U.S. patent application number 17/493160 was filed with the patent office on 2022-06-30 for methods of treating overweight and obesity.
This patent application is currently assigned to Nalpropion Pharmaceuticals LLC. The applicant listed for this patent is Nalpropion Pharmaceuticals LLC. Invention is credited to Preston Klassen, Kristin Taylor.
Application Number | 20220208327 17/493160 |
Document ID | / |
Family ID | 1000006200332 |
Filed Date | 2022-06-30 |
United States Patent
Application |
20220208327 |
Kind Code |
A1 |
Klassen; Preston ; et
al. |
June 30, 2022 |
Methods Of Treating Overweight And Obesity
Abstract
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.
Inventors: |
Klassen; Preston; (La Jolla,
CA) ; Taylor; Kristin; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nalpropion Pharmaceuticals LLC |
Brentwood |
TN |
US |
|
|
Assignee: |
Nalpropion Pharmaceuticals
LLC
Brentwood
TN
|
Family ID: |
1000006200332 |
Appl. No.: |
17/493160 |
Filed: |
October 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16558211 |
Sep 2, 2019 |
11139056 |
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17493160 |
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15491870 |
Apr 19, 2017 |
10403170 |
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16558211 |
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14405775 |
Dec 4, 2014 |
9633575 |
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PCT/US2013/044368 |
Jun 5, 2013 |
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15491870 |
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61656451 |
Jun 6, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01G 19/4146 20130101;
A61P 3/04 20180101; A61P 9/04 20180101; A61K 31/137 20130101; A61K
31/485 20130101; G16H 20/10 20180101; A61P 9/00 20180101; A61P 9/10
20180101; G09B 19/0092 20130101; G09B 5/065 20130101 |
International
Class: |
G16H 20/10 20060101
G16H020/10; A61K 31/137 20060101 A61K031/137; A61K 31/485 20060101
A61K031/485; G01G 19/414 20060101 G01G019/414; A61P 9/04 20060101
A61P009/04; A61P 9/00 20060101 A61P009/00; A61P 9/10 20060101
A61P009/10; A61P 3/04 20060101 A61P003/04; G09B 5/06 20060101
G09B005/06; G09B 19/00 20060101 G09B019/00 |
Claims
1. A method of treating a subject at increased risk of an adverse
cardiovascular outcome comprising for overweight or obesity:
identifying an overweight or obese subject at increased risk of an
adverse cardiovascular outcome; and administering to said 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.
2-35. (canceled)
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 16/558,211, filed Sep. 2, 2019, which is a
continuation of U.S. application Ser. No. 15/491,870, filed Apr.
19, 2017, now U.S. Pat. No. 10,403,170, which is a continuation of
U.S. application Ser. No. 14/405,775, now U.S. Pat. No. 9,633,575,
which is the U.S. National Phase under 35 U.S.C. .sctn. 371 of
International Application No. PCT/US2013/044368, entitled "METHODS
OF TREATING OVERWEIGHT AND OBESITY," filed Jun. 5, 2013, and
published in English on Dec. 12, 2013 as WO 2013/184837, which is a
non-provisional of and claims priority to U.S. Provisional
Application No. 61/656,451 filed on Jun. 6, 2012, which, where
permitted, is herein incorporated by reference in its entirety.
BACKGROUND
Field of the Invention
[0002] 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 optionally in subjects at increased risk of adverse
cardiovascular outcomes.
Description of the Related Art
[0003] Obesity has been defined in terms of body mass index (BMI).
BMI is calculated as weight (kg)/[height (m)].sup.2. According to
the guidelines of the U.S. Centers for Disease Control and
Prevention (CDC) and the World Health Organization (WHO), for
adults over 20 years old, BMI is categorized as follows: below 18.5
is considered underweight, 18.5-24.9 is considered normal,
25.0-29.9 is considered overweight, and 30.0 and above is
considered obese (World Health Organization. Physical status: The
use and interpretation of anthropometry. Geneva, Switzerland: World
Health Organization 1995. WHO Technical Report Series).
[0004] The prevalence of obesity has markedly increased over the
past three decades, 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 heart disease, hypertension, stroke,
dyslipidemia, gallbladder disease, sleep apnea, certain types of
cancer, and osteoarthritis, as well as increased mortality risk
from all causes (NHLBI Clinical Guidelines, 1998). Overweight and
obesity are also associated with increased all-cause mortality.
[0005] Diet and exercise-based behavioral modification is the
mainstay of weight management therapy. However, such intervention
is often of limited effectiveness and difficult for individuals to
adhere to. Therefore, pharmacotherapy has been employed as an
adjunct to diet and exercise. Orlistat, lorcaserin, and
phentermine/topiramate are currently the only three drugs approved
in the United States for the long-term treatment of obesity. A
5-10% weight loss has been determined to lead to significant
medical benefits. While orlistat has a favorable safety profile, it
can cause loose stools and fecal incontinence, making acceptance by
patients difficult. Bariatric surgery (specifically gastric
banding) is now indicated for subjects with BMI .gtoreq.30
kg/m.sup.2 who have at least one obesity-related comorbidity. While
effective in most cases, it is invasive with possible complications
including infection, death, hypoglycemia, failure to lose weight,
gastrointestinal symptoms, nutritional deficiencies, depression,
sexual and relationship problems, and noncompliance with behavioral
recommendations.
[0006] U.S. Pat. Nos. 7,375,111 and 7,462,626 disclose the
combination of naltrexone and bupropion (NB) for weight loss
therapy. Wadden et al. disclose the combination of naltrexone and
bupropion as an adjunct to an intensive behavioral modification
(BMOD) program for weight loss. Obesity (2011) 19:110-120. The BMOD
program described by Wadden et al. was delivered in person to
groups of 10-20 persons. Group meetings lasted 90 min and were held
weekly for the first 16 weeks, every other week for the next 12
weeks, and monthly thereafter (yielding a total of 28 sessions).
Group sessions typically began with a review of participants'
eating and activity records and other homework assignments. Group
leaders then introduced a new topic in weight control which, during
the first 16 weeks, included meal planning, stimulus control,
slowing eating, problem solving, social support, and coping with
high risk situations. Subsequent sessions covered skills required
for maintaining lost weight.
[0007] While the combination of naltrexone and bupropion is known
to be efficacious for weight management for some patient
populations, alone or in combination with an intensive BMOD
program, a need exists for an effective treatment of overweight or
obesity in subjects at increased risk of adverse cardiovascular
outcomes. In addition, there exists 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,
but which is still efficacious, particularly in subjects at
increased risk of adverse cardiovascular outcomes.
SUMMARY
[0008] An embodiment of the invention includes a method of treating
a subject at increased risk of an adverse cardiovascular outcome
comprising for overweight or obesity: identifying an overweight or
obese subject at increased risk of an adverse cardiovascular
outcome; 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 some
embodiments, aid overweight or obese subject is identified as being
at increased risk of an adverse cardiovascular outcome if the
subject: a.) is diagnosed as having cardiovascular disease with at
least one risk factor selected from the group consisting of: a
history of documented myocardial infarction >3 months prior to
the 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, lower extremity atherosclerotic
disease atherectomy, repair of abdominal aorta aneurysm, femoral or
popliteal bypass; angina with ischemic changes, ECG changes on a
graded exercise test, or positive cardiac imaging study; ankle
brachial index <0.9 assessed by simple palpation within prior 2
years of the identification; and .gtoreq.50% stenosis of a
coronary, carotid, or lower extremity artery within prior 2 years
of the identification; and/or b.) is diagnosed as having Type 2
diabetes mellitus with at least 2 risk factors selected from the
group consisting of: hypertension controlled with or without
pharmacotherapy at <145/95 mm Hg; dyslipidemia requiring
pharmacotherapy; documented low HDL cholesterol, <50 mg/dL in
women or <40 mg/dL in men, within prior 12 months of the
identification; and current tobacco smoker.
