Study to Examine Safety, Tolerability, and Effect on Body Weight of Metreleptin Administered in Conjunction With Pramlintide in Obese and Overweight Subjects

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled, dose-ranging study to examine the safety, tolerability and effect on body weight of a range of doses of metreleptin and pramlintide, each administered by a separate subcutaneous (SC) injection in obese and overweight subjects.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Examine the Safety, Tolerability, and Effect on Body Weight of Metreleptin Administered in Conjunction With Pramlintide in Obese and Overweight Subjects.

Conditions
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Overweight, Obesity

Intervention / Treatment
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* Drug: pramlintide acetate
* Drug: metreleptin
* Drug: placebo-P
* Drug: placebo-M


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 65 years old. Is obese (Body Mass Index [BMI]>=30kg/m^2 and <=35kg/m^2); or overweight (BMI>=27kg/m^2 and <30kg/m^2. Has stable body weight, i.e., not varying by >3% within 3 months prior to study. Has not been treated over the past 3 months or is currently treated with any of the following medications: Oral contraceptives (female subjects); Hormone replacement therapy (female subjects); Metformin for the treatment of polycystic ovary syndrome (female subjects); Antihypertensive agents; Lipid-lowering agents; Thyroid replacement therapy; selective serotonin reuptake inhibitors (SSRIs). Is comfortable with having repeated telephone contacts with a lifestyle counselor during the study. Is a nonsmoker (has not smoked for at least 6 months prior to the study). Exclusion Criteria: Has a medical history (e.g., morbid childhood obesity) and/or physical characteristics suggestive of genetic obesity or syndromatic obesity (e.g., Prader-Willi syndrome, Bardet-Biedl syndrome). 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 *antiobesity agents (prescription or over-the-counter), *antipsychotic agents, *antiepileptic agents, *antidepressant agents, *drugs that directly affect gastrointestinal motility, *antidiabetic medications. Has previously received treatment with metreleptin or pramlintide in a clinical study or has received prior treatment with pramlintide (SYMLIN®). 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 had a major surgery or a blood transfusion, or has donated blood over the past 2 months or is planning to donate blood during the study. Has had liposuction, abdominoplasty, or similar procedure over the past year or is planning to have such a procedure during the study.

Ages Eligible for Study
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Minimum Age: 18 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: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo-P + Placebo-M<br>Placebo matched to pramlintide BID plus placebo matched to metreleptin BID | Drug: placebo-P<br>* subcutaneous injection, twice a day<br>* Other names: Placebo matched to pramlintide;Drug: placebo-M<br>* subcutaneous injection, twice a day<br>* Other names: Placebo matched to Metreleptin;|
| Experimental: Pramlintide 360 mcg + Placebo-M<br>360 mcg pramlintide given twice per day (BID) plus Placebo matched to Metreleptin given BID | Drug: pramlintide acetate<br>* subcutaneous injection, twice a day<br>* Other names: Smylin;Drug: placebo-M<br>* subcutaneous injection, twice a day<br>* Other names: Placebo matched to Metreleptin;|
| Experimental: Placebo-P + Metreleptin 5.0 mg<br>Placebo matched to pramlintide BID plus metreleptin 5.0 mg BID | Drug: metreleptin<br>* subcutaneous injection, twice a day<br>Drug: placebo-P<br>* subcutaneous injection, twice a day<br>* Other names: Placebo matched to pramlintide;|
| Experimental: Pramlintide 180 mcg + Metreleptin 2.5 mg<br>Pramlintide 180 mcg BID plus Metreleptin 2.5 mg BID | Drug: pramlintide acetate<br>* subcutaneous injection, twice a day<br>* Other names: Smylin;Drug: metreleptin<br>* subcutaneous injection, twice a day<br>|
| Experimental: Pramlintide 180 mcg + Metreleptin 5.0 mg<br>Pramlintide 180 mcg BID plus Metreleptin 5.0 mg BID | Drug: pramlintide acetate<br>* subcutaneous injection, twice a day<br>* Other names: Smylin;Drug: metreleptin<br>* subcutaneous injection, twice a day<br>|
