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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00392925
• Collaborator: (none)
• Enrollment: 177
• Locations: 12
• Arms: 4
• Duration (Months): 11
• Patients Per Site: 14.8
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Overweight; Obesity	Drug: pramlintide acetate 360 mcg; Drug: metreleptin; Drug: placebo-pramlintide 600 uL; Drug: placebo-metreleptin 1 mL; Drug: Pramlintide acetate 180 mcg	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 177 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Sep 1, 2007
• Actual Study Completion Date: Sep 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo and Metreleptin Placebo-pramlintide 600 microliters (µL) twice a day (BID) and metreleptin (recombinant-methionyl human leptin) 5 milligram (mg) BID, 20 weeks	Drug: metreleptin; subcutaneous injection, twice a day, 5mg; Other Names: recombinant-methionyl human leptin ; Drug: placebo-pramlintide 600 uL; twice a day
Experimental: Pramlintide Acetate and Placebo 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; subcutaneous injection, twice a day, 360mcg; Other Names: SYMLIN® ; Drug: placebo-metreleptin 1 mL; twice a day
Experimental: Pramlintide Acetate and Metreleptin 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; subcutaneous injection, twice a day, 360mcg; Other Names: SYMLIN® ; Drug: metreleptin; subcutaneous injection, twice a day, 5mg; Other Names: recombinant-methionyl human leptin
Other: Lead-In Period 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; subcutaneous injection, twice a day, 360mcg; Other Names: SYMLIN® ; Drug: Pramlintide acetate 180 mcg; subcutaneous injection twice a day, 180 mcg; Other Names: SYMLIN®

Outcome Measures

Primary Outcome Measures

1. Mean Absolute Change From Baseline to Week 16 in Body Weight - Evaluable Population [Baseline to Week 16]

   Absolute change in body weight as measured in kilograms (kg) from baseline to Week 16. Baseline defined as Day 1 of randomized treatment.

Secondary Outcome Measures

1. LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population [Baseline up to Week 20]

   Least Squares (LS) mean percent change in body weight from baseline to Weeks 4 through 20. Baseline defined as Day 1 of randomized treatment.

2. LS Mean Absolute Change From Baseline to Weeks 4, 8, 12, 20 in Body Weight - Evaluable Population [Baseline to Week 20]

   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

3. LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population [Enrollment to Week 20]

   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.

4. LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population [Enrollment to Week 20]

   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.

5. Initial, Late, and Overall Rates of LS Mean Absolute Change in Body Weight From Day 1 to Week 20 - Evaluable Population [Baseline to Week 20]

   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).

6. 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 to Weeks 16 and Weeks 20]

   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.

7. LS Mean Percent Change in Weight From Enrollment to Baseline and LS Mean Percent Change in Excess Weight From Enrollment to Baseline - Evaluable Population [Enrollment to Baseline]

   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.

8. LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population [Enrollment to Week 20]

   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.

9. LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population [Baseline to Week 20]

   Baseline was Visit 4 (Day 1 of randomization period). Waist circumference was measured in centimeters (cm).

10. LS Mean Absolute Change in Hip Circumference From Screening up to Week 20 - Evaluable Population [Screening up to Week 20]

    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).

11. Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population [Enrollment up to Week 16]

    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).

12. Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population [Enrollment up to Week 20]

    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).

13. Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population [Enrollment to Week 16]

    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).

14. Mean Absolute Change From Enrollment to Baseline, Weeks 4 and 16 in Fasting Total Leptin Concentration - Evaluable Population [Enrollment to Week 16]

    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]).

15. Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Amylin -Evaluable Population [Enrollment to Week 16]

    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.

16. Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Insulin - Evaluable Population [Enrollment to Week 16]

    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)

17. LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcome (PRO) Instruments Measuring Quality of Life and Mood - Evaluable Population [Enrollment to Week 16]

    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.

18. LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population [Enrollment to Week 16]

    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;

19. LS Mean Absolute Change From Enrollment to Week 16 in Hospital Anxiety and Depression Scale (HADS) - Evaluable Population [Enrollment to Week 16]

    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.

20. Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population [Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)]

    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.

21. Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Heart Rate - Enrolled Population [Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)]

    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.

22. Number of Chemistry Values of Potential Clinical Importance - Enrolled Population [Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)]

    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.

23. Number of Hematology and Urinalysis Values of Potential Clinical Importance - Enrolled Population [Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)]

    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.

24. Number of Participants With Clinically Significant Abnormal ECG at Weeks 16, 20, or Early Termination - Randomized Population [Weeks 16, 20, early termination]

    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). .

25. Number of Participants With Treatment-emergent Anti-Leptin Antibodies by Week 4, Week 8, Week 12, Week 16 - Intent to Treat Population [Baseline up to Week 16]

    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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Deland	Florida	United States
2	Research Site	Chicago	Illinois	United States
3	Research Site	Indianapolis	Indiana	United States
4	Research Site	Overland Park	Kansas	United States
5	Research Site	Baton Rouge	Louisiana	United States
6	Research Site	Detroit	Michigan	United States
7	Research Site	Edina	Minnesota	United States
8	Research Site	Butte	Montana	United States
9	Research Site	Cincinnati	Ohio	United States
10	Research Site	Portland	Oregon	United States
11	Research Site	Salt Lake City	Utah	United States
12	Research Site	Olympia	Washington	United States

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Lisa Porter, MD, Amylin Pharmaceuticals, LLC.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00392925
• Other Study ID Numbers: DFA101
• First Posted: Oct 26, 2006
• Last Update Posted: Apr 14, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by AstraZeneca: overweight; obesity; pramlintide; leptin; Amylin
• Additional relevant MeSH terms: Overweight; Body Weight; Pramlintide; Islet Amyloid Polypeptide

Study Results

Participant Flow

Recruitment Details	30 October 2006 started Lead-in Period. 20 September 2007 final visit. Study conducted at clinics with obese patients (body mass index [BMI]greater than, equal to [≥]30 to less than, equal to [≤]35 kg/m^2) or overweight patients (BMI ≥27 to <30 kg/m^2) and abdominal obesity = waist circumference >102 centimeters (cm) for males; >88 cm for females.
Pre-assignment Detail	177 participants enrolled into single blind lead-in period with pramlintide treatment and a diet, 38 withdrew before double blind randomization into 1 of 3 treatment arms. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to 1 of 3 treatment groups.

Arm/Group Title	Non-Randomized From 4 Week Lead-In	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	During the 4-week lead-in period, all participants self administered a subcutaneous injection of pramlintide acetate 180 mcg twice per week (BID) for 2 weeks followed by pramlintide 360 mcg BID for 2 weeks while following a diet aimed at creating a 40% caloric deficit relative to their estimated weight-maintenance energy needs. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to 1 of 3 treatment groups (metreleptin, pramlintide, or pramlintide+metreleptin). 38 participants were not Randomized into one of the 3 treatment groups and withdrew from the study.	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 milligram (mg) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Period Title: 4 Week Lead-In Period - Non-Randomized
STARTED	177	0	0	0
COMPLETED	139	0	0	0
NOT COMPLETED	38	0	0	0
Period Title: 4 Week Lead-In Period - Non-Randomized
STARTED	0	27	56	56
COMPLETED	0	19	37	38
NOT COMPLETED	0	8	19	18