[0009] In some embodiments, the method further comprises a lead-in
2-week period during which the subject receive treatment according
to one of two sequences: 1 week of active study medication
comprising sustained release naltrexone, or a pharmaceutically
acceptable salt thereof, and sustained release bupropion, or a
pharmaceutically acceptable salt thereof, once a day followed by 1
week of placebo once a day; or 1 week of placebo followed by 1 week
of active study medication comprising sustained release naltrexone,
or a pharmaceutically acceptable salt thereof, and sustained
release bupropion, or a pharmaceutically acceptable salt
thereof.
[0010] In some embodiments, the subject does not have one or more
characteristics selected from the group consisting of: myocardial
infarction within 3 months prior to the identification; angina
pectoris Grade III or IV as per the Canadian Cardiovascular Society
grading scheme; a clinical history of cerebrovascular disease
including stroke; a history of tachyarrhythmia other than sinus
tachycardia; blood pressure .gtoreq.145/95 mm Hg, irrespective of
treatment with antihypertensive agents; unstable weight within 3
months prior to the identification; planned bariatric surgery,
cardiac surgery, or coronary angioplasty; severe renal impairment
defined by an estimated GFR <30 mL/min; clinical history of
liver failure or documented ALT or AST greater than 3 times the
upper limit of normal; known infection with HIV or hepatitis;
chronic use or positive screen for opioids; recent drug or alcohol
abuse or dependence, with the exception of nicotine dependence,
within 6 months prior to the identification; history of seizures,
including febrile seizures, cranial trauma, or other conditions
that predispose the subject to seizures; history of mania or
current diagnosis of active psychosis, active bulimia or anorexia
nervosa, but not binge eating disorder; a risk for suicide
attempts; acute depressive illness including new onset of
depression or acute exacerbation of symptoms, but not stable
subjects on chronic treatment for depression; any condition with
life expectancy anticipated to be less than 4 years including
congestive heart failure NYHA Class 3 or 4; a history of malignancy
within the previous 5 years, not including non-melanoma skin cancer
or surgically cured cervical cancer; current use of other bupropion
or naltrexone containing products; a history of hypersensitivity or
intolerance to naltrexone or bupropion; use of monoamine oxidase
inhibitors within 14 days prior to the identification; use of any
investigational drug, device, or procedure within 30 days prior to
the identification; a pregnant or breast-feeding woman, or
currently trying to become pregnant, or of child-bearing potential,
including peri-menopausal women who have had a menstrual period
within one year, and not willing to practice birth control; and
inability to consistently access broadband internet.
[0011] 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.
[0012] An embodiment of the 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
phone-based weight management program, or a combination
thereof.
[0013] In some embodiments, the identified subject has a BMI
.gtoreq.30 and .ltoreq.45 kg/m.sup.2 with uncomplicated obesity. In
some embodiments, the identified subject has a BMI of .gtoreq.27
and .ltoreq.45 kg/m.sup.2 with dyslipidemia and/or controlled
hypertension. In some embodiments, the subject is treated for at
least 26 weeks. In some embodiments, the phone-based weight
management program comprise one or more coaching calls to the
subject. In some embodiments, the phone-based weight management
program optionally comprises one or more web coaching tools. In
some embodiments, the web-based or phone-based weight management
program provides the subject with one or more of behavioral,
nutritional or fitness education.
[0014] In some embodiments, the education are delivered by a
trained health or fitness coach and/or a registered dietitian. In
some embodiments, the trained health or fitness coach and/or the
registered dietitian counsel the subject via the phone or via a
website for the subject, and provide one or more of the topics
selected from the group consisting of tips and motivational
messages; coaching through question and answer; weekly office hours
for real-time responses to the subject's inquiries via the website;
weekly educational materials; video lessons; weight, exercise, or
diet tracking with badge rewards; goal setting; progress tracking;
and communications to encourage the subject to engage in the weight
management program.
[0015] In some embodiments, 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, is administered to the subject. In some
embodiments, the subject is administered the sustained release
naltrexone, or a pharmaceutically acceptable salt thereof, and the
sustained release bupropion, or a pharmaceutically acceptable salt
thereof, in a tablet containing 8 mg of sustained release
naltrexone and 90 mg of sustained release bupropion.
[0016] In some embodiments, the treatment with naltrexone and
bupropion does not increase the subject's risk of an adverse
cardiovascular outcome. In some embodiments, the treatment with
naltrexone and bupropion decreases the subject's risk of an adverse
cardiovascular outcome. In some embodiments, the adverse
cardiovascular outcome is cardiovascular death, nonfatal myocardial
infarction, or nonfatal stroke. In some embodiments, the subject
achieves a percentage of weight loss of at least 5%, at least 10%
or at least 15%. In some embodiments, the weight management program
has a period of at least 52 weeks or at least 78 weeks.
[0017] In some embodiments, the subject does not receive in-person
counseling as part of a weight management program. In some
embodiments, the subject does not receive more than 5 in-person
counseling sessions as part of a weight management program. In some
embodiments, the subject does not receive an intensive behavioral
modification (BMOD) program for weight loss.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] So that the manner in which the recited features of the
present disclosure can be understood in detail, a more particular
description of the disclosure, briefly summarized above, may be had
by reference to embodiments, some of which are illustrated in the
appended drawings. It is to be noted, however, that the appended
drawings illustrate only typical embodiments of this disclosure and
are therefore not to be considered limiting of its scope, for the
disclosure may admit to other equally effective embodiments.
[0019] FIG. 1 shows a visual representation of a study design
demonstrating that treatment with Naltrexone SR/Bupropion SR does
not increase or decreases the occurrence of Major Adverse
Cardiovascular Events (MACE) in overweight and obese subjects with
cardiovascular risk factors as presented in Example 1; and
[0020] FIG. 2 shows a visual representation of a study design
demonstrating the beneficial effect of Naltrexone SR/Bupropion SR
on body weight and cardiovascular risk factors in overweight and
obese subjects in conjunction with a comprehensive lifestyle
intervention (CLI) program compared minimal lifestyle intervention
program as presented in Example 2.
DETAILED DESCRIPTION
[0021] 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 lifestyle intervention (CLI) program including a
web-based weight management program, a phone-based weight
management program, and a combination thereof. In some embodiments,
the subject being treated for overweight and obesity are subjects
at increased risk of adverse cardiovascular outcomes. In a
preferred embodiment, the treatment of a subject at increased risk
of adverse cardiovascular outcomes with naltrexone plus bupropion
in combination with a comprehensive web-based and/or
telephone-based weight management program results in no more major
adverse cardiovascular outcomes than treatment with the web-based
and/or telephone-based weight management program alone. In some
embodiments, the treatment of a subject at increased risk of
adverse cardiovascular outcomes with naltrexone plus bupropion in
combination with a comprehensive web-based and/or telephone-based
weight management program surprisingly results in fewer major
adverse cardiovascular outcomes than treatment with the web-based
and/or telephone-based weight management program alone. Major
adverse cardiovascular outcomes are cardiovascular death (including
fatal myocardial infarction and fatal stroke), nonfatal myocardial
infarction, nonfatal stroke, or nonfatal unstable angina requiring
hospitalization.
