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

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).

Time frame: Baseline to Week 28

Population: Evaluable population includes all intent to treat participants (received at least one dose of randomized treatment) who had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding.

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).

Time frame: Weeks 4 and 24

Population: Evaluable population: participants 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. Number (n) analyzed at Week 4: n=39,36,37,36,35,31 in each arm, respectively; Week 24 n=46, 35, 42, 39, 33, 35 in each arm, respectively.

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).

Time frame: Week 4 and Week 24

Population: Evaluable population: participants 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. Number (n) analyzed at Week 4 n=46,40,41,40,40,33 in each arm, respectively; Week 24 n=48,38, 44,40,35,36 in each arm, respectively.

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.

Time frame: Week 4 and Week 24

Population: Evaluable population: participants 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. Number (n) analyzed at Week 4:n=46, 40,41, 40,40,33 in each arm respectively;Week 24:n=48, 38, 44, 40, 35, 36.

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.

Time frame: Baseline to Week 28

Population: Evaluable population includes participants 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. Number analyzed (n) were of evaluable participants with valid DEXA scan at Week 28.

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).

Time frame: Baseline to Week 28

Population: Evaluable population: received at least one dose of randomized treatment, had adequate exposure to treatment, complied with the protocol as assessed prior to database lock and unblinding. Number analyzed (n) presented above for TC, LDL and HDL cholesterol. Glucose n= 43, 50, 41, 46, 45, 43,44,36; Triglycerides n= 44,50,41,46,45,44,44.38.

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).

Time frame: Baseline to Week 28

Population: Evaluable population includes participants 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. Number analyzed (n) were of evaluable participants with valid DEXA scan at Week 28.

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).

Time frame: Baseline to Week 28

Population: Evaluable population includes participants 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. Number analyzed (n) were of evaluable participants with valid DEXA scan at Week 28.

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.

Time frame: Baseline to Week 28

Population: Evaluable population includes all intent to treat participants (received at least one dose of randomized treatment) who had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding.

Waist circumference was measured at baseline (Day 1), Weeks 12, 28 (or at early termination) in centimeters (cm).

Time frame: Baseline to Weeks 12 and Week 28

Population: Participants who received at least 1 dose of randomized treatment and who had adequate exposure to treatment and complied with the protocol as assessed prior to database lock/unblinding. Numbers (n) analyzed Week 12 n=45,51,41,47,45,45,45,38 in each treatment group respectively; Week 28 n= 44, 51, 41, 46, 45, 44, 43, 38 in each group, respectively.

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).

Time frame: Baseline to Week 28

Population: Evaluable population includes participants 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.

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.

Time frame: Baseline to Week 28

Population: Number analyzed (n) at baseline above. Week 4: n=41 45,46, 45, 45, 38; Week 8: n=41,45,46,44,45,37; Week 12: n=41, 46, 46, 45,45,38; Week 16: n=41,47,46,45,45,38; Week 20: n=41, 45,45,45,45,38; Week 24: n=40, 43, 46, 42, 44,38; Week 28: n=41, 45, 45, 44, 43, 36. Leptin concentration for placebo and pramlintide plus placebo groups not presented.

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.

Time frame: Screening to Week 24

Population: Evaluable population includes participants 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. Missing item responses may be imputed for each subject as appropriate before summarization.

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

Time frame: Screening to Week 24

Population: Evaluable population includes participants 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. Missing item responses may be imputed for each subject as appropriate before summarization.

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.

Time frame: Screening to Week 24

Population: Evaluable population includes participants 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. Missing item responses may be imputed for each subject as appropriate before summarization.

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.

Time frame: Screening to Week 24

Population: Evaluable population includes participants 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. Missing item responses may be imputed for each subject as appropriate before summarization.

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.

Time frame: Screening to Week 24

Population: Evaluable population includes participants 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. Missing item responses may be imputed for each subject as appropriate before summarization.

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.

Time frame: Screening to Week 24

Population: Evaluable population includes participants 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. Missing item responses may be imputed for each subject as appropriate before summarization.

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

Time frame: Screening to Week 24

Population: Evaluable population includes participants 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. Missing item responses may be imputed for each subject as appropriate before summarization.

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).

Time frame: Screening to Week 28 (or study termination)

Population: Intent to treat population included all randomized participants who received at least one injection of study medication.

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).

Time frame: Screening to Week 28 (or early termination)

Population: Intent to treat population included all randomized participants who received at least one injection of study medication.

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.

Time frame: Baseline to Week 28

Population: Intent to treat population included all randomized participants who received at least one injection of study medication.

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

Time frame: Baseline to Week 28

Population: Intent to treat population included all randomized participants who received at least one injection of study medication.

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.

Time frame: Screening to Week 28

Population: Intent to treat population included all randomized participants who received at least one injection of study medication.

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.

Time frame: Screening to Week 28

Population: Intent to treat population included all randomized participants who received at least one injection of study medication.

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.

Time frame: Baseline to Week 28

Population: Evaluable population includes all intent to treat participants (received at least one dose of randomized treatment) who had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding.

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.

Time frame: Baseline to Week 28

Population: Intent to treat population included all randomized participants who received at least one injection of study medication.