doses and administered twice or more times a day.In some embodiments, naltrexone and bupropion are divided into different doses and administered twice or more times a day.In one such embodiment, one dose of naltrexone or bupropion is divided, but the other dose is not divided.

[0046] In some embodiments, one or both of naltrexone and bupropion are administered once, twice, three times, four or more times per day. Either or both compounds can be administered less than once per day, for example, every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or once per week or every two weeks, or a range defined by any two of the foregoing values. In some embodiments, the number of administrations per day is constant (e.g., once per day). In other embodiments, the number of administrations is variable. The number of administrations may vary depending on the efficacy of the dosage form, observed side effects, external factors (e.g., changes in another medication), or the length of time the dosage form has been administered.

[0047] In some embodiments, the daily dose of naltrexone may range from about 4 mg to about 50 mg, or from about 4 mg to about 32 mg, or from about 8 mg to about 32 mg, or from about 8 mg to about 16 mg. In some embodiments, the daily dose is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg, or about 48 mg of naltrexone, or a range defined by any two of the foregoing values. Selection of a specific dose may be based on the patient's weight. Selection of a specific dose may also be based on the identity, dose, and / or dosing schedule of other co-administered compounds. However, in some embodiments, it may be necessary to use a dose outside these ranges. In some embodiments, the daily dose is administered in a single oral dosage form. In some embodiments, the daily dose of naltrexone is the same, and in some embodiments, the daily doses are different.

[0048] In some embodiments, the daily dose of bupropion may range from about 30 mg to about 500 mg, or from about 30 mg to about 360 mg, or from about 90 mg to about 360 mg. In some embodiments, the daily dose is about 30 mg, about 90 mg, about 180 mg, about 360 mg, or about 450 mg of bupropion, or a range defined by any two of the foregoing values. Selection of a specific dose may be based on the patient's weight. Selection of a specific dose may also be based on the identity, dose, and / or dosing schedule of other co-administered compounds. However, in some embodiments, it may be necessary to use a dose outside these ranges. In some embodiments, the daily dose is administered in a single oral dosage form. In some embodiments, the daily dose of bupropion is the same, and in some embodiments, the daily doses are different.

[0049] The compositions described herein can be distributed, provided to patients for self-administration, or administered to individuals. In some embodiments, the combination naltrexone / bupropion therapy includes a third compound.

[0050] In some embodiments, naltrexone and / or bupropion are provided or administered as an oral dosage form. In some embodiments, the oral dosage form is in the form of a pill, tablet, uncoated tablet, capsule, caplet, loose powder, liquid, or suspension. In preferred embodiments, the oral dosage form is in the form of a pill, tablet, or capsule. In some embodiments, the combined naltrexone / bupropion therapy is provided in a single oral dosage form. In some embodiments, the oral dosage form is in the form of a trilayer tablet, as described in U.S. Patent Application Publication No. 2008 / 0113026, the entire contents of which are incorporated herein by reference and for all purposes, including, but not limited to, purposes of describing trilayer tablets, methods of making and formulating trilayer tablets, and methods of administering them.

[0051] In some embodiments, at least one of naltrexone and bupropion is administered at a varying frequency during treatment. In some of these embodiments, the varying frequency includes a decreasing frequency over time. For example, one or both of naltrexone and bupropion may be initially administered twice or more times daily, and then administered only once daily at a later time point in treatment. In some embodiments, the daily dose of at least one of naltrexone and bupropion remains consistent despite the varying administration frequency. For example, in some embodiments, two tablets of naltrexone and bupropion are initially administered twice daily, but four tablets of naltrexone and bupropion are administered once daily at a later time point in treatment. Alternatively, in some embodiments, one or two tablets of naltrexone and bupropion are administered at a later time point in treatment, with the one or two tablets having a total daily dose equivalent to the two tablets of naltrexone and bupropion initially administered twice daily.

[0052] In some embodiments, one or both of the naltrexone and bupropion are administered less than once daily in a controlled-release or sustained-release (SR) formulation, the dose of which is selected so that the patient receives a daily dose that is approximately the same as the daily doses described herein.