[0022] In some embodiments, the subject being treated by the
methods disclosed herein is at increased risk of adverse
cardiovascular outcomes. Subjects at increased risk of adverse
cardiovascular outcomes include subjects having a.) cardiovascular
disease (confirmed diagnosis or at high likelihood of
cardiovascular disease) with at least one of the following: history
of documented myocardial infarction >3 months prior to
screening; history of coronary revascularization (i.e., coronary
artery bypass graft surgery, stent placement, percutaneous
transluminal coronary angioplasty, or laser atherectomy); history
of carotid or peripheral revascularization (i.e., carotid
endarterectomy, lower extremity atherosclerotic disease
atherectomy, repair of abdominal aorta aneurysm, femoral or
popliteal bypass); angina with ischemic changes (resting ECG), ECG
changes on a graded exercise test (GXT), or positive cardiac
imaging study; ankle brachial index <0.9 (by simple palpation)
within prior 2 years; .gtoreq.50% stenosis of a coronary, carotid,
or lower extremity artery within prior 2 years; and/or b. Type 2
diabetes mellitus with at least 2 of the following: hypertension
(controlled with or without pharmacotherapy at <145/95 mm Hg);
dyslipidemia requiring pharmacotherapy; documented low HDL
cholesterol (<50 mg/dL in women or <40 mg/dL in men) within
prior 12 months; current tobacco smoker.
[0023] In some such embodiments, the subject being treated has
uncomplicated 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.
[0024] In some embodiments the 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
phone-based program. In some other embodiments, the weight
management program is a combination of both web-based and
phone-based programs. In some embodiments, the subject does not
receive more than 15, 10, 5, 4, 3, 2, or 1 in-person counseling
sessions as part of a weight management program. In some
embodiments, the subject does not receive any in-person counseling
sessions as part of a weight management program.
[0025] Web-Based Weight Management Program
[0026] Preferably, the web-based program provides a progressive
nutrition and exercise program with goal setting and tracking
tools. Each subject is assigned to a health and fitness
professional who counsels them online throughout the program.
Additional educational tools include weekly web-based
informational, educational and motivational resources supplemented
by video lessons (Table 1) presented at regular intervals. Content
for the program consists of: a weekly email that announces the
goals for the week, provides motivation, and encourages continued
participation; weekly goals (from email) that align with each
week's theme (Table 1), along with a detailed explanation and a
strategy for achieving these goals, placed on the MyWeightMate.com
subject pages; three pieces of additional weekly content posted to
user pages (tips and educational information) to help subjects
reach their weekly goals; motivational messages throughout the week
posted on participant pages; triggered event emails sent to users
based on behaviors (i.e. absence from program activity, successful
logging); video lessons provided on the MyWeightMate.com site for
participants to view and archived for future access: weekly for the
first 16 weeks, biweekly for the next 12 weeks, monthly for the
remaining duration of the study, and two refresher campaigns that
include 4 weekly sessions each year during the third and fourth
year of the trial. Video lessons focus on relevant topics and are
developed by subject matter experts.
TABLE-US-00001 TABLE 1 Weekly Themes and Video Topics for First 16
Weeks of the Weight Management Program Week Theme Video Lesson
Topic 1 Get Started Setting Yourself Up For Success: Getting Your
Mind Right 2 Perfect Portions SMART Goals 3 Avoid Pitfalls Proper
Form When You Move 4 Get More Vitamin Zzz Healthful Substitutions
for Food and Exercise 5 Boost Your Fitness Fitness Myths 6 Skinny
Food Secrets Smart Strategies for Eating Less 7 Smash Sugar Spikes
How Do You Make Time For Your Health and Why is It Psychologically
Important? 8 Take the Show on the Road Accidental Exercise 9 Take
Some Pressure Off Powering Up Your Exercise 10 Metabolism
Superchargers Staying Fit If You Sit 11 Clobber High Cholesterol
Healthy Choices 12 Motivation Boosters Breaking Weight Loss
Plateaus 13 Kick It Up Replacing Bad Habits With Healthy Ones 14
Rut Busters The Diet Hype Trap 15 Shore Up Your Self- Healthy
Living Guide: Live Confidence Your Best Life 16 Review and Renew
Boost Your Metabolism
[0027] The web-based weight management program provides behavioral,
nutritional and fitness education delivered by trained health and
fitness coaches. The website provides a "WeightMate Coach" who
counsels the subject via the participant's individual webpage, and
provides one or more of the following: tips and motivational
messages; coaching through Q&A; weekly office hours for
real-time response via the website; weekly educational materials;
content developed with subject matter experts; video lessons to
supplement the weekly themes; weight, exercise, and diet tracking
with badge rewards; suggested activity and coaching tip;
communication to encourage engagement; and a contemporary website
that is fun and intuitive.
[0028] In one embodiment, new themes and goals are introduced each
Monday, with 2-3 goals of the week, relevant content and/or video
lesson(s) (Table 1) are provided, and motivational messages are
provided on one or more days of the week. Optionally, additional
tips are provided one or more days during the week. In some
embodiments, video lessons supplement the weekly educational
themes. The produced video content ensures quality and uniformity
of message to subjects, and a Q&A function allows patients to
ask questions with <24 hour turnaround.
[0029] In some embodiments, web-based individual counseling is
provided by a coach; preferably the subject has unlimited access to
coach. Preferably the coach provides a schedule to the subject
which includes weekly `office hours` for real-time Q&A
responses. The program emphasizes weekly weigh ins with daily food
and activity tracking. Preferably, the website can track calories
for each meal using a computer database of calories for specific
foods and/or meals, and save favorite foods and meals. Four
reference menus based on caloric needs and food preferences are
provided. In some embodiments the subject is rewarded with badges
for meeting particular goals (e.g., for 7 days of activity logged;
for 7 days of food logged; for 3 weeks of weight logged; for first
15 pounds lost; for 12 weeks of program participation; for 26 weeks
of program participation; for 52 weeks of program participation;
for 78 weeks of program participation; for 5% weight loss; for 10%
weight loss; for 15% weight loss). In a preferred embodiment, the
subject periodically establishes a weight loss goal which is
recorded as part of the program. The subject's progress toward the
subject's goal(s) can be provided to the subject via the subject's
webpage. The weight loss goal can be the goal for a one week, two
week, month, two month, six month, year or longer period of time.
The program provides the option for the participating subject to
set a specific weight loss goal at the beginning of the program.
The program also provides the option to track and log weight loss,
and the progress towards achieving the specific goal on a daily or
weekly basis. Optionally, a graphic representation 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, behavior-based automated messages from
trainers are provided for increased motivation and
participation.
[0030] In some embodiments, the exercise portion of the web-based
weight management program encourages 5 days of activity and 2 days
of rest, preferably on nonconsecutive days (e.g. Monday and
Friday). In some embodiments, the exercise program provides
instructions on stretching, walking and other light cardio
activity. Video clips can provide educational demonstration for
stretches and exercise maneuvers. The website can track calories
burned by the subject through exercise and activity logs.
[0031] In a preferred embodiment, the web-based weight management
program does not involve any in-person therapy or group
meetings.
