Safety and Efficacy of Different Combinations of Zonisamide-CR Plus Bupropion-SR to Treat Uncomplicated Obesity

Condition(s) targeted: Obesity

Intervention: Zonisamide CR and Bupropion SR (Drug); Placebo (Other)

Phase: Phase 2

Status: Completed

Sponsored by: Orexigen Therapeutics, Inc

Official(s) and/or principal investigator(s):
Frank Greenway, MD, Principal Investigator, Affiliation: Pennington Biomedical Research Center

The purpose of this study is to determine which of seven combinations of Zonisamide CR and Bupropion SR gives the best weight loss and is safe and well tolerated for the treatment of obesity not associated with the complications of obesity such as diabetes. In a previous study, the combination of zonisamide and bupropion SR was shown to be effective for weight loss compared to either zonisamide, bupropion SR alone or placebo. It is thought that by adjusting the doses of each drug, giving zonisamide in a controlled release (CR) form and increasing the doses more slowly, more weight loss and less side effects can be attained.

Official title: A Dose Parallel, Randomized, Placebo-Controlled, Multicenter Study of the Safety and Efficacy of Multiple Regimens of the Combination of Zonisamide CR Plus Bupropion SR in the Treatment of Subjects With Uncomplicated Obesity

Study design: Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: % change in total body weight as measured between baseline and week 24 (ITT-LOCF analysis)

Secondary outcome:

Absolute change in total body weight in kg.

Proportion of subjects achieving > 5% weight loss.

Proportion of subjects achieving > 10% weight loss.

Proportion of subjects achieving > 5% weight loss at week 24 who maintain response to week 48

Change in measures of quality of life, sleep quality and sleep quantity

Change in fasting triglycerides level

Change in fasting blood glucose

Change in systolic and diastolic blood pressure

Change in HAMD-17 Maier subscale scores

Change in Brief Assessment of Cognition composite scores

Detailed description: Over the past few years, knowledge of the pathways and neural circuits that sense body energy stores has increased dramatically. In particular, it has been shown that the melanocortin system, a group of neuronal circuits in the arcuate nucleus of the hypothalamus, is the "final common pathway" for most energy state signals, and that melanocortin signaling is necessary for normal control of food intake and energy expenditure. Stimulation of POMC neurons by serotonergic and dopaminergic agents results in release of α-, β- and γ-MSH through the action of prohormone convertase-2 with a consequent decrease in appetite. A second counter-regulatory system that inhibits POMC activation is β-endorphin, which binds to a mu-opioid receptor (MOP-R) and acts as an auto-inhibitory "brake" on the activity of the melanocortin circuits. Bupropion is an approved antidepressant that blocks reuptake of

serotonin and dopamine. This stimulates secretion of both α - MSH and β-endorphin. α -MSH

binds to melanocortin receptors which in turn results in appetite suppression and increased energy expenditure. β-endorphin, however, binds to a mu-opioid receptor (MOP-R) and inhibits the activity of the melanocortin circuits. Zonisamide has multiple effects that may protect against seizures, including blockade of sodium channels, and reducing voltage dependent inward (T type) calcium currents, leading to neuronal stabilization. In addition to these actions, however, it is known to increase 5-hydroxytryptophan and dopamine levels,

simultaneously stimulating α - MSH release while inhibiting AGRP release. Thus, the

combination of bupropion and zonisamide stimulates the melanocortin system while blocking an important feedback inhibitory pathway.

The combination of zonisamide 400 mg/day and bupropion SR 300 mg/day has been shown to be more effective for weight loss than either monotherapy or placebo in subjects with uncomplicated obesity. The hypothesis for the current trial is that greater efficacy and improved tolerability can be achieved by adjusting the doses and titration of both bupropion SR and zonisamide, and by giving zonisamide in a controlled release (CR) formulation.