[0053] In some embodiments, the naltrexone, alone or in combination therapy, is not in a sequestered form. For example, in some embodiments, the naltrexone is in a non-sequestered controlled-release formulation. In some embodiments, the naltrexone is in a non-sequestered sustained-release formulation. In preferred embodiments, at least 50% of the naltrexone is released within 24 hours of administration.

[0054] In some embodiments, at least one of naltrexone or bupropion is administered at a consistent daily dose throughout the treatment period. In some embodiments, at least one of naltrexone or bupropion is administered at a varying daily dose throughout the treatment period. In some of these embodiments, the daily dose comprises a daily dose that increases over time. In some of these embodiments, the daily dose comprises a daily dose that decreases over time.

[0055] In some embodiments, naltrexone and bupropion are administered separately. In some embodiments, naltrexone and bupropion are administered in a single pharmaceutical composition containing naltrexone and bupropion. In some embodiments, at least one of naltrexone or bupropion is in a sustained-release or controlled-release formulation. For example, sustained-release forms of naltrexone are described in U.S. Patent Application Publication No. 2007 / 0281021, which is incorporated herein by reference in its entirety and for all purposes, including but not limited to, for purposes of describing sustained-release forms of naltrexone and bupropion, how to make them and formulate them into suitable dosage forms, and how to administer them. In some embodiments, at least one of naltrexone or bupropion is administered with a physiologically acceptable carrier, diluent, or excipient, or a combination thereof. Non-limiting examples of naltrexone / bupropion combinations, their formulations, and methods of administering them are disclosed in U.S. Patent Nos. 7,375,111 and 7,462,626, both of which are incorporated herein by reference in their entirety and for all purposes, including but not limited to, for purposes of describing naltrexone and bupropion combinations, how to make them and formulate them into suitable dosage forms, and how to administer them. References herein to the use or administration of naltrexone and naltrexone / bupropion combinations are understood to include all modes of administration disclosed or mentioned herein, including, but not limited to, individual administration, administration in a single dosage form, administration in the form of a salt and / or metabolite, and / or administration in sustained-release form. Techniques for formulating and administering the compounds of the present application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th Edition, 1990, which is incorporated herein by reference in its entirety.

[0056] In some embodiments, naltrexone is administered before bupropion. In some embodiments, naltrexone is administered after bupropion. In some embodiments, naltrexone and bupropion are administered simultaneously. As used herein, "simultaneous administration" includes administration in a single dosage form or in separate dosage forms administered at or near the same time.

[0057] In some embodiments, administration of naltrexone and bupropion continues for at or about 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, or 52 weeks, or a range defined by any two of the preceding values. In some embodiments, administration of naltrexone and bupropion continues until a reduction in disease symptoms, impairment, or symptoms stabilizes for at least 1, 2, 3, 4, 5, 6 weeks, or for at least about 1, 2, 3, 4, 5, 6 weeks, or a range defined by any two of the preceding values. For example, in some embodiments, administration of the combination naltrexone / bupropion therapy is continued until the individual's reduced weight gain or promoted weight loss stabilizes for 1, 2, 3, 4, 5, 6 weeks or more, or for about 1, 2, 3, 4, 5, 6 weeks or more, or over a range defined by any two of the foregoing values. In some embodiments, administration of naltrexone, or naltrexone and bupropion, is continued until the individual no longer requires treatment.

[0058] In some embodiments, "administering" a drug includes an individual obtaining and ingesting the drug themselves. For example, in some embodiments, an individual obtains the drug from a pharmacy and self-administers the drug according to the methods provided herein.

[0059] In some embodiments, the present invention relates to a kit. The kit may include one or more unit dosage forms containing naltrexone, bupropion, or naltrexone and bupropion. The unit dosage form may be an oral formulation. For example, the unit dosage form may include a pill, tablet, or capsule. The kit may include multiple unit dosage forms. In some embodiments, the unit dosage form is in a container. In some embodiments, the dosage form is a single oral dosage form containing naltrexone and bupropion or a pharmaceutically acceptable salt thereof.