[0032] Phone-Based Weight Management Program
[0033] In some embodiments, the telephone-based program comprises
personalized coaching through one or more phone calls. In one
embodiment, the phone calls are conducted by a dedicated coach to
the subject receiving treatment. In another embodiment, the phone
calls are conducted by a registered dietitian to the subject
receiving treatment. In some such embodiments, the phone-based
program includes 6 to 15, preferably 12 scheduled calls over the
first 3 to 8, preferably 6 months of the treatment. The topics of
said scheduled calls can include cognitive behavioral coaching and
nutrition coaching (See, for example, Table 2). In some such
embodiments, the phone-based program includes 6 to 15, preferably
12 additional calls over the next 3 to 8, preferably 6 months of
treatment.
[0034] In some embodiments, the phone-based program optionally
comprises on-line coaching tools, such as an integrated web support
for web coaching, including the web-based program described above.
The web coaching can include the essential practices for weight
loss and maintaining weight loss, progress tracking, and/or virtual
coaching. Non-limiting examples of the essential practices can
include E-lessons, videos and podcasts, articles and games relating
to topics such as healthy cooking, setting realistic goals, and
controlling stress. Non-limiting examples of items the progress
trackers can track include weight, nutrition intake, activity,
stress, biometrics, coaching calls, etc. Non-limiting example of
virtual coating can include generating and updating of to-do list
for a subject participating in the program, sending emails,
etc.
[0035] In some embodiments, the phone-based program can also
optionally include one or more electronic devices for wireless
activity monitoring. Non-limiting example of such electronic device
is FitLinxx.RTM.ActiPed to be used in conjunction with a USB access
point to track steps, distance, calories and activity time. The
electronic device(s) can be wirelessly synced with the web support.
In one embodiment, the phone-based program is the Weight Talk.RTM.
Program available from Alere.TM..
[0036] A subject receiving the treatment of naltrexone and
bupropion can enroll in the phone-based program via various
methods, including both web enrollment and phone enrollment. In
some embodiments, the phone-based program also include frontline
support to identify patients who qualify for the clinical study,
discuss benefit of the phone-based program, set realistic
expectations, assist in enrollment and refer specific question to
coaches.
TABLE-US-00002 TABLE 2 Exemplary Phone-based Weight Management
Program Call Topics Call # Call Topics Call 1: Getting Started:
Core Values, goal setting and tracking Call 2: Reducing calories
and healthy eating (with registered dietitian) Call 3: Increasing
physical activity Call 4: Managing stress Call 5: Changing
unhelpful thoughts Call 6: Gaining control of your environment
(with registered dietitian) Call 7: Developing time management
skills and improving sleep Call 8: Navigating difficult situations:
social situations and restaurants Call 9: Weight maintenance skills
Call 10: Rebounding from lapses Call 11: Maintaining motivation
Call 12: Evaluation and Participant Feedback
[0037] In a preferred embodiment, treatment with a combination of
naltrexone sustained-release (SR)/bupropion SR (NB), alone or in
conjunction with a web-based and/or telephone-based weight
management program, does not increase, or more preferably
decreases, the occurrence of major adverse cardiac events, defined
as cardiovascular death, nonfatal myocardial infarction, or
nonfatal stroke in overweight and obese subjects, as compared to
placebo or a web-based and/or telephone-based weight management
program alone. In some embodiments, treatment with NB, alone or in
conjunction with a web-based and/or telephone-based weight
management program, does not increase, or more preferably
decreases, the occurrence of one or more of cardiovascular death,
nonfatal myocardial infarction, nonfatal stroke, or nonfatal
unstable angina requiring hospitalization in overweight and obese
subjects, as compared to placebo or a web-based and/or
telephone-based weight management program alone. In some
embodiments, treatment with NB, alone or in conjunction with a
web-based and/or telephone-based weight management program, does
not increase, or more preferably decreases, one or more of: the
occurrence of all cause mortality; the occurrence of unstable
angina requiring hospitalization; and the occurrence of coronary
revascularization procedures, as compared to placebo or a web-based
and/or telephone-based weight management program alone. In some
embodiments, treatment with NB, alone or in conjunction with a
web-based and/or telephone-based weight management program,
decreases body weight or improves systolic and/or diastolic blood
pressure, as compared to placebo or a web-based and/or
telephone-based weight management program alone. In some
embodiments, the individual treated is overweight or obese, and at
increased risk of adverse cardiovascular outcomes.
[0038] In some embodiments, treatment with a combination of
naltrexone sustained-release (SR)/bupropion SR (NB), alone or in
conjunction with a web-based and/or telephone-based weight
management program, increases one or more of: the percent change in
body weight from baseline; the percentage of subjects achieving a
loss of at least 5%, 10%, and 15% of baseline body weight; and the
absolute change in body weight from baseline, compared to Usual
Care (no study medication and minimal lifestyle intervention
program). In some embodiments, treatment with NB, alone or in
conjunction with a web-based and/or telephone-based weight
management program, improves one or more of: 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); measures of glucose metabolism (one or more of fasting
glucose, fasting insulin, and HOMAIR); measurements derived from
patient reported outcomes (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)), as compared to Usual Care (no study
medication and minimal lifestyle intervention program). In some
embodiments, the above mentioned increases or improvements are
measured at week 26 of treatment in comparison to baseline, in some
embodiments the measurements are at week 52 or 78 of treatment in
comparison to baseline. In some embodiments that treated individual
is female or male, 18 to 60 years, inclusive, of age, with a BMI
.gtoreq.30 and .ltoreq.45 kg/m.sup.2 for subjects with
uncomplicated obesity, and a BMI of .gtoreq.27 and .ltoreq.45
kg/m.sup.2 for subjects who are overweight or obese and have
dyslipidemia and/or controlled hypertension. In some embodiments
the treated individual is overweight or obese, and at increased
risk of adverse cardiovascular outcomes. In some embodiments, the
treated individual is not overweight or obese, and at increased
risk of adverse cardiovascular outcomes.
[0039] In some embodiments, treatment with a combination of
naltrexone sustained-release (SR)/bupropion SR (NB), in conjunction
with a web-based and/or telephone-based weight management program,
is the same or increases one or more of: the percent change in body
weight from baseline; the percentage of subjects achieving a loss
of at least 5%, 10%, and 15% of baseline body weight; and the
absolute change in body weight from baseline, compared to NB in
conjunction with an intensive behavioral modification (BMOD)
program for weight loss delivered in person. In some embodiments,
treatment with NB, alone or in conjunction with a web-based and/or
telephone-based weight management program, is the same or improves
one or more of: 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); measures of
glucose metabolism (one or more of fasting glucose, fasting
insulin, and HOMA-IR); measurements derived from patient reported
outcomes (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)), as compared to NB in conjunction with an
intensive behavioral modification (BMOD) program for weight loss
delivered in person. In some embodiments, the above mentioned
increases or improvements are measured at week 26 of treatment in
comparison to baseline, in some embodiments the measurements are at
week 52 or 78 of treatment in comparison to baseline. In some
embodiments that treated individual is female or male, 18 to 60
years, inclusive, of age, with a BMI .gtoreq.30 and .ltoreq.45
kg/m.sup.2 for subjects with uncomplicated obesity, and a BMI of
.gtoreq.27 and .ltoreq.45 kg/m.sup.2 for subjects who are
overweight or obese and have dyslipidemia and/or controlled
hypertension. In some embodiments the treated individual is
overweight or obese, and at increased risk of adverse
cardiovascular outcomes. In some embodiments, the treated
individual is not overweight or obese, and at increased risk of
adverse cardiovascular outcomes.