Minimum age: 18 Years. Maximum age: 60 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Have body mass index (BMI) of 30 to 43 kg/m2

- Free from any other clinically significant illness or disease as determined by medical

history and physical examination

- Non-smoker and no use of tobacco or nicotine products for at least 6 months prior to

screening

- Normotensive (systolic <140 mm Hg; diastolic <90 mm Hg). Anti-hypertensive medications

are allowed with the exception of adrenergic blockers, beta-blockers and clonidine. Medical regimen must be stable for at least 6 weeks

- LDL cholesterol < 190 mg/dL and triglycerides < 400 mg/dL. Medications for treatment

of dyslipidemia are allowed as long as medical regimen has been stable for at least 6 weeks

- Negative serum pregnancy test in women with an intact uterus

- Score < 15 for depression and score < 15 for anxiety on Hospital Anxiety and

Depression Scale (HADS)

- No clinically significant abnormality on ECG

- Not on eExcluded concomitant medications

- If female with intact uterus, be non-lactating, and agree to use effective

contraception throughout the study period and for 30 days after discontinuation of study drugs.

- Able to comply with all required study procedures and schedule

- Able to use and have access to a touch tone telephone and to speak and read English

Exclusion Criteria:

- Obesity of known endocrine or genetic origin

- Serious medical condition

- Serious psychiatric illness

- Active suicidal ideation; score > 2 on the Mood Assessment questionnaire

- A response to Bipolar Disorder questions indicating the presence of Bipolar Disorder

- Type I diabetes mellitus or Type II diabetes mellitus requiring pharmacotherapy

- History of alcohol or drug abuse, current or within 5 years

- History of bulimia or anorexia nervosa

- History of surgical intervention for obesity

- History of seizure disorder or predisposition to seizures (e. g., history of

cerebrovascular accident, significant head trauma, brain surgery, skull fracture, subdural hematoma, or alcohol withdrawal or febrile seizures)

- History of hypersensitivity to sulfonamides ("sulfa"), bupropion, or zonisamide

- History of nephrolithiasis (renal calculi)

- History of treatment with bupropion SR (Wellbutrin, Zyban) or zonisamide (Zonegran)

within 12 months

- Use of drugs, herbs, or dietary supplements known to significantly affect body weight

or participation in a weight loss management program within one month prior to baseline

- Loss or gain of more than 4. 0 kilos within 3 months

- Women of child bearing potential not adhering to an acceptable form of contraception

- Pregnant or breast-feeding women

- Use of investigational drug, device or procedure within 30 days

- Participation in any previous clinical trial conducted by Orexigen Therapeutics

- Planned surgical procedure that can impact the conduct of the study

- Any condition which in the opinion of the investigator makes the subject unsuitable

for inclusion in this study

SelfCenter, PC, Fairhope, Alabama 36532, United States

Scripps Clinic Del Mar, San Diego, California 92130, United States

UCLA Center for Human Nutrition, Los Angeles, California 90095, United States

Center for Human Nutrition University of Colorado Health Sciences Center, Denver, Colorado 80220, United States

George Washington University Weight Management Program, Washington, District of Columbia 20037, United States

CSRA Partners in Health, Inc, Augusta, Georgia 30909, United States

Springfield Diabetes and Endocrine Center, Springfield, Illinois 62704, United States

Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, United States

Nutrition and Weight Mangement Center Boston Medical Center, Boston, Massachusetts 02118, United States

Center for Nutrition and Metabolic Diseases, Reno, Nevada 89557, United States

Comprehensive Weight Control Program, New York, New York 10021, United States

Center for Nutrition and Preventive Medicine, Charlotte, North Carolina 28211, United States

MUSC Weight Mnagement Center, Charleston, South Carolina 29425, United States

The Cooper Institute, Dallas, Texas 75230, United States

Baylor Endocrine Center, Dallas, Texas 75246, United States

Starting date: May 2006
Ending date: August 2007
Last updated: April 18, 2008