[0060] The methods, compositions, and kits disclosed herein may include information. This information may be in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, and the notice reflects the agency's approval of the drug form for administration to humans or animals. Such information may be, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. The information may include information required regarding dosage and dosage form, administration schedule and route, adverse events, contraindications, warnings and precautions, drug interactions, and use in specific populations (see, e.g., 21 CFR § 201.57, incorporated herein by reference in its entirety), which in some embodiments is required to be present on or associated with a drug for sale. Dosage forms containing the sustained-release naltrexone formulations of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for treatment of an indicated condition. In some embodiments, the kit is for sale as a prescription drug that requires approval and is subject to regulation by a government agency, such as the U.S. Food and Drug Administration. In some embodiments, the kit includes a label or product insert required by an agency, such as the FDA, for sale of the kit to consumers in the United States.

[0061] The information may include instructions for administering the unit dosage form at a dose of about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg, or about 48 mg of naltrexone or a pharmaceutically acceptable salt thereof. The information may include instructions for administering the unit dosage form at a dose of about 30 mg, about 90 mg, about 180 mg, about 360 mg, or about 450 mg of bupropion or a pharmaceutically acceptable salt thereof. These instructions can be provided in a variety of ways. The information may include instructions regarding when to administer the unit dosage form. For example, the information may include instructions regarding when to administer the unit dosage form relative to the administration of another drug or food. In a preferred embodiment, the information instructs the individual to take naltrexone, or naltrexone and bupropion, with food, preferably a meal.

[0062] Some embodiments include information, preferably printed information, that taking naltrexone or a pharmaceutically acceptable salt thereof with food results in increased bioavailability of naltrexone or a pharmaceutically acceptable salt thereof compared to taking the same amount of naltrexone or a pharmaceutically acceptable salt thereof without food. Some embodiments include information, preferably printed information, that taking bupropion or a pharmaceutically acceptable salt thereof with food results in increased bioavailability of bupropion or a pharmaceutically acceptable salt thereof compared to taking the same amount of bupropion or a pharmaceutically acceptable salt thereof without food. Some embodiments include information, preferably printed information, that taking naltrexone and bupropion or a pharmaceutically acceptable salt thereof with food results in increased bioavailability of naltrexone and / or bupropion or a pharmaceutically acceptable salt thereof compared to taking the same amount of naltrexone and bupropion or a pharmaceutically acceptable salt thereof without food. Some embodiments include information, preferably printed information, that ingesting naltrexone and / or bupropion, or a pharmaceutically acceptable salt thereof, with food results in fewer or less severe drug-related adverse events than ingesting the same amounts of naltrexone and bupropion, or a pharmaceutically acceptable salt thereof, without food. In some embodiments, the adverse events are gastrointestinal events. In some embodiments, the subject is provided with information regarding bioavailability, adverse events, or instructions for administration, and the subject is provided with a dosage form containing the drug described in the information, and the dosage form is administered in accordance with the information. In some embodiments, the subject is a patient in need of the drug. In some embodiments, the drug is administered as a therapy for a disorder described herein.

[0063] In some embodiments, the methods, compositions, and kits disclosed herein may include information regarding enrollment in and / or access to a web-based and / or telephone-based weight management program. In some embodiments, enrollment in a web-based and / or telephone-based weight management program is a prerequisite for obtaining a therapeutic medication. In some embodiments, enrollment in a web-based and / or telephone-based weight management program is permitted only after obtaining a prescription for the therapeutic medication or actual medication. In some embodiments, the treatment method includes enrollment in a web-based and / or telephone-based weight management program prior to and / or as a condition for receiving the therapeutic medication. In some embodiments, the information includes a unique login or registration key for enrollment in and / or access to a web-based and / or telephone-based weight management program.

