A Weight Loss Study in Overweight Men and Women

Study Overview
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Brief Summary
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The purpose of this study is to determine if LY377604 + sibutramine work better than LY377604 or sibutramine alone in the treatment of obesity.

Official Title
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LY377604 + Sibutramine Hydrochloride Monohydrate: A Phase 2 Weight Loss Efficacy Study in Overweight/Obese Men and Women

Conditions
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Obesity

Intervention / Treatment
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* Drug: LY377604
* Drug: Sibutramine
* Drug: Metoprolol
* Drug: Placebo sibutramine
* Drug: Placebo Metoprolol
* Drug: Placebo LY377604


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are between the body mass index (BMI) of 27 and 45 kg/m^2, inclusive, at the time of screening. Exclusion Criteria: Have a Diastolic Blood Pressure (DBP) greater than 90 mm Hg or less than 55 mm Hg, and/or Systolic Blood Pressure (SBP) >140 mm Hg or <90 mmHg, confirmed by at least 1 repeat measurement. Subjects with hypertension treated with antihypertensive medication are not excluded if blood pressure is within the prescribed limits and they are not treated with excluded medications. Changes in antihypertensive medication are not permitted within 30 days prior to randomization Previous history of poorly controlled hypertension, (that is, >160/100 or hypertension which requires more than 2 drugs for control). Have a pulse rate >90 bpm or <50 bpm. Evidence or history of prior significant cardiovascular disease, coronary artery disease, cardiovascular surgery, significant valvular disease, heart failure, arrhythmias, sick sinus syndrome or stroke. Current treatment with β-blockers, calcium channel blockers, digitalis glycosides (for example, digoxin, etc), or clonidine. Recent treatment (within 2 weeks prior to randomization) with catecholamine-depleting drugs (such as reserpine or tetrabenazine, monoamine oxidase inhibitors (MAOIs). Current treatment with serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRI), any drug that is a serotonin, norepinephrine, or dopamine reuptake inhibitor, triptan or ergot therapies for migraine or nausea, or serotonin-releasing agents. Treatment with significant inhibitors of Cytochrome P2D6 (CYP2D6), such as bupropion, fluoxetine, paroxetine, quinidine, duloxetine, amiodarone, cimetidine, chlorpheniramine, clomipramine, doxepin, haloperidol, methadone, mibefradil, and ritonavir. Participants with bronchospastic diseases or who are treated with bronchodilators or other prescription or nonprescription beta adrenergic agonists. Peripheral vascular disease History of thyrotoxicosis History of seizures (except for childhood febrile convulsion) or at increased risk of seizures (for example, history of significant head trauma or intracranial surgery). Have had a significant change in weight, defined as a gain or loss of at least 4 kg (9 lb) in the 90 days prior to randomization Have had bariatric surgery (for example, gastric banding or gastric bypass) Have had liposuction within 90 days prior to randomization Have a disease that affects adipose mass or distribution of energy balance (for example, Cushing's syndrome, uncontrolled hyper- or hypothyroidism). Have taken in the 30 days prior to randomization, a medication, herbal product, or nutritional supplement that affects adipose mass or distribution or energy balance, such as glucocorticoids, antiretrovirals, atypical antipsychotics, lithium, valproic acid, lamotrigine, or other anticonvulsants, mirtazapine, bupropion, phentermine, sibutramine, orlistat, rimonabant, amphetamine, or ephedra-containing supplements. Note: Medications that have small and transient effects on weight or medications that may affect weight independent of adipose mass (for example, estrogens or diuretics), may be continued, but may not be started, stopped, or changed during the course of the study. Have been diagnosed with an eating disorder, such as anorexia, bulimia, binge eating disorder, or nocturnal eating disorder. Have diabetes mellitus treated with medication, or type 2 diabetes mellitus managed with diet and exercise with hemoglobin A1c (HbA1C) >7.0%. Symptomatic cholelithiasis in the 90 days prior to randomization. Any lifetime history of suicide attempt. History of major depressive disorder in the last 2 years or any lifetime history of severe psychiatric disorders (for example, schizophrenia or bipolar disorder).