Baseline Characteristics

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin	Non-Randomized From 4 Week Lead-In	Total
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	During the 4-week lead-in period, all participants self administered subcutaneous (SC) injections of pramlintide acetate 180 mcg twice per week (BID) for 2 weeks followed by pramlintide acetate 360 mcg BID for 2 weeks while following a diet aimed at creating a 40% caloric deficit relative to their estimated weight-maintenance energy needs. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to 1 of 3 treatment groups (metreleptin, pramlintide, or pramlintide+metreleptin). 38 participants were not randomized into one of the 3 treatment groups and withdrew from the study.	Total of all reporting groups
Overall Participants	27	56	56	38	177
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.5 (8.06)	38.3 (9.13)	38.5 (8.42)	37.9 (7.51)	38.6 (8.39)
Sex: Female, Male (Count of Participants)
Female	17 63%	35 62.5%	35 62.5%	24 63.2%	111 62.7%
Male	10 37%	21 37.5%	21 37.5%	14 36.8%	66 37.3%
Region of Enrollment (participants) [Number]
United States	27 100%	56 100%	56 100%	38 100%	177 100%
Body Weight at Enrollment (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	93.80 (14.322)	91.70 (11.085)	93.89 (12.834)	94.54 (16.027)	93.32 (13.246)
Body Weight at Baseline (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	89.83 (13.389)	88.05 (10.507)	89.88 (12.355)	NA (NA)	89.13 (11.807)
Body Mass Index (BMI) at Enrollment (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.0 (2.15)	31.5 (2.03)	32.0 (2.10)	32.5 (1.95)	32.0 (2.07)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol as per the sponsor. Participants excluded from the Evaluable Population were identified prior to the unblinding process. n=number with non-missing body weight data at Week 16 in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide Acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide Acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Least Squares Mean (Standard Error) [kg]	-2.68 (0.952)	-3.30 (0.698)	-6.46 (0.682)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pramlintide Acetate, Pramlintide Acetate + Metreleptin
	Comments	Based on an Analysis of Covariance model including factors for treatment group, sex, enrollment body mass index (BMI) category, lead-in body weight loss category, and baseline (Day 1) weight as a covariate. The p-value is for testing the null hypothesis of no difference between treatments. Analysis performed two-sided at a 5% significance level to compare treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population
Description	Least Squares (LS) mean percent change in body weight from baseline to Weeks 4 through 20. Baseline defined as Day 1 of randomized treatment.
Time Frame	Baseline up to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with protocol (per sponsor). Those excluded were identified prior to the unblinding process. n=number with non-missing body weight data (at visit) in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Week 4 (n=19, 38, 36)	-0.70 (0.429)	-1.55 (0.310)	-2.36 (0.311)
Week 8 (n=19, 38, 36)	-2.08 (0.591)	-2.74 (0.427)	-4.81 (0.429)
Week 12 (n=19, 38, 36)	-3.17 (0.796)	-3.39 (0.575)	-6.13 (0.577)
Week 16 (n=19, 38, 36)	-3.37 (1.025)	-3.85 (0.740)	-7.59 (0.743)
Week 20 (n=19, 37, 36)	-3.62 (1.277)	-3.89 (0.925)	-8.21 (0.926)

3. Secondary Outcome

Title	LS Mean Absolute Change From Baseline to Weeks 4, 8, 12, 20 in Body Weight - Evaluable Population
Description	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
Time Frame	Baseline to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with protocol (per sponsor). Those excluded were identified prior to the unblinding process. n=number with non-missing body weight data (at visit) in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Week 4 (n=19, 38, 36)	-0.66 (0.387)	-1.43 (0.284)	-2.13 (0.277)
Week 8 (n=19, 38, 36)	-1.66 (0.540)	-2.32 (0.396)	-4.16 (0.387)
Week 12 (n=19, 38, 36)	-2.59 (0.742)	-2.97 (0.544)	-5.28 (0.532)
Week 20 (n=19, 37, 36)	-2.80 (1.199)	-3.30 (0.881)	-6.90 (0.859)