| Experimental: Pramlintide 360 mcg + Metreleptin 1.25 mg<br>Pramlintide 360 mcg BID plus Metreleptin 1.25 mg BID | Drug: pramlintide acetate<br>* subcutaneous injection, twice a day<br>* Other names: Smylin;Drug: metreleptin<br>* subcutaneous injection, twice a day<br>|
| Experimental: Pramlintide 360 mcg + Metreleptin 2.5 mg<br>Pramlintide 360 mcg BID plus Metreleptin 2.5 mg BID | Drug: pramlintide acetate<br>* subcutaneous injection, twice a day<br>* Other names: Smylin;Drug: metreleptin<br>* subcutaneous injection, twice a day<br>|
| Experimental: Pramlintide 360 mcg + Metreleptin 5.0 mg<br>Pramlintide 360 mcg BID plus Metreleptin 5.0 mg BID | Drug: pramlintide acetate<br>* subcutaneous injection, twice a day<br>* Other names: Smylin;Drug: metreleptin<br>* subcutaneous injection, twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares (LS) Mean Percent Change in Body Weight From Baseline to Week 28 - Evaluable Population | Body weight was measured in kilogram (kg). Baseline is defined as Day 1. If Day 1 was missing or after the first dose date of randomized treatment, the last available value prior to Day 1 was used. Drug Randomization stratified by sex and 3 categories baseline BMI (12 arms); 3 treatment arms combined for summaries as single placebo treatment group; 3 combined for summaries as single pramlintide monotherapy treatment group (total: 8 treatment groups). | Baseline to Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving at Least 5% and at Least 10% Body Weight Loss From Baseline to Week 28 - Evaluable Population | Baseline refers to Day 1. If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. | Baseline to Week 28 | 
| Mean Absolute Change From Baseline to Weeks 4, 12, 28 in Mean Trough Concentration of Total Leptin - Evaluable Population | Mean fasting plasma total leptin concentration (nanograms per milliliter; ng/mL) change from baseline over time by pooled metreleptin dose (sex, baseline BMI category, and baseline value). Baseline defined as Day 1. If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Evaluable population: all participants who received at least one dose of randomized treatment, had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding. Leptin concentrations measured using a validated immunoenzymetric assay utilizing polyclonal capture antibody, monoclonal detection antibody, and colorimetric readout by Amylin Pharmaceuticals, Inc. | Baseline to Week 28 | 
| LS Mean Absolute Change in Body Weight From Baseline to Weeks 4, 12, and 28 - Evaluable Population | Least Squares (LS) mean absolute change in Body weight was measured in kilograms (kg). Baseline is defined as Day 1. If Day 1 was missing or after the first dose date of randomized treatment, the last available value prior to Day 1 was used. | Baseline to Week 28 | 
| LS Mean Change in Waist Circumference From Baseline to Week 12 and Week 28 - Evaluable Population | Waist circumference was measured at baseline (Day 1), Weeks 12, 28 (or at early termination) in centimeters (cm). | Baseline to Weeks 12 and Week 28 | 
| Geometric Mean of the Total Area Under the Concentration Time Curve (AUC) From Time 0 to Last Quantifiable Concentration (Tlast) for Pramlintide at Weeks 4 and 24 - Evaluable Population Receiving Pramlintide | Assessment of AUC was over a period of 2 hours following pramlintide administration. AUC (0 to time of last quantifiable concentration (-tlast). For AUC calculation, concentration at -5 min will be considered as 0 h concentration if quantifiable, otherwise, t=0 h. AUC measured as picograms*hour/milliliter (pg*h/mL). Pramlintide concentrations measured using a colorimetric immunoenzymetric assay employing monoclonal antibodies against pramlintide for both capture and detection. | Week 4 and Week 24 | 
| Geometric Mean of AUC From Time 0 to Infinity for Pramlintide at Weeks 4 and 24 - Evaluable Population Treated With Pramlintide | Assessment of AUC was over a period of 2 hours following pramlintide administration. Area under the concentration curve (AUC) time 0 to infinity (-inf). For AUC calculations, concentration at -5 min will be considered as 0 h concentration if quantifiable. AUC measured in picograms*hour/milliliter (pg*h/mL). | Weeks 4 and 24 | 
| Geometric Mean of the Maximum Observed Plasma Concentration (Cmax) for Pramlintide at Weeks 4 and 24 - Evaluable Population Receiving Pramlintide | Assessment of Cmax was over a period of 2 hours following pramlintide administration at Weeks 4 and 24. Cmax was measured as picograms/milliliter (pg/mL). | Week 4 and Week 24 | 