[0064] The instructions and / or information may be present in various forms, such as printed information on a suitable medium or substrate (e.g., a piece of paper with the information printed on it), a computer-readable medium (e.g., a disk, CD, etc. with the information recorded on it), or a website address that can be accessed via the Internet. The printed information can be provided, for example, on a label accompanying the drug product, on a container for the drug product, packaged with the drug product, or given separately to the patient apart from the drug product, or in a manner (e.g., a website) that allows the patient to independently obtain the information. The printed information can also be provided to a medical caregiver involved in the patient's treatment. In some embodiments, the information is provided to the person orally.

[0065] Some embodiments include therapeutic packaging suitable for commercial sale. Some embodiments include a container. The container may be in any conventional shape or form known in the art made from pharmaceutically acceptable materials, such as a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (e.g., to hold "refills" of tablets to be placed in different containers), or a blister pack containing individual doses to be extruded from the pack according to a treatment schedule. The container used may depend on the exact dosage form contained; for example, a traditional cardboard box would not generally be used to hold a liquid suspension. It is feasible to use two or more containers simultaneously in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which in turn may be contained in a box. Non-limiting examples of packaging and dispensers and oral dosage forms are disclosed in U.S. Patent Application Publication Nos. 2008 / 0110792 and 2008 / 0113026, both of which are incorporated by reference in their entirety for all purposes, including but not limited to, purposes of describing combinations of naltrexone and bupropion, methods of preparing and formulating those combinations into suitable dosage forms, methods of packaging and dispensing those dosage forms, and methods of administering those dosage forms.

[0066] The information can be associated with the container by, for example, being written on a label (e.g., a prescription label or individual label) adhesively affixed to a bottle containing a dosage form described herein; being contained inside the container as a written packaging insert, such as inside a box containing unit dose packets; being applied directly to the container, such as being printed on the wall of a box; or being attached, for example, by being tied or taped as an instruction card affixed to the neck of the bottle via a string, cord or other line, lanyard, or tether-type device. The information can be printed directly on the unit dose pack or blister pack or blister card.

[0067] The term "bupropion" may be used generally herein to refer to bupropion free base, a pharmaceutically acceptable salt of bupropion (anhydrous form, e.g., anhydrous bupropion), a bupropion metabolite (e.g., hydroxybupropion, threohydrobupropion, and erythrohydrobupropion), a bupropion isomer, or a mixture thereof.

[0068] The term "naltrexone" may be used herein in a general manner to refer to naltrexone free base, pharmaceutically acceptable salts of naltrexone (including hydrated and anhydrous forms, e.g., naltrexone hydrochloride dihydrate and anhydrous naltrexone hydrochloride), metabolites of naltrexone, isomers of naltrexone, or mixtures thereof.

[0069] As used herein, the term " pharmaceutically acceptable salt " refers to a compound formulation that does not cause significant irritation to the organism to which it is administered and does not neutralize the biological activity and properties of the compound. Pharmaceutical salts can be obtained by routine experimentation. Non-limiting examples of pharmaceutically acceptable salts include bupropion hydrochloride, radafaxine hydrochloride, naltrexone hydrochloride, and 6-β-naltrexol hydrochloride.

[0070] Throughout this disclosure, when a particular compound is described by name (e.g., bupropion or naltrexone), it is understood that the scope of the disclosure includes pharmaceutically acceptable salts, esters, amides, or metabolites of the named compound. For example, in any of the embodiments herein, an active metabolite of naltrexone (e.g., 6-beta-naltrexol) can be used in conjunction with or in place of naltrexone. In any of the embodiments herein, an active metabolite of bupropion, such as S,S-hydroxybupropion (i.e., radafaxine), can be used in conjunction with or in place of bupropion.

[0071] The term "sustained 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, the controlled release of a drug from a dosage form over an extended period of time. For example, in some embodiments, an extended release dosage form has a release rate that is slower than that of a comparable immediate release form, e.g., less than 80% of the release rate of the immediate release dosage form.