4. Secondary Outcome

Title	LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population
Description	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.
Time Frame	Enrollment to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with protocol (per sponsor). Those excluded were identified prior to the unblinding process. n=number with non-missing body weight data (at visit) in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Week 4 (n=19, 38, 36)	-5.22 (0.483)	-5.93 (0.353)	-6.72 (0.346)
Week 8 (n=19, 38, 36)	-6.25 (0.635)	-6.85 (0.464)	-8.77 (0.455)
Week 12 (n=19, 38, 36)	-7.18 (0.822)	-7.50 (0.60)	-9.89 (0.590)
Week 16 (n=19, 38, 36)	-7.28 (1.028)	-7.84 (0.751)	-11.07 (0.737)
Week 20(n=19, 37, 36)	-7.41 (1.262)	-7.86 (0.923)	-11.52 (0.904)

5. Secondary Outcome

Title	LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population
Description	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.
Time Frame	Enrollment to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with protocol (per sponsor). Those excluded were identified prior to the unblinding process. n=number with non-missing body weight data (at visit) in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Week 4 (n=19, 38, 36)	-5.46 (0.512)	-6.20 (0.369)	-7.18 (0.371)
Week 8 (n=19, 38, 36)	-6.77 (0.654)	-7.33 (0.473)	-9.50 (0.474)
Week 12 (n=19, 38, 36)	-7.80 (0.836)	-7.95 (0.604)	-10.75 (0.606)
Week 16 (n=19, 38, 36)	-7.99 (1.058)	-8.37 (0.764)	-12.13 (0.767)
Week 20 (n=19, 37, 36)	-8.22 (1.286)	-8.42 (0.931)	-12.72 (0.932)

6. Secondary Outcome

Title	Initial, Late, and Overall Rates of LS Mean Absolute Change in Body Weight From Day 1 to Week 20 - Evaluable Population
Description	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).
Time Frame	Baseline to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with protocol (per sponsor). Those excluded were identified prior to the unblinding process.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Initial rate of absolute change	-0.23 (0.060)	-0.25 (0.044)	-0.46 (0.043)
Late rate of absolute change	-0.02 (0.079)	-0.05 (0.058)	-0.20 (0.057)
Overall rate of absolute change	-0.16 (0.059)	-0.17 (0.043)	-0.36 (0.042)

7. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to Weeks 16 and Weeks 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with protocol (per sponsor). Those excluded were identified prior to the unblinding process. n=number with non-missing body weight data (at visit) in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Weight Loss of 5% or more Week 16 (n=19, 38, 36)	5 18.5%	13 23.2%	22 39.3%
Weight Loss of 5% or more Week 20(n=19, 37, 36)	6 22.2%	14 25%	25 44.6%
5% Loss Week 16 Sustained (n=19, 38, 36)	5 18.5%	12 21.4%	21 37.5%
Weight Loss of 10% or more Week 16(n=19, 38, 36)	1 3.7%	1 1.8%	9 16.1%
Weight Loss of 10% or more Week 20(n=19, 37, 36)	2 7.4%	2 3.6%	11 19.6%
10% Loss Week 16 Sustained (n=19, 38, 36)	1 3.7%	1 1.8%	9 16.1%

8. Secondary Outcome

Title	LS Mean Percent Change in Weight From Enrollment to Baseline and LS Mean Percent Change in Excess Weight From Enrollment to Baseline - Evaluable Population
Description	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.
Time Frame	Enrollment to Baseline

Outcome Measure Data

Analysis Population Description

Evaluable: randomized with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with protocol (per sponsor). Those excluded were identified prior to the unblinding process. Number with non-missing body weight data at Day 1 of Randomization were analyzed.

Arm/Group Title	Lead-In Participants Randomized to Treatment on Day 1
Arm/Group Description	During the 4-week lead-in period, all participants self administered subcutaneous (SC) injections of pramlintide 180 mcg twice per week (BID) for 2 weeks followed by pramlintide 360 mcg BID for 2 weeks while following a diet aimed at creating a 40% caloric deficit relative to their estimated weight-maintenance energy needs. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to a treatment group.
Measure Participants	93
Percent Change in Weight from Enrollment	-4.42 (0.171)
Percent Change in Excess Weight from Enrollment	-25.24 (1.085)