[0040] In some embodiments, the individual has a body mass index
(BMI) of at least 25 kg/m.sup.2. In some embodiments, the
individual has a BMI of at least 30 kg/m.sup.2. In some
embodiments, the individual has a BMI of at least 40 kg/m.sup.2. In
some embodiments, the individual has a BMI of less than 25
kg/m.sup.2, or develops a BMI less than 25 kg/m.sup.2 during the
course of administration of naltrexone and bupropion. In these
embodiments, it may be beneficial for health or cosmetic purposes
to mitigate subsequent weight gain or to promote weight loss,
thereby reducing the BMI even further. In some embodiments, the
individual has been diagnosed by a physician as being overweight or
obese. In some embodiments, the individual is identified, including
self-identified, as overweight or obese, or is identified as having
been diagnosed as overweight or obese. In some embodiments, the
individual is suffering from dyslipidemia and/or controlled
hypertension in addition to being overweight, or in addition to
being obese.
[0041] In some embodiments, the promotion of weight loss is
measured by a percent change from a baseline body weight. In some
of these embodiments, the amount of weight loss is, is about, is at
least, is at least about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%,
7%, 8%, 9%, 10%, 12%, 15%, or more of initial body weight, or a
range defined by any two of the preceding values. In some
embodiments, the promotion of weight loss is measured as a
reduction in weight gain relative to the amount of weight gain
experienced by the relevant control, and the amount of reduction in
weight gain is, is about, is at least, is 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
preceding values.
[0042] In some embodiments, the dosage is adjusted so that the
patient loses weight at a rate of about 3% of baseline body weight
every six months. However, the rate of weight loss for a patient
may be adjusted by the treating physician based on the patient's
particular needs.
[0043] In some embodiments, the mitigation of weight gain or
promotion of weight loss occurs by increasing satiety in the
individual. In some embodiments, the mitigation of weight gain or
promotion of weight loss occurs by suppressing the appetite of the
individual. In some embodiments, the treatment comprises
instituting a regimen of diet and/or increased activity.
[0044] In some embodiments, the naltrexone or combination therapy,
including naltrexone in combination with bupropion or fluoxetine,
is in an amount sufficient to affect weight loss, reduce a
cardiovascular risk factor, increase insulin sensitivity, reduce
food cravings, treat a visceral fat condition, mitigate weight gain
or promote weight loss during smoking cessation, or provide weight
loss therapy in patients with major depression. Nonlimiting
examples of such methods of treatment are disclosed in U.S. Pat.
Nos. 7,375,111 and 7,462,626; in U.S. Patent Publication Nos.
2007/0275970, 2007/0270450, 2007/0117827, 2007/0179168,
2008/0214592, 2007/0128298, and 2007/0129283; in U.S. patent
application Ser. Nos. 12/751,970, 61/167,486, and 61/293,844; and
in WO 2009/158114, each of which is hereby incorporated herein by
reference in their entirety and for all purposes, including without
limitation for the purpose of describing methods of affecting
weight loss, reducing cardiovascular risk factors, increasing
insulin sensitivity, reducing food cravings, treating visceral fat
conditions, mitigating 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
factor includes 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 factor includes one or more of the following:
total cholesterol level, HDL cholesterol level, and triglyceride
level.
[0045] In some embodiments, the increased efficacy of a weight loss
treatment described herein comprises an improvement in an outcome
measure. For example, in some embodiments, the increased efficacy
increases the amount of weight loss. In some embodiments, the
increase in efficacy decreases the frequency or severity of adverse
events, including but not limited to nausea, constipation,
vomiting, dizziness, dry mouth, headache, and insomnia. In some
embodiments, the increased efficacy improves another secondary
endpoint, including 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 skill in the art recognizes, in some
circumstances, it is desirable to decrease waist circumference,
hs-CRP levels, triglyceride levels, and the ratio of LDL/HDL
cholesterol levels, and to increase HDL cholesterol levels. In some
embodiments, the improvement in the outcome measure is, is about,
is at least, or is 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 as compared to baseline or the relevant
control.
[0046] In some embodiments, naltrexone or naltrexone and bupropion
are each administered once per day. In some embodiments, naltrexone
and bupropion are each divided into equal doses and administered
more than once per day. In some embodiments, naltrexone and
bupropion are each divided into unequal doses and administered more
than once per day. In some embodiments, naltrexone and bupropion
are divided into a different number of doses and are administered a
different number of times per day. In one such embodiment, the dose
of one of naltrexone or bupropion is divided, while the dose of the
other is not.
[0047] In some embodiments, one or both of naltrexone and bupropion
is administered one, two, three, four, or more times per day.
Either or both compounds can be administered less than once per
day, for example once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
or 14 days, or every 1 or 2 weeks, or a range defined by any two of
the preceding values. In some embodiments, the number of
administrations per day is constant (e.g., one time per day). In
other embodiments, the number of administrations is variable. The
number of administrations may change depending on effectiveness of
the dosage form, observed side effects, external factors (e.g., a
change in another medication), or the length of time that the
dosage form has been administered.
[0048] In some embodiments, the daily dose of naltrexone can range
from about 4 mg to about 50 mg, or about 4 mg to about 32 mg, or
about 8 mg to about 32 mg, or 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 preceding values. The selection of a
particular dosage may be based on the weight of the patient. The
selection of a particular dosage may be based on the identity,
dosage, and/or dosing schedule of another co-administered compound.
However, in some embodiments, it may be necessary to use dosages
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 dose is different.
[0049] In some embodiments, the daily dose of bupropion can range
from about 30 mg to about 500 mg, or about 30 mg to about 360 mg,
or 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 preceding
values. The selection of a particular dosage may be based on the
weight of the patient. The selection of a particular dosage may be
based on the identity, dosage and/or dosing schedule of another
co-administered compound. However, in some embodiments, it may be
necessary to use dosages 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 dose is different.
[0050] The compositions described herein may be distributed,
provided to a patient for self-administration, or administered to
an individual. In some embodiments, the combined
naltrexone/bupropion therapies include a third compound.
[0051] 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,
core, capsule, caplet, loose powder, solution, or suspension. In a
preferred embodiment, 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 Publication No.
2008/0113026, which is incorporated herein by reference in its
entirety and for all purposes, including without limitation for the
purpose of describing trilayer tablets, methods of making and
formulating trilayer tablets, and methods of administering
them.
[0052] In some embodiments, at least one of naltrexone and
bupropion is administered with varying frequency during treatment.
In some of these embodiments, the varying frequency comprises a
decreased frequency over time. For example, one or both of
naltrexone and bupropion can be initially administered more than
once per day, followed by administration only once per day at a
later point in treatment. In some embodiments, the daily dosage of
at least one of naltrexone and bupropion is consistent despite the
varying frequency of administration. For example, in some
embodiments, two tablets of each of naltrexone and bupropion are
initially administered twice per day, while four tablets of each of
naltrexone and bupropion are administered once per day at a later
point in treatment. Alternatively, in some embodiments, one or two
tablets of each of naltrexone and bupropion are administered at a
later point in treatment, where the one or two tablets have an
equivalent total daily dosage as the two tablets each of naltrexone
and bupropion initially administered twice per day.
[0053] In some embodiments where one or both of naltrexone and
bupropion are administered less than once per day in a controlled
release or sustained release (SR) formulation, the dose is selected
so that the patient receives a daily dose that is about the same as
a daily dose described herein.