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br> | Drug: Placebo sibutramine<br>* given daily, orally for 24 weeks<br>Drug: Placebo Metoprolol<br>* given daily, orally for 26 weeks (24 weeks plus 2 weeks of taper)<br>Drug: Placebo LY377604<br>* given daily, orally for 24 weeks<br>|
| Experimental: LY377604 (75 mg)<br> | Drug: LY377604<br>* Given daily, orally for 24 weeks<br>Drug: Placebo sibutramine<br>* given daily, orally for 24 weeks<br>Drug: Placebo Metoprolol<br>* given daily, orally for 26 weeks (24 weeks plus 2 weeks of taper)<br>|
| Active Comparator: sibutramine (30 mg)/metoprolol (200 mg)<br> | Drug: Sibutramine<br>* given daily, orally for 24 weeks<br>Drug: Metoprolol<br>* given daily, orally for 24 weeks (100 mg for 1 week followed by 200 mg for 23 weeks. Patients unable to tolerate 200 mg will be dose reduced to 100 mg), followed by a 2 week taper (1 week at 100 mg/day followed by 1 week at 50 mg/day).<br>|
| Experimental: LY377604 (40 mg)/sibutramine (30 mg)<br> | Drug: LY377604<br>* Given daily, orally for 24 weeks<br>Drug: Sibutramine<br>* given daily, orally for 24 weeks<br>Drug: Placebo Metoprolol<br>* given daily, orally for 26 weeks (24 weeks plus 2 weeks of taper)<br>|
| Experimental: LY377604 (75 mg)/sibutramine (30 mg)<br> | Drug: LY377604<br>* Given daily, orally for 24 weeks<br>Drug: Sibutramine<br>* given daily, orally for 24 weeks<br>Drug: Placebo Metoprolol<br>* given daily, orally for 26 weeks (24 weeks plus 2 weeks of taper)<br>|
| Experimental: LY377604 (15 mg)/sibutramine (30 mg)<br> | Drug: LY377604<br>* Given daily, orally for 24 weeks<br>Drug: Sibutramine<br>* given daily, orally for 24 weeks<br>Drug: Placebo Metoprolol<br>* given daily, orally for 26 weeks (24 weeks plus 2 weeks of taper)<br>|
| Experimental: LY377604 (75 mg)/sibutramine (15 mg)<br> | Drug: LY377604<br>* Given daily, orally for 24 weeks<br>Drug: Sibutramine<br>* given daily, orally for 24 weeks<br>Drug: Placebo Metoprolol<br>* given daily, orally for 26 weeks (24 weeks plus 2 weeks of taper)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Body Weight From Baseline to 24 Week Endpoint | Body weight percentage change from baseline is presented as Least Squares Mean (LSMean) with treatment, visit, and their interaction as fixed effects, subject as a random effect, baseline body weight, age, gender were used as covariates. | Baseline, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Mean Change in Body Weight From Baseline to 24 Week Endpoint | Body weight change from baseline is presented as Least Squares Mean (LSMean) with treatment, visit, and their interaction as fixed effects, subject as a random effect, baseline body weight, age, gender were used as covariates. | Baseline, 24 weeks | 
| Percentage of Participants Who Achieve a Minimum of 10% Weight Loss From Baseline at 24 Weeks |  | 24 weeks | 
| Change in Heart Rate From Baseline to 24 Week Endpoint | Heart rate change from baseline is presented as Least Squares Mean (LSMean) with treatment, visit, and their interaction as fixed effects, subject as a random effect, baseline heart rate, age, gender were used as covariates. | Baseline, 24 weeks | 
| Change in Blood Pressure From Baseline to 24 Week Endpoint | Blood pressure change from baseline is presented as Least Squares Mean (LSMean) with treatment, visit, and their interaction as fixed effects, subject as a random effect, baseline blood pressure, age, gender were used as covariates. | Baseline, 24 weeks | 