[0072] A suitable immediate-release naltrexone formulation for use as a reference standard is the immediate-release naltrexone formulation widely marketed under the trademark REVIA® naltrexone hydrochloride or its equivalent. A suitable immediate-release bupropion formulation for use as a reference standard is the immediate-release bupropion formulation widely marketed under the trademark WELLBUTRIN® or its equivalent. The United States government regulates the manner in which prescription drugs can be labeled, and thus references herein to REVIA® brand naltrexone hydrochloride and WELLBUTRIN® brand bupropion have well-known, fixed, and definite meanings to those skilled in the art.

[0073] The term "oral dosage form," as used herein, has its ordinary meaning as understood by those of skill in the art, including, but not limited to, a formulation of a drug or drugs in a form that can be administered to a human, such as a pill, tablet, core, capsule, caplet, loose powder, solution, and suppository.

[0074] The terms "reducing" weight gain or "reduction" of weight gain, as used herein, encompass, for example, the suppression or reduction of weight gain associated with the administration of a drug or a change in lifestyle. In some embodiments, reduction in weight gain is measured relative to the amount of weight gain typically experienced when administering naltrexone or bupropion alone or neither.

[0075] As used herein, the term "promoting" weight loss includes causing weight loss compared to baseline weight for at least a portion of the treatment period. This includes individuals who initially gain some weight but lose weight over the course of treatment compared to baseline weight before treatment begins, as well as individuals who regain some or all of the weight lost by the end of the treatment period. In preferred embodiments, at the end of the treatment period, the individual has lost weight compared to baseline. In preferred embodiments, the reduction in weight gain or promotion of weight loss in patients administered naltrexone and bupropion is greater than when neither naltrexone nor bupropion is administered, or when only one of them is administered, and more preferably is at least an additive effect, or better than an additive or synergistic effect, when the two compounds are administered.

[0076] In any of the embodiments described herein, the methods of treatment can optionally include use claims, such as Swiss-type use claims. For example, a method of treating overweight or obesity with a composition may optionally involve use of the composition in the manufacture of a medicament for treating overweight or obesity, or use of the composition for treating overweight or obesity.

[0077] Those skilled in the art will appreciate that many different modifications can be made without departing from the spirit of the present invention. Accordingly, it should be clearly understood that the embodiments of the present invention disclosed herein are illustrative only and are not intended to limit the scope of the present invention. All references cited herein are incorporated by reference in their entirety with respect to the material discussed herein.

[0078] (Example) The following examples are non-limiting and merely representative of various aspects of the present invention.

[0079] Example 1 summarizes the protocol for a clinical trial to demonstrate that treatment with sustained-release (SR) naltrexone / sustained-release bupropion does not increase or reduces the incidence of major adverse cardiovascular events (MACE) in overweight and obese subjects with cardiovascular risk factors.

[0080] [Table 3A]

[0081] [Table 3B]

[0082] [Table 3C]

[0083] [Table 3D]

[0084] [Table 3E]

[0085] [Table 3F]

[0086] [Table 3G]

[0087] [Table 3H]

[0088] [Table 4A]

[0089] [Table 4B]

[0090] Example 2 summarizes the protocol for a clinical study to demonstrate the beneficial effects of sustained-release naltrexone / sustained-release bupropion in conjunction with a comprehensive lifestyle intervention (CLI) program on body weight and cardiovascular risk factors compared with a minimal lifestyle intervention program in overweight and obese subjects.

[0091] [Table 5A]

[0092] [Table 5B]

[0093] [Table 5C]

[0094] [Table 5D]

[0095] [Table 5E]

[0096] [Table 5F]

[0097] [Table 6A]

[0098] [Table 6B]

[0099] Table 7

[0100] Table 8

Claims

1. 1. A kit for use in a method of treating a subject at increased risk for an adverse cardiovascular outcome for overweight or obesity, comprising: the kit comprising sustained-release naltrexone or a pharmaceutically acceptable salt thereof and sustained-release bupropion or a pharmaceutically acceptable salt thereof; The method comprises: identifying an overweight or obese subject at increased risk of an adverse cardiovascular outcome; and administering to said subject therapeutically effective amounts of sustained-release naltrexone, or a pharmaceutically acceptable salt thereof, and sustained-release bupropion, or a pharmaceutically acceptable salt thereof. Including, the overweight or obese subject High blood pressure controlled with or without medication to less than 145 / 95 mmHg; Dyslipidemia requiring drug therapy, Low HDL cholesterol documented within the 12 months prior to identification: <50 mg / dL in women and <40 mg / dL in men; and Current tobacco smoker A subject is identified as being at increased risk for an adverse cardiovascular outcome if the subject has been diagnosed with type 2 diabetes accompanied by at least two risk factors selected from the group consisting of: kit.

