A Study to Evaluate the Effect on Body Weight of Leptin Administered in Conjunction With Pramlintide in Overweight and Obese Subjects

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, and effect on body weight of leptin, injected subcutaneously, in combination with pramlintide, injected subcutaneously.

Official Title
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A Phase 2A, Randomized, Controlled, Double-Blind, Multicenter Study to Evaluate the Safety, Tolerability, and Effect on Body Weight of Recombinant-Methionyl Human Leptin Administered in Conjunction With Pramlintide in Overweight and Obese Subjects

Conditions
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Overweight, Obesity

Intervention / Treatment
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* Drug: pramlintide acetate 360 mcg
* Drug: metreleptin
* Drug: placebo-pramlintide 600 uL
* Drug: placebo-metreleptin 1 mL
* Drug: Pramlintide acetate 180 mcg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is obese (Body Mass Index [BMI]>=30kg/m^2 and <=35kg/m^2); or overweight (BMI>=27kg/m^2 and <30kg/m^2) with abdominal obesity, based on the following: *waist circumference >102 cm if male, *waist circumference >88 cm if female Is a nonsmoker (has not smoked for at least 6 months prior to the study) Consumes a morning and evening meal each day Exclusion Criteria: Is diagnosed with type 2 diabetes Is currently enrolled or plans to enroll in a diet, weight loss, or exercise program with the specific intent of losing weight (subjects who have been following an exercise regimen resulting in stable weight maintenance for at least 2 months prior to enrollment are eligible for study inclusion) Has been treated over the past 2 months, is currently treated, or is expected to require or undergo treatment with any of the following medications: *antiobesity agents (prescription or over-the-counter), *antipsychotic agents, *antiepileptic agents, *antidepressant agents, *drugs that directly affect gastrointestinal motility Has received any investigational drug within 30 days or within a period corresponding to 5 half-lives of that drug, whichever is greater, prior to this study starting Has previously received treatment with recombinant leptin or pramlintide

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo and Metreleptin<br>Placebo-pramlintide 600 microliters (µL) twice a day (BID) and metreleptin (recombinant-methionyl human leptin) 5 milligram (mg) BID, 20 weeks | Drug: metreleptin<br>* subcutaneous injection, twice a day, 5mg<br>* Other names: recombinant-methionyl human leptin;Drug: placebo-pramlintide 600 uL<br>* twice a day<br>|
| Experimental: Pramlintide Acetate and Placebo<br>Lead-in period: 2 weeks pramlintide acetate 180 mcg BID, then 2 weeks pramlintide acetate 360 mcg BID Study period: Pramlintide acetate 360 mcg BID and placebo-metreleptin 1 mL BID, 20 weeks | Drug: pramlintide acetate 360 mcg<br>* subcutaneous injection, twice a day, 360mcg<br>* Other names: SYMLIN®;Drug: placebo-metreleptin 1 mL<br>* twice a day<br>|
| Experimental: Pramlintide Acetate and Metreleptin<br>Lead-in period: 2 weeks pramlintide acetate 180 mcg BID, then 2 weeks pramlintide acetate 360 mcg BID Study period: Pramlintide acetate 360 mcg BID and metreleptin (recombinant-methionyl human leptin) 5 mg BID, 20 weeks | Drug: pramlintide acetate 360 mcg<br>* subcutaneous injection, twice a day, 360mcg<br>* Other names: SYMLIN®;Drug: metreleptin<br>* subcutaneous injection, twice a day, 5mg<br>* Other names: recombinant-methionyl human leptin;|
| Other: Lead-In Period<br>During the Lead-In Period before a participant was randomized to a study arm, the participant received 180 mcg pramlintide acetate twice a day (BID) for 2 weeks, followed by 360 mcg pramlintide acetate BID for 2 weeks (total of 4 weeks in the Lead-In Period). | Drug: pramlintide acetate 360 mcg<br>* subcutaneous injection, twice a day, 360mcg<br>* Other names: SYMLIN®;Drug: Pramlintide acetate 180 mcg<br>* subcutaneous injection twice a day, 180 mcg<br>* Other names: SYMLIN®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Absolute Change From Baseline to Week 16 in Body Weight - Evaluable Population | Absolute change in body weight as measured in kilograms (kg) from baseline to Week 16. Baseline defined as Day 1 of randomized treatment. | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population | Least Squares (LS) mean percent change in body weight from baseline to Weeks 4 through 20. Baseline defined as Day 1 of randomized treatment. | Baseline up to Week 20 | 
| LS Mean Absolute Change From Baseline to Weeks 4, 8, 12, 20 in Body Weight - Evaluable Population | Least Squares (LS) mean absolute change in body weight as measured in kilograms (kg) from baseline to Weeks 4, 8, 12, 20. Baseline defined as Day 1 of randomized treatment | Baseline to Week 20 | 
| LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population | Least Squares (LS) mean change in body weight as measured in kilograms (kg) from enrollment to each study visit. Enrollment was Visit 2 (Week -4) which was the start of the Lead-In Period. After the 4 week Lead-In Period, at Day 1, the participant was randomized to one of the 3 study arms and the participant was treated as per that arm up to Week 20. | Enrollment to Week 20 | 
| LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population | Least Squares (LS) mean percent change is percentage that body weight changed over time at each visit. Enrollment was Visit 2 (Week -4) which was the start of the Lead-In Period. After the 4 week Lead-In Period, at Day 1, the participant was randomized to one of the 3 study arms and treated up to Week 20. | Enrollment to Week 20 | 
| Initial, Late, and Overall Rates of LS Mean Absolute Change in Body Weight From Day 1 to Week 20 - Evaluable Population | Initial (Day 1 through Week 12), late (Week 12 through Week 20), and overall (Day 1 through Week 20) rates of Least squares (LS) mean absolute change in body weight were defined by the slopes of the regression lines fitted to the observed body weights during the periods from Baseline (Day 1) through each visit to Week 20. Initial, late and overall absolute change was measured in kilograms of body weight per week (kg/week). Baseline refers to Visit 4 (Day 1 of randomization period). | Baseline to Week 20 | 
| Number of Participants Achieving at Least 5% and at Least 10% Body Weight Loss From Baseline to Weeks 16 and 20, and Number of Participants With Sustained Weight Loss in Each Category - Evaluable Population | Baseline refers to Visit 4 (Day 1 of randomization period). Number of participants with 5% or more and 10% or more change in weight from baseline at each visit. Number of participants with 5% or more change in weight that was sustained through Week 16. Number of participants with 10% or more change in weight that was sustained through Week 20. | Baseline to Weeks 16 and Weeks 20 | 
| LS Mean Percent Change in Weight From Enrollment to Baseline and LS Mean Percent Change in Excess Weight From Enrollment to Baseline - Evaluable Population | Excess body weight: the difference between a participant's actual body weight and the weight a participant of his/her height would have if his/her BMI were 24.9 kg/m2. Excess body weight at a given visit was calculated as body weight in kilograms (kg) at that visit minus 24.9 × height in meters (m)^2 or 0, whichever was greater. If a participant achieved a normal BMI (24.9 kg/m^2), that subject was considered to have no excess weight. Additional weight loss that occurred after a normal BMI was achieved was not included in the calculation of excess weight loss. Enrollment was Visit 2 (Week -4), the start of the Lead-In Period. Baseline was Day 1 of the randomization to a study arm. | Enrollment to Baseline | 
| LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population | Waist circumference was measured in centimeters (cm). Least Squares mean = LS mean. Enrollment was Visit 2 (Week -4) which was the start of the 4 week Lead-In Period. At Day 1, the participant was randomized to one of the 3 study arms and the participant was treated up to Week 20. | Enrollment to Week 20 | 
| LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population | Baseline was Visit 4 (Day 1 of randomization period). Waist circumference was measured in centimeters (cm). | Baseline to Week 20 | 
| LS Mean Absolute Change in Hip Circumference From Screening up to Week 20 - Evaluable Population | Screening (Week -5 or -6) was the first visit for a participant. This first visit determined participant eligibility and occurred prior to enrollment (Week -4). Hip circumference was measured in centimeters (cm). | Screening up to Week 20 | 
| Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population | BMI was measured as kilogram per meter of height squared (kg/m^2). Enrollment was Visit 2 (Week -4). Participants who were obese (BMI of 30 kg/m^2 to <35 kg/m^2) at enrollment were evaluated at Week 16 to see if the same number who were obese at enrollment were still obese at Week 16 or if they had changed to an BMI of overweight (BMI of 25 kg/m^2 to <30 kg/m^2) or a BMI of normal (BMI of <25 kg/m^2) or a greater obesity (BMI >35 kg/m^2). Participants who were overweight (BMI of 25 kg/m^2 to <30 kg/m^2) at enrollment were evaluated at Week 16 to see if the same number who were overweight at enrollment were still overweight at Week 16 or if they had changed to normal (or obese). | Enrollment up to Week 16 | 
| Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population | BMI was measured as kilogram per meter of height squared (kg/m^2). Enrollment was Visit 2 (Week -4). Participants who were obese (BMI of 30 kg/m^2 to <35 kg/m^2) at enrollment were evaluated at Week 20 to see if the same number who were obese at enrollment were still obese at Week 20 or if they had changed to an BMI of overweight (BMI of 25 kg/m^2 to <30 kg/m^2) or a BMI of normal (BMI of <25 kg/m^2) or a greater obesity (BMI >35 kg/m^2). Participants who were overweight (BMI of 25 kg/m^2 to <30 kg/m^2) at enrollment were evaluated at Week 20 to see if the same number who were overweight at enrollment were still overweight at Week 20 or if they had changed to normal (or obese). | Enrollment up to Week 20 | 
| Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population | Enrollment was Visit 2 (Week -4). Baseline refers to Visit 4 (Day 1 of randomization period). Fasting Lipids included: total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and Triglycerides. Fasting Glucose and Lipids were measured in milligrams per deciliter (mg/dL). | Enrollment to Week 16 | 
| Mean Absolute Change From Enrollment to Baseline, Weeks 4 and 16 in Fasting Total Leptin Concentration - Evaluable Population | Enrollment was Visit 2 (Week -4). Baseline refers to Visit 4 (Day 1 of randomization period). Leptin was measured in nanograms per milliliter (ng/mL). Plasma total leptin (including endogenous leptin and exogenous metreleptin) concentrations were measured using a validated sandwich-type immunoenzymetric assay utilizing polyclonal capture antibody, monoclonal detection antibody, and colorimetric readout by Amylin Pharmaceuticals, Inc. This assay is not specific for metreleptin and detects both endogenous leptin and exogenous recombinant-methionyl human leptin [metreleptin]). | Enrollment to Week 16 | 
| Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Amylin -Evaluable Population | Enrollment was Visit 2 (Week -4). Baseline refers to Visit 4 (Day 1 of randomization period). Fasting total plasma amylin (peptide produced by beta cells in the pancreas) concentration was measured in picomolar (pM) and samples were obtained at screening, enrollment, baseline, Week 4 and Week 16. | Enrollment to Week 16 | 
| Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Insulin - Evaluable Population | Enrollment was Visit 2 (Week -4). Baseline refers to Visit 4 (Day 1 of randomization period). Total insulin was measured in micro international units per milliliter (µIU/mL) | Enrollment to Week 16 | 
| LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcome (PRO) Instruments Measuring Quality of Life and Mood - Evaluable Population | Enrollment was Visit 2 (Week -4). PRO: Total Score in Impact of Weight on Quality of Life Questionnaire-lite Version (IWQOL-Lite), 31-item instrument used to assess the effect of weight on physical function, self-esteem, sexual life, public distress, and work. Individual items range from 1 to 5 with 5=always true and 1= never true. Total score measured on scale from 0 (worst) to 100 (best). Higher scores indicate improvement; Profile of Mood States (POMS), 65 mood adjectives that assess participants' mood over the past seven days. The POMS-B is an authorized, 30-item brief version of the POMS consisting of five items for each: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. Scores range from 0= Not at All to 4=Extremely. Factor scores added for total score. Lower score indicates improvement. 0=best outcome; 120=worst outcome. | Enrollment to Week 16 | 
| LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population | Enrollment was Visit 2 (Week -4). PRO for eating behavior: Binge Eating Scale (BES) Total Score (16-item questionnaire assessed the behavioral and cognitive correlates of binge eating, including participants' perceived self-control over eating behavior using a range of 1 to 4 with 1=positive perceptions and 4= negative perceptions. Minimum and maximum scores were 0 and 55, respectively); Susceptibility to Eating Questionnaire (SEQ) Total Score (measure of appetite, satiety, and perceived control over portion size using 10 VAS items with each response measured on a 100 mm visual analogue scale [ranges vary from Never to Very Often; Not at All Difficult to Extremely Difficult; Not at all Strong to Very Strong]. Responses to these items rated over the past 7 days; | Enrollment to Week 16 | 
| LS Mean Absolute Change From Enrollment to Week 16 in Hospital Anxiety and Depression Scale (HADS) - Evaluable Population | The HADS is a questionnaire that uses 14 items to assess both anxiety and depression over the past week. The odd numbered items constitute the anxiety subscale, and the even numbered items constitute the depression subscale. The individual response scores for each subscale component are added together to obtain the individual subscale scores. The minimum and maximum score for each subscale is 0 and 21, respectively. The lower the score the more improvement a participant shows. | Enrollment to Week 16 | 
| Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population | Enrollment was Visit 2 (Week -4). Blood pressure (BP) was measured after 5 minutes of quiet rest with the participant in a sitting position and was measured in millimeters of mercury (mm Hg). Blood pressure was taken at each visit (screening, Week -4, Week -2, Day 1, Weeks 4, 8, 12, 16, 20 (or early termination). After the Lead-In Period, participants were either randomized to one of the 3 arms of the study or they were dropped from the study so the time frame for evaluation of all participants in the study was either: enrollment up to Week 20 for Randomized participants or enrollment up to, but not including Day 1 for Non-Randomized participants who participated only in the Lead-In Period. | Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group) | 
| Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Heart Rate - Enrolled Population | Enrollment was Visit 2 (Week -4). Heart rate was measured after the participant rested for 5 minutes and was sitting. Heart Rate was measured in beats per minute (bpm). Vital signs were taken at each visit (screening, Week -4, Week -2, Day 1, Weeks 4, 8, 12, 16, 20 (or early termination). After the Lead-In Period, participants were either randomized to one of the 3 arms of the study or they were dropped from the study so the time frame for evaluation of all participants in the study was either: enrollment up to Week 20 for Randomized participants or enrollment up to, but not including Day 1 for Non-Randomized participants who participated only in the Lead-In Period. | Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group) | 
| Number of Chemistry Values of Potential Clinical Importance - Enrolled Population | Number of values (not participants). Greater than (>), Less than (<), high (H), low (L). Criteria for laboratory values of potential clinical importance for obese and overweight (BMI>=25 kg/m^2) participants: Total bilirubin H > 2 mg/dL; glucose fasting or non-fasting H >200 mg/dL, L <60 mg/dL; Albumin L <2.5 g/dL; Creatine Phosphokinase (CPK) H >3*Upper limit of Normal (ULN); Sodium L<130 milliequivalents per liter (mEq/L), H >150 mEq/L; potassium L<3.0 mEq/L, H>5.5 mEq/L;bicarbonate L<18 mEq/L, H>35 mEq/L;calcium L <8 mg/dL, H>11 mg/dL; triglycerides H>500 mg/dL; Cholesterol L < 100 mg/dL, H > 350 mg/dL; Alkaline phosphatase H >3*ULN; Gamma-glutamyltransferase (GGT) H>3*ULN; creatinine males >1.6 mg/dL, females >1.4 mg/dL; alanine aminotransferase (ALT) H >3*ULN; aspartate aminotransferase (AST) H >3*ULN; urea nitrogen H >45 mg/dL; uric acid males >10.0 mg/dL, females > 8.0 mg/dL; Phosphorus L <1.0 mg/dL H >6.0 mg/dL. Time frame differs depending on randomization status. | Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group) | 
| Number of Hematology and Urinalysis Values of Potential Clinical Importance - Enrolled Population | Number of laboratory values of potential clinical importance (not participants) observed. Criteria for laboratory values of potential clinical importance for obese and overweight (BMI >= 25 kg/m^2) participants: Platelets high (H) >500,000/µL; low (L) <75,000/µL. Hematocrit males <36%, females <30%. Hemoglobin males <12 g/dL, females <10 g/dL. White blood cell count (WBC) H >18,000/µL; L <1,500/µL. Urine protein H >= 3+ or >= 500 mg/dL. Urine glucose H >= 3+ or >= 500 mg/dL. Urine ketones >= 3+ or Large. Time frame of evaluation differs depending on randomization status. | Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group) | 
| Number of Participants With Clinically Significant Abnormal ECG at Weeks 16, 20, or Early Termination - Randomized Population | A 12-Lead electrocardiogram (ECG) was obtained at Week -4, Day 1, Week 16, Week 20 or early termination and the overall interpretation of the ECG was made by the investigator as normal, abnormal (not clinically significant) and abnormal (clinically significant). The ECG consisted of the PR interval = time from beginning of the P wave to the beginning of the QRS complex; (Note: QRS complex is a name for the combination of 3 of the graphical deflections seen in an ECG); QRS (time from the beginning to the end of the QRS complex) interval; QT interval (measure between Q wave and T wave in the heart's electrical cycle); and QT interval corrected for heart rate using Fridericia's formula (QTcF) were measured in milliseconds (msec). . | Weeks 16, 20, early termination | 
| Number of Participants With Treatment-emergent Anti-Leptin Antibodies by Week 4, Week 8, Week 12, Week 16 - Intent to Treat Population | Serum titer determinations for antibodies to leptin were made using a validated electrochemical luminescence (ECLA) bridging assay. Antibody titers were assessed according to the following dilutions: 0, 5, 25, 125, 625, 3125, 15625, and 78125. Participants were considered to have a positive titer to treatment-emergent antibodies to leptin at a given visit if they had a titer >=5 following a negative or missing titer at baseline or if they had a titer that had increased by at least 2 dilutions from a detectable level at baseline. All participants were evaluated (including those who did not receive metreleptin as their randomized study drug). Baseline was Day 1 (randomization). | Baseline up to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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overweight, obesity, pramlintide, leptin, Amylin