| Least Squares (LS) Mean Absolute Change From Baseline to Week 28 in Percent of Body Fat - Evaluable Population | Parameters of body composition were measured with a Dual Energy X-ray absorptiometry (DEXA) scan and reported as a percent (%). Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Absolute change from baseline was defined as percent body fat at Week 28 - percent body fat at baseline. | Baseline to Week 28 | 
| LS Mean Absolute Change From Baseline to Week 28 in Total Body Fat Mass (k) - Evaluable Population | Parameters of body composition were measured with a Dual Energy X-ray absorptiometry (DEXA) scan. Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Body fat mass was measured in kilogram (k). | Baseline to Week 28 | 
| LS Mean Absolute Change From Baseline to Week 28 in Fat-free Mass (kg) - Evaluable Population | Parameters of body composition were measured with a Dual Energy X-ray Absorptiometry (DEXA) scan. Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Fat-free mass were measured in kilogram (k). | Baseline to Week 28 | 
| LS Mean Absolute Change From Baseline to Week 28 in Fasting Plasma Glucose, Total Cholesterol (TC), Triglycerides, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol - Evaluable Population | Baseline refers to Visit 5 (Day 1). If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Fasting samples were obtained at baseline, Weeks 4, 12, and 28. All parameters were measured in milligrams per deciliter (mg/dL). | Baseline to Week 28 | 
| Mean Absolute Change From Baseline to Week 28 for Insulin - Evaluable Population | Baseline refers to Visit 5 (Day 1). If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Fasting samples were obtained at baseline, Weeks 4, 12, and 28. Parameter was measured micro international units per milliliter. (µIU/mL). | Baseline to Week 28 | 
| Mean Absolute Change From Screening to Week 24 in Impact of Weight on Quality of Life Questionnaire-lite Version (IWQOL-Lite) Total Score - Evaluable Population | Subjective effects of weight loss were measured using the IWQOL-Lite questionnaire, a 31-item patient reported outcome (PRO) instrument used to assess the effect of weight on physical function, self-esteem, sexual life, public distress, and work. Individual items have a range of 1 to 5 with 5=always true and 1= never true. The total score for the IWQOL-Lite instrument is measured on a scale from 0 (worst) to 100 (best). Higher scores indicate improvement. Values were obtained for this questionnaire on Visit 3 in the screening period. | Screening to Week 24 | 
| Mean Absolute Change From Screening to Week 24 in Binge Eating Scale (BES) Total Score - Evaluable Population | The Binge Eating Scale (BES) is a 16-item questionnaire that assesses 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. The minimum and maximum score for the BES instrument is 0 and 55, respectively. The higher the score the worse the outcome. Values were obtained for this questionnaire on Visit 3 in the screening period. | Screening to Week 24 | 
| Mean Absolute Change From Screening to Week 24 in Susceptibility to Eating Questionnaire (SEQ) Item Scores - Evaluable Population | The eating questionnaire is an exploratory 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). Lower scores indicate improvement. The Eating Questionnaire instructed participants to rate their responses to these items over the past 7 days. Values were obtained for this questionnaire on Visit 3 in the screening period. | Screening to Week 24 | 
| Mean Absolute Change From Screening to Week 24 in Hospital Anxiety and Depression Scale (HADS) Total Scores - 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 higher the score, the worse the outcome. Values were obtained for this questionnaire on Visit 3 in the screening period | Screening to Week 24 | 
| Mean Absolute Change From Screening to Week 24 in Summary Scores for Profile of Mood States - Brief (POMS-B) - Evaluable Population | The POMS is a mood scale consisting of 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 of the six POMS factors. The mood adjectives load onto 6 mood factors, which are as follows: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. Scores range from 0= Not at All to 4=Extremely. The factor scores are added to obtain the total mood disturbance score. A lower total mood disturbance score indicates improvement. Values were obtained for this questionnaire on Visit 3 in the screening period. | Screening to Week 24 | 