| Change in Body Composition Using Dual Energy X-ray Absorptiometry (DXA) From Baseline to 24 Week Endpoint | Change in body composition (lean body mass and fat mass) was assessed using dual energy x-ray absorptiometry (DXA) and is presented as LSMEAN values with treatment, visit, and their interaction as fixed effects, subject as a random effect, baseline body composition, age, gender were used as covariates. | Baseline, 24 weeks | 
| Change in Waist Circumference From Baseline to 24 Week Endpoint | Change from baseline to endpoint is presented as LSMEAN with treatment, visit, and their interaction as fixed effects, subject as a random effect, baseline waist circumference, age, gender were used as covariates. | Baseline, 24 weeks | 
| Percentage Change in Waist Circumference From Baseline to 24 Week Endpoint | Percentage change from baseline to endpoint is presented as LSMEAN with treatment, visit, and their interaction as fixed effects, subject as a random effect, baseline waist circumference, age, gender were used as covariates. | Baseline, 24 weeks | 
| Change in Total Cholesterol From Baseline to 24 Weeks Endpoint |  | Baseline, 24 weeks | 
| Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to 24 Weeks Endpoint |  | Baseline, 24 weeks | 
| Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to 24 Weeks Endpoint |  | Baseline, 24 weeks | 
| Change in Triglycerides From Baseline to 24 Weeks Endpoint |  | Baseline, 24 weeks | 
| Change From Baseline for Obesity Weight Loss Quality of Life Instrument (OWL-QoL) | Results presented as Least Squares Mean with treatment, visit, and their interaction as fixed effects, subject as random effect, baseline body mass index used as covariate. OWL-QoL consists of 17 items on scale ranging from 0 (Not at all) to 6 (A very great deal). Before calculating scores, each item is reversed. A single quality of life score is computed by summing each item and transforming this raw score onto standardized scale of 0 (greatest impact) to 100 (lowest impact) using formula: score = [(sum of component items score (minus) lowest possible score/ possible raw score range)*100]. | Baseline, 24 weeks | 
| Change From Baseline in Vitality Scale of Medical Outcomes Short Form - 36 (SF-36) Scale | Vitality change from baseline is presented as Least Squares Mean (LSMean) with treatment, visit, and their interaction as fixed effects, subject as a random effect, baseline body mass index was used as covariate. SF-36 is a self-reported questionnaire that consists of 36 questions covering 8 health domains including vitality. The vitality domain results are presented. The vitality domain is scored by summing the individual items and transforming the scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. | Baseline, 24 weeks | 
| Change in Glycated Hemoglobin A1c (HbA1c) From Baseline | Analysis of change in HbA1c was not conducted due to an inadequate number of samples. | Baseline, 24 weeks | 
| Change in Fasting Glucose From Baseline to 24 Weeks Endpoint | Analysis of change in fasting glucose was not conducted due to an inadequate number of samples. | Baseline, 24 weeks | 
| Change in Fasting Insulin From Baseline to 24 Weeks Endpoint | Analysis of change in fasting insulin was not conducted due to an inadequate number of samples. | Baseline, 24 weeks | 
| Change in Insulin Resistance From Baseline to 24 Weeks Endpoint | Analysis of change in insulin resistance was not conducted due to an inadequate number of samples. | Baseline, 24 weeks | 
| Pharmacokinetics: Area Under the Concentration Time Curve (AUC) | Analysis of AUC was not conducted due to an inadequate number of samples collected. | 4 weeks, 12 weeks, and 24 weeks | 
| Pharmacokinetics: Maximum Concentration (Cmax) | Analysis of Cmax was not conducted due to an inadequate number of samples collected. | 4 weeks, 12 weeks, and 24 weeks |