9. Secondary Outcome

Title	LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population
Description	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.
Time Frame	Enrollment to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. n=number with non-missing anthropometric data at visit in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Week 4 (n=19, 38, 36)	-5.49 (0.940)	-6.78 (0.679)	-7.28 (0.682)
Week 8 (n=19, 38, 36)	-5.74 (0.974)	-7.76 (0.703)	-8.75 (0.706)
Week 12 (n=19, 38, 36)	-7.06 (1.077)	-8.46 (0.778)	-9.88 (0.782)
Week 16 (n=19, 38, 36)	-6.84 (1.281)	-9.00 (0.925)	-10.66 (0.929)
Week 20 (n=19, 37, 36)	-7.99 (1.509)	-9.17 (1.092)	-11.61 (1.094)

10. Secondary Outcome

Title	LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population
Description	Baseline was Visit 4 (Day 1 of randomization period). Waist circumference was measured in centimeters (cm).
Time Frame	Baseline to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. n=number with non-missing anthropometric data at visit in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Week 4 (n=19, 38, 36)	-1.08 (0.868)	-2.55 (0.626)	-2.95 (0.630)
Week 8 (n=19, 38, 36)	-1.29 (0.833)	-3.51 (0.601)	-4.39 (0.605)
Week 12 (n=19, 38, 36)	-2.63 (0.941)	-4.22 (0.679)	-5.54 (0.683)
Week 16 (n=19, 38, 36)	-2.40 (1.177)	-4.75 (0.849)	-6.30 (0.854)
Week 20 (n=19, 37, 36)	-3.60 (1.421)	-4.90 (1.029)	-7.28 (1.031)

11. Secondary Outcome

Title	LS Mean Absolute Change in Hip Circumference From Screening up to Week 20 - Evaluable Population
Description	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).
Time Frame	Screening up to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol as per the sponsor. Those excluded from the Evaluable Population were identified prior to the unblinding process. Number with non-missing anthropometric data in each treatment group were analyzed.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate+ Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	37	36
Least Squares Mean (Standard Error) [cm]	-6.36 (1.475)	-8.07 (1.082)	-10.27 (1.070)

12. Secondary Outcome

Title	Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population
Description	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).
Time Frame	Enrollment up to Week 16

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. Number analyzed were those participants with non-missing BMI data at enrollment and Week 16.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Obese BMI at Enrollment	14 51.9%	30 53.6%	27 48.2%
Continued Obese BMI at Week 16	9 33.3%	11 19.6%	11 19.6%
Decreased BMI to Overweight at Week 16	5 18.5%	19 33.9%	16 28.6%
Decreased BMI to Normal at Week 16	0 0%	0 0%	0 0%
Overweight BMI at Enrollment	5 18.5%	8 14.3%	9 16.1%
Continued Overweight BMI at Week 16	4 14.8%	8 14.3%	5 8.9%
Decreased BMI to Normal at Week 16	1 3.7%	0 0%	4 7.1%

13. Secondary Outcome

Title	Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population
Description	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).
Time Frame	Enrollment up to Week 20

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 20 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. Number analyzed were those participants with non-missing BMI data at enrollment and Week 20.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate+ Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	37	36
Obese BMI at Enrollment	14 51.9%	29 51.8%	27 48.2%
Continued Obese BMI at Week 20	7 25.9%	10 17.9%	10 17.9%
Greater Obesity at Week 20	1 3.7%	0 0%	0 0%
Decreased BMI to Overweight at Week 20	6 22.2%	19 33.9%	17 30.4%
Decreased BMI to Normal at Week 20	0 0%	0 0%	0 0%
Overweight BMI at Enrollment	5 18.5%	8 14.3%	9 16.1%
Continued Overweight BMI at Week 20	4 14.8%	8 14.3%	5 8.9%
Decreased BMI to Normal at Week 20	1 3.7%	0 0%	4 7.1%

14. Secondary Outcome

Title	Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population
Description	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).
Time Frame	Enrollment to Week 16