| Mean Absolute Change From Screening to Week 24 in Minutes to Fall Asleep, Hours of Sleep and The Pittsburgh Sleep Quality Index (PSQI) Global Score - Evaluable Population | The Pittsburgh Sleep Quality Index (PSQI) is a questionnaire which assesses sleep quality and sleep disturbances over a period of 1 month. The PSQI provides ratings on seven domains of sleep (subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction). The sum of the individual domains yields a global sleep quality score with a range of 0-21. A PSQI score >5 is indicative of poor sleep, which is characterized by severe difficulties in at least two domains, or moderate difficulties in three or more domains. Values were obtained for this questionnaire on Visit 3 in the screening period. | Screening to Week 24 | 
| Mean Absolute Change From Screening to Week 24 in the Epworth Sleepiness Scale (ESS) Total Score - Evaluable Population | The Epworth Sleepiness Scale (ESS) is an eight-item questionnaire that assesses sleep propensity in daily situations of increasing sleepiness on a four-point scale with 0=would never doze and 3=high chance of dozing. Lower scores indicate improvement. Values were obtained for this questionnaire on Visit 3 in the screening period | Screening to Week 24 | 
| Number of Hematology and Urinalysis Laboratory Values of Potential Clinical Importance Observed From Screening to Week 28 - Intent to Treat Population | 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. Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28. Numbers of values are cumulative across the study. | Screening to Week 28 | 
| Number of Chemistry Laboratory Values of Potential Clinical Importance Observed From Screening to Week 28 - Intent to Treat Population | Obtained at: Screening, Days -7, 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28. Numbers of laboratory values are cumulative across the study. Criteria for values of potential clinical importance for obese and overweight (BMI>=25 kg/m^2) participants: Total bilirubin High (H) > 2 mg/dL; Plasma/serum glucose fasting or non-fasting H > 200 mg/dL, low (L) < 60 mg/dL; Albumin L <2.5 g/dL; Creatine kinase 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 <8mg/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 H>3*ULN; creatinine males > 1.6 mg/dL, females > 1.4 mg/dL; alanine aminotransferase H > 3*ULN; aspartate aminotransferase 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. | Screening to Week 28 | 
| Mean Change in Systolic and Diastolic Blood Pressure From Baseline to Week 28 - Intent to Treat Population | Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Blood pressure was taken while the participant was sitting and was measured in millimeters of mercury (mm Hg). Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28 | Baseline to Week 28 | 
| Mean Change in Heart Rate From Baseline to Week 28 - Intent to Treat Population | Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Heart rate was measured while the participant was sitting and was measured in beats per minute (bpm). Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28. | Baseline to Week 28 | 
| Number of Participants With Treatment-emergent Positive Anti-leptin Antibody Titers at Week 28 - Intent to Treat Population | Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Serum titer determinations for antibodies to metreleptin 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 metreleptin 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. | Baseline to Week 28 | 
| Mean Change From Screening to Week 28 in Electrocardiogram Parameters - Intent to Treat Population | A 12-Lead electrocardiogram (ECG) was obtained at Screening, Day 1, Weeks 1, 12, 28 (study termination). The PR interval, which is 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 interval (time from the beginning to the end of the QRS complex); 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). | Screening to Week 28 (or study termination) | 
| Mean Change From Screening to Week 28 in the Electrocardiogram Parameter of Heart Rate - Intent to Treat Population | A 12-Lead electrocardiogram (ECG) was obtained at Screening (visit 2), Day 1, Weeks 1, 12, 28 (study termination). Heart Rate was measured in beats per min (bpm). | Screening to Week 28 (or early termination) | 

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