[0054] In some embodiments, the naltrexone, alone or in a
combination treatment, is not a sequestered form of naltrexone. For
example, in some embodiments, naltrexone is in a non-sequestered,
controlled release formulation. In some embodiments, naltrexone is
a non-sequestered, sustained release formulation. In preferred
embodiments, at least 50% of the naltrexone is released within 24
hours of administration.
[0055] In some embodiments, at least one of naltrexone or bupropion
is administered in consistent daily dosages throughout the period
of treatment. In some embodiments, at least one of naltrexone or
bupropion is administered in varying daily dosages during the
period of treatment. In some of these embodiments, the daily
dosages comprise increasing daily dosages over time. In some of
these embodiments, the daily dosages comprise decreasing daily
dosages over time.
[0056] In some embodiments, naltrexone and bupropion are
administered individually. In some embodiments, naltrexone and
bupropion are administered in a single pharmaceutical composition
comprising 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 Publication No.
2007/0281021, which is incorporated herein by reference in its
entirety and for all purposes, including without limitation for the
purpose of describing sustained release forms of naltrexone and
bupropion, methods of making and formulating them into suitable
dosage forms, and methods of administering 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, formulations thereof, and
methods of administering them are disclosed in U.S. Pat. Nos.
7,375,111 and 7,462,626, both of which are incorporated herein by
reference in their entirety and for all purposes, including without
limitation for the purpose of describing combinations of naltrexone
and bupropion, methods of making and formulating them into suitable
dosage forms, and methods of administering them. Reference herein
to the use or administration of naltrexone and naltrexone/bupropion
combinations is understood to include all modes of administration
disclosed or referred to herein, including without limitation
separate administration, administration in a single dosage form,
administration in the form of salts, and/or metabolites, and/or
administration in sustained release forms. Techniques for
formulation and administration of the compounds of the instant
application may be found in "Remington's Pharmaceutical Sciences,"
Mack Publishing Co., Easton, Pa., 18th edition, 1990, which is
incorporated herein by reference in its entirety.
[0057] In some embodiments, naltrexone is administered prior to
bupropion. In some embodiments, naltrexone is administered
subsequent to bupropion. In some embodiments, naltrexone and
bupropion are co-administered. As used herein, co-administration
includes administration in a single dosage form, or separate dosage
forms that are administered at, or nearly at, the same time.
[0058] In some embodiments, the administration of naltrexone and
bupropion is continued for a period of, or of 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, the
administration of naltrexone and bupropion is continued until the
reduction in symptoms of a disease, disorder, or condition is
stabilized for a period of, or of about, 1, 2, 3, 4, 5, 6, or more
weeks, or a range defined by any two of the preceding values. For
example, in some embodiments, the administration of a combined
naltrexone/bupropion therapy is continued until the mitigation of
weight gain or promotion of weight loss in an individual is
stabilized for a period of, or of about, 1, 2, 3, 4, 5, 6, or more
weeks, or a range defined by any two of the preceding values. In
some embodiments, administration of naltrexone, or naltrexone and
bupropion, is continued until the individual no longer needs a
treatment.
[0059] In some embodiments, "administering" a drug includes an
individual obtaining and taking a drug on their own. For example,
in some embodiments, an individual obtains a drug from a pharmacy
and self-administers the drug in accordance with the methods
provided herein.
[0060] In some embodiments, the present invention relates to a kit.
The kit may include one or more unit dosage forms comprising
naltrexone, bupropion, or naltrexone and bupropion. The unit dosage
forms may be of an oral formulation. For example, the unit dosage
forms may comprise pills, tablets, or capsules. The kit may include
a plurality of unit dosage forms. In some embodiments, the unit
dosage forms are in a container. In some embodiments, the dosage
forms are single oral dosage forms comprising naltrexone and
bupropion or pharmaceutically acceptable salts thereof.
[0061] The methods, compositions and kits disclosed herein may
include information. The information may be in a form prescribed by
a governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such information, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. The information can include
required information regarding dose and dosage forms,
administration schedules and routes of administration, adverse
events, contraindications, warning and precautions, drug
interactions, and use in specific populations (see, e.g., 21 C.F.R.
.sctn. 201.57 which is incorporated herein by reference in its
entirety), and in some embodiments is required to be present on or
associated with the drug for sale of the drug. Dosage forms
comprising a sustained-release naltrexone formulation of the
invention formulated in a compatible pharmaceutical carrier may
also be prepared, placed in an appropriate container, and labeled
for treatment of an indicated condition. In some embodiments, a kit
is for sale of a prescription drug requiring the approval of and
subject to the regulations of a governmental agency, such as the
Food and Drug Administration of the United States. In some
embodiments, the kit comprises the label or product insert required
by the agency, such as the FDA, for sale of the kit to consumers,
for example in the U.S.
[0062] The information may comprise instructions to administer the
unit dosage form at a dosage 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
comprise instructions to administer the unit dosage form at a
dosage 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 may be provided in a variety of ways.
The information may comprise instructions about when to administer
the unit dosage forms. For example, the information may comprise
instructions about when to administer the unit dosage forms
relative to the administration of another medication or food. In
preferred embodiments, the information instructs an individual to
take naltrexone, or naltrexone and bupropion, with food, preferably
a meal.
[0063] Some embodiments include information, preferably printed,
that taking naltrexone or a pharmaceutically acceptable salt
thereof with food results in an increase in the 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, that taking bupropion or a
pharmaceutically acceptable salt thereof with food results in an
increase in the 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,
that taking naltrexone and bupropion, or a pharmaceutically
acceptable salts thereof, with food results in an increase in the
bioavailability of naltrexone and/or bupropion, or a
pharmaceutically acceptable salts thereof, compared to taking the
same amount of naltrexone and bupropion, or a pharmaceutically
acceptable salts thereof, without food. Some embodiments include
information, preferably printed, that taking naltrexone, and/or
bupropion or pharmaceutically acceptable salts thereof with food
results in fewer or less severe drug associated adverse events than
taking the same amount of naltrexone and bupropion, or a
pharmaceutically acceptable salts thereof, without food. In some
embodiments, the adverse events are gastrointestinal events. In
some embodiments, information regarding bioavailability, adverse
events, or instructions on administration regimes are provided to a
subject, a dosage form comprising the medication described in the
information is provided to the subject, and the dosage form is
administered in accordance to the information. In some embodiments
the subject is a patient in need of the medication. In some
embodiments the medication is administered as a therapy for a
disease as described herein.
[0064] In some embodiments, the methods, compositions and kits
disclosed herein may include information regarding enrolling and/or
accessing a web-based and/or telephone-based weight management
program. In some embodiments, the enrollment in a web-based and/or
telephone-based weight management program is a requirement of
obtaining the treatment medication. In some embodiments, the
enrollment in a web-based and/or telephone-based weight management
program is permitted only after obtaining a prescription for the
treatment medication or the actual medication. In some embodiments,
the method of treatment comprises enrolling in a web-based and/or
telephone-based weight management program prior to and/or as a
condition of receiving the treatment medication. In some
embodiments, the information includes a unique login or enrollment
key for enrolling and/or accessing a web-based and/or
telephone-based weight management program.
[0065] Instructions and/or information may be present in a variety
of forms, including printed information on a suitable medium or
substrate (e.g., a piece or pieces of paper on which the
information is printed), computer readable medium (e.g., diskette,
CD, etc. on which the information has been recorded), or a website
address that may be accessed via the internet. Printed information
may, for example, be provided on a label associated with a drug
product, on the container for a drug product, packaged with a drug
product, or separately given to the patient apart from a drug
product, or provided in manner that the patient can independently
obtain the information (e.g., a website). Printed information may
also be provided to a medical caregiver involved in treatment of
the patient. In some embodiments, the information is provided to a
person orally.