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. n=number with non-missing data for lipids and glucose in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Glucose (n=19, 35, 35)	-2.21 (8.574)	-1.86 (10.347)	-3.00 (7.412)
Total Cholesterol (n=19, 38, 36)	2.68 (25.164)	-10.76 (20.285)	-20.64 (25.798)
HDL cholesterol (n=19, 38, 36)	1.74 (6.358)	1.63 (7.321)	-0.64 (7.761)
LDL cholesterol (n=19, 38, 36)	1.11 (22.266)	-5.50 (18.064)	-13.25 (17.986)
Triglycerides (n=19, 37, 35)	30.37 (77.920)	1.57 (75.063)	-9.54 (53.844)

15. Secondary Outcome

Title	Mean Absolute Change From Enrollment to Baseline, Weeks 4 and 16 in Fasting Total Leptin Concentration - Evaluable Population
Description	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]).
Time Frame	Enrollment to Week 16

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. n=number with non-missing data at visit in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Baseline (Day 1) (n=18, 38, 35)	-6.16 (6.919)	-7.98 (6.932)	-7.23 (8.157)
Week 4 (n=19, 38, 36)	53.54 (98.124)	-6.56 (7.766)	18.94 (38.475)
Week 16 (n=19, 38, 36)	375.28 (340.885)	-3.58 (13.296)	262.61 (268.501)

16. Secondary Outcome

Title	Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Amylin -Evaluable Population
Description	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.
Time Frame	Enrollment to Week 16

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. n=number analyzed with non-missing data at visit.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	18	37	36
Baseline (Day 1) (n=18, 37, 36)	-0.89 (4.258)	-2.18 (5.641)	-3.28 (4.378)
Week 16 (n=18, 34, 36)	-3.31 (4.731)	-1.60 (5.720)	-2.17 (12.416)

17. Secondary Outcome

Title	Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Insulin - Evaluable Population
Description	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)
Time Frame	Enrollment to Week 16

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. n=number with non-missing data at visit in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	17	35	34
Baseline (Day 1) (n=17, 35, 34)	0.00 (4.108)	-1.14 (4.095)	-0.68 (4.183)
Week 16 (n=18, 34, 35)	-0.61 (4.877)	-0.65 (4.792)	-2.80 (3.385)

18. Secondary Outcome

Title	LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcome (PRO) Instruments Measuring Quality of Life and Mood - Evaluable Population
Description	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.
Time Frame	Enrollment to Week 16

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. n=number with non-missing data at visit in each treatment group. (POMS)n=19, 38, 36; (IWQOL-Lite)n=19, 38, 36

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
POMS Total Mood Disturbance Score(n=19, 38, 36)	-2.8 (6.17)	-4.5 (4.45)	-6.0 (4.50)
IWQOL-Lite Total Score(n=19, 38, 36)	12.14 (2.553)	11.92 (1.843)	12.49 (1.863)

19. Secondary Outcome

Title	LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population
Description	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;
Time Frame	Enrollment to Week 16

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. n=number with non-missing data at visit in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
BES Total Score (n=17, 36, 34)	-5.5 (1.27)	-3.8 (0.87)	-6.4 (0.89)
SEQ Food Craving Frequency(n=19, 38, 36)	-21.8 (5.32)	-19.5 (3.84)	-24.6 (3.86)
SEQ Strength of Food Cravings(n=19, 38, 36)	-16.8 (5.39)	-11.5 (3.88)	-19.8 (3.91)
SEQ Difficult to Control Eating(n=19, 38, 36)	-23.0 (5.77)	-20.9 (4.17)	-29.3 (4.19)
SEQ Difficult to Resist Food Cravings(n=19, 38, 36	-22.7 (5.47)	-18.6 (3.95)	-30.2 (3.97)
SEQ Response to Food Cravings(n=19, 38, 36)	-22.0 (5.30)	-22.6 (3.83)	-33.4 (3.85)
SEQ Control Portion Sizes(n=19, 38, 36)	-24.8 (5.26)	-27.5 (3.78)	-33.1 (3.78)
SEQ How Hungry(n=19, 38, 36)	-21.1 (5.20)	-18.5 (3.77)	-28.5 (3.77)
SEQ How Full After Meal(n=19, 38, 36)	-3.0 (5.20)	2.8 (3.76)	-4.6 (3.77)
SEQ Thoughts of Food(n=19, 38, 36)	-20.4 (5.62)	-11.6 (4.07)	-21.5 (4.07)
SEQ How Pleasant Meals(n=19, 38, 36)	-3.2 (4.73)	-0.8 (3.42)	-6.5 (3.44)