2. the overweight or obese subject a history of myocardial infarction documented more than 3 months prior to identification; history of coronary revascularization, including coronary artery bypass graft surgery, stent placement, percutaneous transluminal coronary angioplasty, or laser atherectomy; history of carotid or peripheral revascularization, including carotid endarterectomy, atherectomy for lower extremity atherosclerotic disease, abdominal aortic aneurysm repair, and femoral or popliteal bypass; ischemic changes on graded exercise stress test or positive cardiac imaging study, angina with ECG changes, Ankle-brachial index less than 0.9 assessed by simple palpation within 2 years prior to identification, and 50% or greater stenosis of the coronary arteries, carotid arteries, or lower limb arteries within 2 years prior to identification 10. The kit of claim 1, wherein the subject is identified as being at increased risk of an adverse cardiovascular outcome if the subject has been diagnosed with cardiovascular disease with at least one risk factor selected from the group consisting of:

3. The method further comprises: an active study drug containing sustained-release naltrexone or a pharmaceutically acceptable salt thereof and sustained-release bupropion or a pharmaceutically acceptable salt thereof once daily for one week, followed by a placebo once daily for one week; or Placebo for one week, followed by one week of study active medication, including sustained-release naltrexone or a pharmaceutically acceptable salt thereof and sustained-release bupropion or a pharmaceutically acceptable salt thereof.

3. The kit of claim 1 or 2, further comprising a two-week lead-in period during which the patient is treated with one of the following:

4. The subject has had a myocardial infarction within three months prior to said identification; angina pectoris, grade III or IV according to the Canadian Cardiovascular Society classification; a clinical history of cerebrovascular disease, including stroke; a history of tachyarrhythmia other than sinus tachycardia; blood pressure ≥ 145 / 95 mmHg despite treatment with antihypertensive medication; weight instability within three months prior to said identification; planned bariatric surgery, cardiac surgery, or coronary angioplasty; severe renal impairment as defined by a predicted GFR of less than 30 mL / min; a clinical history of liver failure or a GFR greater than three times the upper limit of normal ALT or AST recorded above; known infection with HIV or hepatitis; chronic opioid use or a positive opioid screen; recent drug or alcohol abuse or dependence within 6 months prior to the identification other than nicotine dependence; history of seizures, including febrile convulsions, cranial trauma, or other conditions that predispose the subject to seizures; history of mania or a recent diagnosis of active psychosis, active binge eating disorder, or anorexia nervosa that is not binge eating disorder; risk of suicide attempts; the use of a monoamine oxidase inhibitor within 14 days prior to said identification; the use of any investigational drug, device, or procedure within 30 days prior to said identification; a woman who is pregnant or breastfeeding, or who has recently been trying to become pregnant, or a woman of childbearing potential, including a perimenopausal woman who has had a menstrual cycle within the past year and who does not consent to birth control practices; or the lack of consistent access to broadband internet.

5. 5. The kit of any one of claims 1 to 4, wherein the subject is treated for at least 26 weeks.

6. 6. The kit of any one of claims 1 to 5, wherein the method further comprises providing the subject with a web-based weight management program, a telephone-based weight management program, or a combination thereof.

7. 7. The kit of claim 6, wherein the telephone-based weight management program comprises one or more coaching calls to the subject.

8. 8. The kit of claim 6 or 7, wherein the telephone-based weight management program optionally includes one or more web-based instructional tools.

9. 9. The kit of any one of claims 6 to 8, wherein the web-based or phone-based weight management program provides one or more behavioral, nutritional or fitness education sessions to the subject.