[0066] Some embodiments comprise a therapeutic package suitable for
commercial sale. Some embodiments comprise a container. The
container can be in any conventional shape or form as known in the
art which is made of a pharmaceutically acceptable material, for
example a paper or cardboard box, a glass or plastic bottle or jar,
a re-sealable bag (e.g., to hold a "refill" of tablets for
placement into a different container), or a blister pack with
individual dosages for pressing out of the pack according to a
therapeutic schedule. The container employed can depend on the
exact dosage form involved, e.g., a conventional cardboard box
would not generally be used to hold a liquid suspension. It is
feasible that more than one container can be used together in a
single package to market a single dosage form. For example, tablets
may be contained in a bottle which is in turn contained within a
box. Non-limiting examples of packs and dispensers as well as oral
dosage forms are disclosed in U.S. Patent Publication Nos.
2008/0110792 and 2008/0113026, both of which are hereby
incorporated herein by reference in their entirety and for all
purposes, including without limitation for the purpose of
describing combinations of naltrexone and bupropion, methods of
making and formulating them into suitable dosage forms, methods of
packing and dispensing them, and methods of administering them.
[0067] The information can be associated with the container, for
example, by being: written on a label (e.g., the prescription label
or a separate label) adhesively affixed to a bottle containing a
dosage form described herein; included inside a container as a
written package insert, such as inside a box which contains unit
dose packets; applied directly to the container such as being
printed on the wall of a box; or attached as by being tied or
taped, e.g., as an instructional card affixed to the neck of a
bottle via a string, cord or other line, lanyard or tether type
device. The information may be printed directly on a unit dose pack
or blister pack or blister card.
[0068] The term "bupropion" may be used in a general way herein to
refer to a free base of bupropion, a pharmaceutically acceptable
bupropion salt (including anhydrous forms, e.g., anhydrous
bupropion), a bupropion metabolite (e.g., hydroxybupropion,
threohydrobupropion, and erythrohydrobupropion), a bupropion
isomer, or mixtures thereof.
[0069] The term "naltrexone" may be used in a general way herein to
refer to a free base of naltrexone, a pharmaceutically acceptable
naltrexone salt (including hydrates and anhydrous forms, e.g.,
naltrexone hydrochloride dihydrate and anhydrous naltrexone
hydrochloride), a naltrexone metabolite, a naltrexone isomer, or
mixtures thereof.
[0070] The term "pharmaceutically acceptable salt," as used herein,
refers to a formulation of a compound that does not cause
significant irritation to an organism to which it is administered
and does not abrogate 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-.beta. naltrexol
hydrochloride.
[0071] Throughout the present disclosure, when a particular
compound is mentioned by name, for example, bupropion or
naltrexone, it is understood that the scope of the present
disclosure encompasses 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 combination with, or
instead of, naltrexone. In any of the embodiments herein, an active
metabolite of bupropion, including S,S-hydroxybupropion (i.e.,
radafaxine), can be used in combination with, or instead of,
bupropion.
[0072] 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, sustained-release dosage forms are
those that have a release rate that is slower that of a comparable
immediate release form, e.g., less than 80% of the release rate of
an immediate-release dosage form.
[0073] An immediate-release naltrexone formulation appropriate for
use as a reference standard is the immediate-release naltrexone
formulation, widely available commercially as the REVIA.RTM. brand
of naltrexone hydrochloride, or an equivalent thereof. An
immediate-release bupropion formulation appropriate for use as a
reference standard is the immediate-release bupropion formulation,
widely available commercially as the WELLBUTRIN.RTM. brand of
bupropion, or an equivalent thereof. The U.S. government regulates
the manner in which prescription drugs can be labeled and thus
reference herein to the REVIA.RTM. brand of naltrexone
hydrochloride and WELLBUTRIN.RTM. brand of bupropion have
well-known, fixed, and definite meanings to those skilled in the
art.
[0074] The term "oral dosage form," as used herein, has its
ordinary meaning as understood by those skilled in the art and thus
includes, by way of non-limiting example, a formulation of a drug
or drugs in a form administrable to a human, including pills,
tablets, cores, capsules, caplets, loose powder, solutions, and
suspensions.
[0075] The terms "mitigate" or "mitigation" of weight gain, as used
herein, include preventing or decreasing the amount of weight gain
associated, e.g., with the administration of a drug or a change in
life activity. In some embodiments, mitigation of weight gain is
measured relative to the amount of weight gain typically
experienced when only one or neither of naltrexone or bupropion is
administered.
[0076] The term "promotion" of weight loss, as used herein,
includes causing weight loss relative to a baseline weight for a
least a portion of the period of treatment. This includes an
individual that initially gains some weight, but during the course
of treatment loses weight relative to a baseline prior to beginning
treatment, as well as individuals that regain a portion or all of
the weight that is lost by the end of the treatment period. In a
preferred embodiment, at the end of the treatment period, the
individual has lost weight relative to a baseline. In a preferred
embodiment, mitigation of weight gain or promotion of weight loss
in a patient administered naltrexone and bupropion is greater than
when neither or only one of naltrexone or bupropion is
administered, and more preferably an at least additive, or better
than additive, or synergistic, effect of administering the two
compounds is achieved.
[0077] In any of the embodiments described herein, methods of
treatment can alternatively entail use claims, such as Swiss-type
use claims. For example, a method of treating overweight or obesity
with a composition can alternatively entail the use of a
composition in the manufacture of a medicament for the treatment of
overweight or obesity, or the use of a composition for the
treatment of overweight or obesity.
[0078] It is understood by those of skill in the art that numerous
and various modifications can be made without departing from the
spirit of the present invention. Therefore, 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. Any reference referred to herein is
incorporated by reference for the material discussed herein, and in
its entirety.
Examples
[0079] The examples below are non-limiting and are merely
representative of various aspects of the invention.
[0080] Example 1 summarizes the protocol for a clinical study
demonstrating that treatment with Naltrexone SR/Bupropion SR does
not increase or decreases the occurrence of Major Adverse
Cardiovascular Events (MACE) in overweight and obese subjects with
cardiovascular risk factors.