20. Secondary Outcome

Title	LS Mean Absolute Change From Enrollment to Week 16 in Hospital Anxiety and Depression Scale (HADS) - Evaluable Population
Description	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.
Time Frame	Enrollment to Week 16

Outcome Measure Data

Analysis Population Description

Evaluable: randomized participants with at least 1 dose of any treatment; completed Week 16 procedures and adequately complied with the protocol (per sponsor). Those excluded from Evaluable were identified prior to unblinding. Number with non-missing data in each treatment group were analyzed (n).

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	38	36
Anxiety Total (n=19, 38, 36)	-0.7 (0.71)	-0.1 (0.51)	-0.3 (0.51)
Depression Total (n=19, 38, 36)	-0.7 (0.56)	-0.5 (0.40)	-0.5 (0.40)

21. Secondary Outcome

Title	Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population
Description	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.
Time Frame	Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)

Outcome Measure Data

Analysis Population Description

ITT:those randomized, received at least 1 injection of any component of the randomized medication. Enrolled not randomized: those who received at least 1 dose of pramlintide in 4-week lead-in period. n=number with non-missing data at visit in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin	Non-Randomized From 4 Week Lead-In
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	During the 4-week lead-in period, all participants self administered subcutaneous (SC) injections of pramlintide acetate 180 mcg twice per week (BID) for 2 weeks followed by pramlintide acetate 360 mcg BID for 2 weeks while following a diet aimed at creating a 40% caloric deficit relative to their estimated weight-maintenance energy needs. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to 1 of 3 treatment groups (metreleptin, pramlintide, or pramlintide+metreleptin). 38 participants were not randomized into one of the 3 treatment groups and withdrew from the study.
Measure Participants	27	56	56	38
Systolic BP Change up to Week -2(n=27,56,56,23)	-1.2 (8.06)	-3.5 (8.74)	-2.8 (9.08)	0.9 (9.94)
Diastolic BP Change up to Week -2(n=27,56,56,23)	-3.7 (6.10)	-1.8 (6.51)	-1.9 (7.06)	-0.6 (6.08)
Systolic BP Change to Week 16(n=19,39,38)	-6.3 (7.98)	-4.5 (9.41)	-1.6 (10.06)	NA (NA)
Diastolic BP Change to Week 16(n=19,39,38)	-3.7 (6.88)	-2.6 (7.16)	0.3 (8.57)	NA (NA)
Systolic BP Change to Week 20(n=19,37,38)	-1.2 (11.28)	-3.9 (9.64)	-1.9 (8.76)	NA (NA)
Diastolic BP Change to Week 20(n=19,37,38)	-1.5 (8.12)	-1.0 (8.15)	1.8 (7.59)	NA (NA)

22. Secondary Outcome

Title	Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Heart Rate - Enrolled Population
Description	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.
Time Frame	Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)