10. 10. The kit of claim 9, wherein the education is provided by a trained health or fitness instructor and / or a registered dietitian.

11. The kit of claim 10, wherein the trained health or fitness instructor and / or registered dietitian counsels the subject via telephone or via a website for the subject and provides one or more of the topics selected from the group consisting of tips and motivational messages; guidance via question and answer sessions; weekly check-up time for immediate response to the subject's questions via a website; weekly educational materials; video lessons; weight, exercise or diet tracking with badge awarding; goal setting; progress tracking; and communication to encourage the subject to engage in a weight management program.

12. 12. The kit of any one of claims 6 to 11, wherein the weight management program includes the steps of: introducing a new behavioral, nutritional and / or fitness education theme and two or more goals each week; providing informational content and / or video lessons related to the new theme and goals each week; and providing one or more motivational messages from the trained health or fitness instructor to the subject on one or more days per week.

13. 13. The kit of any one of claims 6 to 12, wherein the weight management program comprises the trained health or fitness instructor providing the subject with a schedule for instant question and response responses.

14. 14. The kit of any one of claims 6 to 13, wherein the weight management program comprises one or more activities selected from recording the subject's weight weekly, recording the subject's food intake daily, and recording the subject's activity daily.

15. 15. The kit of any one of claims 6 to 14, wherein the weight management program comprises a step of the subject recording their food intake, and the program is capable of tracking calories for the recorded food intake using a computer database of calories for particular foods and / or meals.

16. 16. The kit of any one of claims 6 to 15, wherein the web-based weight management program includes awarding a badge to the subject when the subject meets a particular program goal.

17. 17. The kit of any one of claims 6 to 16, wherein the weight management program comprises providing the subject with a graphical display of weight loss progress.

18. 18. The kit of any one of claims 6 to 17, wherein the subject sets a weight loss goal that is recorded as part of a weight management program.

19. 19. The kit of any one of claims 6 to 18, wherein the weight management program comprises providing the subject with instructions for stretching, walking, or other mild cardiovascular activity.

20. 20. The kit of any one of claims 6 to 19, wherein the weight management program includes providing short videos demonstrating how to perform stretching and exercise activities.

21. 21. The kit of any one of claims 6 to 20, wherein the weight management program includes tracking calories burned by the subject based on exercise and activity records recorded by the subject.

22. 22. The kit of any one of claims 6 to 21, wherein the weight management program has a duration of at least 26, 52 or 78 weeks.

23. 23. The kit of any one of claims 1 to 22, wherein 32 mg per day of sustained-release naltrexone or a pharmaceutically acceptable salt thereof and 360 mg per day of sustained-release bupropion or a pharmaceutically acceptable salt thereof are administered to the subject.

24. A kit described in any one of claims 1 to 23, wherein the sustained-release naltrexone or a pharmaceutically acceptable salt thereof, and the sustained-release bupropion or a pharmaceutically acceptable salt thereof are administered to the subject as tablets containing 8 mg of sustained-release naltrexone and 90 mg of sustained-release bupropion.

25. 25. The kit of any one of claims 1 to 24, wherein the treatment with naltrexone and bupropion does not increase the subject's risk of an adverse cardiovascular outcome.

26. 26. The kit of any one of claims 1 to 25, wherein said treatment with naltrexone and bupropion reduces the risk of an adverse cardiovascular outcome in said subject.

27. 27. The kit of any one of claims 1 to 26, wherein the adverse cardiovascular outcome is cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

28. A kit described in any one of claims 1 to 27, wherein the subject achieves a weight loss rate of at least 5%, 10%, or 15%.

29. The kit of any one of claims 1 to 28, wherein the subject does not receive face-to-face counseling as part of a weight management program.

30. A kit described in any one of claims 1 to 28, wherein the subject does not receive more than five face-to-face counseling sessions as part of the weight management program.

31. The kit of any one of claims 1 to 28, wherein the subject is not undergoing an intensive behavioral modification (BMOD) program for weight loss.

Images