TABLE-US-00003 APPENDIX 1 APPENDIX 1: SCHEDULE OF STUDY PROCEDURES
Period: Treatment Visit 7-13 Visit 14 Screening Lead-in Visit 3
(Wks 26, 52, (Wk 208; End of Visit 1 Visit 2 (Day 1) Visit 4 Visit
5 Visit 6 78, 104, 130, End-of- Treatment Remote (Screening) (Wk
-2) (Baseline) (Wk 2) (Wk 8) (Wk 16) 156, 182) Study).sup.5
Visit.sup.6 Contacts.sup.7 Informed Consent X Eligibility Criteria
X X X (labs) Demographics X Medical History X Height X Weight X X X
X X X X X X Waist X X X Circumference Vital Signs (BP and X X X X X
X X X X HR) Concomitant X .sup. X.sup.1 X X Medications Pregnancy
Test X (urine).sup.2 Drug Screen (urine) X Chemistry, X Hematology,
Urinalysis, Lipids, HbAlc, hsCRP Electrocardiogram X Enrollment and
X Lead-in Randomization Study Training X X .sup. X.sup.3 Evaluation
of Study X Medication and Food Diary X Compliance Treatment X
Randomization MACE X X X X X X X X SAEs, AEs Leading X X X X X X X
X to Discontinuation, Pregnancies Weight Management Program
Evaluation to X Continue Treatment Study Medication X X X X X X X
Dispensing/Return.sup.4 Study Medication X X X X X X X X Compliance
The visit window for Visit 3 (Day 1) is .+-.3 days relative to
Visit 2 (Week -2). Post-baseline visit windows are .+-.3 days at
Visit 4, .+-.1 week at Visit 5 and 6, .+-.2 weeks for subsequent
visits. .sup.1For Visits 8, 10, and 12 only. .sup.2Women of
child-bearing potential (including peri-menopausal women who have
had a menstrual period within one year) only. .sup.3Visit 7
training will focus on remote internet or telephone contact
procedures. .sup.4Visit 2 = dispensing only, Visit 14/End-of-Study
Visit, and End-of-Treatment Visit = return only. .sup.5Subjects
with an End-of-Treatment Visit will not return study medication or
have compliance or concomitant medications recorded at Visit
14/End-of-Study Visit. .sup.6Subjects who discontinue study
medication before Week 208 will be asked to return to the study
site for the indicated end-of-treatment assessments, and asked to
return for their remaining visits through Week 208 for follow-up.
.sup.7After Visit 7 and through the remainder of the study,
subjects will answer specific questions pertaining to compliance
and any occurrence of hospitalization through an internet or
telephone based data collection system every 2 months between
visits. Hospitalization information will be used to identify
potential MACE or SAEs.
[0081] Example 2 summarizes the protocol for a clinical study
demonstrating the beneficial effect of Naltrexone SR/Bupropion SR
on body weight and cardiovascular risk factors in overweight and
obese subjects in conjunction with a comprehensive lifestyle
intervention (CLI) program compared minimal lifestyle intervention
program.
TABLE-US-00004 APPENDIX 2 Schedule of Study Procedures for Example
2 Screening Visit 2 Controlled Treatment Period Visit 1 (Day 1)
Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 (Screen) (Baseline)
(Wk 2) (Wk 6) (Wk 10) (Wk 16) (Wk 20) (Wk 26) Informed Consent X
Eligibility Criteria X X Demographics X Medical History X X Height
X Electrocardiogram, X Physical Exam Chemistry, Hematology, X
Urinalysis, Drug Screen (urine) Randomization X Weight, Vital Signs
X X X X X X X X (BP and HR) Waist X X Circumference Concomitant X X
X X X X X X Medications Review Pregnancy Test X X X X X X X X
(urine) Lipids, Glucose, X (glucose, X X X Insulin TG only) Patient
Reported X X X Outcome Measures (BES, ASEX, IWQOL-Lite) Query for
SAEs X X X X X X Minimal Lifestyle X X Intervention (Usual Care
only) Evaluation to X Continue Treatment (NB only) Review CLI X X X
X X X X participaton (NB only) Study Medication X X X X X X
Dispensing/Return (NB only) Study Medication X X X X X X Compliance
(NB only) The visit window between Visit 1 (Screening) and Visit 2
(Day 1, Baseline) is up to 2 weeks. Visit windows are days at Visit
4 and 4; week at Visits 5, 6, 7, and 8 relative to Visit 2.
Subjects should arrive having fasted (no food or beverage except
water) overnight for at least 8 hours before this visit. Subjects
should receive a call from a member of the study site staff 1 to
days prior to these visits (except Visit 1) reminding them to fast
for at least hours prior to the visit. Women of child-bearing
potential (including peri-menopausal women who have had a menstrual
period within one year) only. Glucose and glycerides at Visit are
to confirm subject eligibility. Measures at Visit are to obtain
baseline values. Subjects are to be registered for the CLI program
and receive instructions at this visit. Subjects randomized to
Usual Care who switch to NB and CLI are to be registered for the
CLI program and receive instructions at this visit. Dispensing only
at this visit. Subjects randomized to Usual Care who switch to NB
are to be dispensed study medications at this visit. Uncontrolled
Treatment Period End of Full Visit 9 Visit 10 Visit 11 Visit 12
Visit 13 Visit 14 Visit 15 Participation (Wk 32) (Wk 36) (Wk
42).sup.1 (Wk 46) (Wk 52).sup.1 (Wk 65) (Wk 78).sup.1 Visit Weight.
Vital Signs X X X X X X X X (BP, HR) Waist Circumference X X X X
Concomitant X X X Medications Pregnancy Test (urine).sup.2 X X X X
X X X X Lipids, Glucose, Insulin X X X Patient Repented .sup.
X.sup.3 Outcome Measures (BES, ASEX, IWQOL- Lite) Query for SAEs X
X X X X X X X Evaluation to Continue X Treatment (Usual care
.fwdarw. NB only) Review CLI X X X X X X X .sup. X.sup.4
participation Study Medication X X X X X X .sup. X.sup.5 .sup.
X.sup.5 Dispensing/Return Studs- Medication X X X X X X X X
Compliance Visit windows are .+-.3 days at Visit 9; .+-.1 week at
Visits 10, 11, 12, and 13 relative to Visit 2: .+-.2 weeks at Visit
14 and 15 relative to Visit 2. .sup.1Subjects should arrive having
fasted (no food or beverage except water) overnight for at least 8
hours before this visit. Subjects should receive a call from a
member of the study site staff 1 to 3 days prior to these visits
reminding them to fast for at least 8 hours prior to the visit.
.sup.2Women of child-bearing potential (including peri-menopausal
women who have had a menstrual period within one year) only.
.sup.3To be completed if the End of Full Participation Visit occurs
during the Controlled Treatment Period. .sup.4NB only at this
visit. .sup.5Returning only at this visit. indicates data missing
or illegible when filed
TABLE-US-00005 TABLE 3 Canadian Cardiovascular Society grading
scheme for angina pectoris Grade Description Grade I Ordinary
physical activity does not cause angina, such as walking and
climbing stairs. Angina with strenuous or rapid or prolonged
exertion at work or recreation. Grade II Slight limitation of
ordinary activity. Walking or climbing stairs rapidly, walking
uphill, walking or stair climbing after meals, or in cold, or in
wind, or under emotional stress, or during the few hours after
awaking. Walking more than two blocks on the level and climbing
more than one flight of ordinary stairs at a normal pace and in
normal conditions. Grade III Marked limitation of ordinary physical
activity. Walking one or two blocks on the level and climbing one
flight of stairs in normal conditions and at normal pace. Grade IV
Inability to carry on any physical activity without discomfort,
angina syndrome may be present at rest. Campeau, 1976. Available on
the Canadian Cardiovascular Society Website at www.ccs.ca
TABLE-US-00006 TABLE 4 New York Heart Association: the stages of
heart failure Class Patient symptoms Class I (Mild) No limitation
of physical activity. Ordinary physical activity does not cause
undue fatigue, palpitation, or dyspnea (shortness of breath). Class
II (Mild) Slight limitation of physical activity. Comfortable at
rest, but ordinary physical activity results in fatigue,
palpitation, or dyspnea. Class III (Moderate) Marked limitation of
physical activity. Comfortable at rest, but less than ordinary
activity causes fatigue, palpitation, or dyspnea. Class IV (Severe)
Unable to carry out any physical activity without discomfort.
Symptoms of cardiac insufficiency at rest. If any physical activity
is undertaken, discomfort is increased. Available on the Heart
Failure Society of America website at www.abouthf.org
* * * * *
References