Outcome Measure Data

Analysis Population Description

ITT: those randomized, received at least 1 injection of any component of the randomized medication. Enrolled not randomized: those who received at least 1 dose of pramlintide in 4-week lead-in period. n=number with non-missing data at visit in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin	Non-Randomized From 4 Week Lead-In
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	During the 4-week lead-in period, all participants self administered subcutaneous (SC) injections of pramlintide acetate180 mcg twice per week (BID) for 2 weeks followed by pramlintide acetate 360 mcg BID for 2 weeks while following a diet aimed at creating a 40% caloric deficit relative to their estimated weight-maintenance energy needs. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to 1 of 3 treatment groups (metreleptin, pramlintide, or pramlintide+metreleptin). 38 participants were not randomized into one of the 3 treatment groups and withdrew from the study.
Measure Participants	27	56	56	38
Week -2 (n=27,56,56,23)	-1.3 (10.76)	-0.8 (7.82)	-1.1 (8.83)	1.3 (12.05)
Week 16 (n=19, 39, 38)	-0.2 (11.09)	-2.1 (7.58)	-4.2 (9.47)	NA (NA)
Week 20 (n=19, 37, 38)	-0.2 (8.90)	-1.6 (6.50)	-3.8 (10.21)	NA (NA)

23. Secondary Outcome

Title	Number of Chemistry Values of Potential Clinical Importance - Enrolled Population
Description	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.
Time Frame	Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)

Outcome Measure Data

Analysis Population Description

The Enrolled Population includes all enrolled participants who received at least 1 dose of pramlintide during the 4-week lead-in period or who had nonmissing data at Week -4. n=number with non-missing data in each treatment group who were in the analysis.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin	Non-Randomized From 4 Week Lead-In
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	During the 4-week lead-in period, all participants self administered subcutaneous (SC) injections of pramlintide acetate 180 mcg twice per week (BID) for 2 weeks followed by pramlintide acetate 360 mcg BID for 2 weeks while following a diet aimed at creating a 40% caloric deficit relative to their estimated weight-maintenance energy needs. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to 1 of 3 treatment groups (metreleptin, pramlintide, or pramlintide+metreleptin). 38 participants were not randomized into one of the 3 treatment groups and withdrew from the study.
Measure Participants	27	56	56	37
ALT (n=27, 56, 56, 37)	0	1	0	0
AST (n=27, 56, 56, 37)	0	1	0	0
Bicarbonate (n=27, 55, 56, 37)	3	7	4	0
CPK (n=27, 56, 56, 37)	0	1	6	0
GGT (n=27, 56, 56, 37)	1	2	0	0
Phosphorus (n=27, 56, 56, 37)	0	0	0	1
Potassium (n=27, 56, 56, 37)	0	1	0	2
Sodium (n=27, 56, 56, 37)	0	1	0	0
Total bilirubin (n=27, 56, 56, 37)	0	1	0	0
Triglycerides (n=27, 56, 56, 37)	1	0	0	0
Uric Acid (n=27, 56, 56, 37)	1	0	0	0

24. Secondary Outcome

Title	Number of Hematology and Urinalysis Values of Potential Clinical Importance - Enrolled Population
Description	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.
Time Frame	Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)

Outcome Measure Data

Analysis Population Description

The Enrolled Population includes all enrolled participants who received at least 1 dose of pramlintide during the 4-week lead-in period or who had nonmissing vital signs data at Week -4. n=number with non-missing data in each treatment group

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin	Non-Randomized From 4 Week Lead-In
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	During the 4-week lead-in period, all participants self administered subcutaneous (SC) injections of pramlintide acetate180 mcg twice per week (BID) for 2 weeks followed by pramlintide acetate 360 mcg BID for 2 weeks while following a diet aimed at creating a 40% caloric deficit relative to their estimated weight-maintenance energy needs. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to 1 of 3 treatment groups (metreleptin, pramlintide, or pramlintide+metreleptin). 38 participants were not randomized into one of the 3 treatment groups and withdrew from the study.
Measure Participants	27	56	56	38
Hematocrit (n=27, 55, 54, 35)	0 0%	3 5.4%	1 1.8%	0 0%
Hemoglobin (n=27, 56, 54, 36)	0 0%	2 3.6%	1 1.8%	0 0%
Urine Protein Positive (n=27, 56, 56, 37)	0 0%	1 1.8%	4 7.1%	0 0%

25. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormal ECG at Weeks 16, 20, or Early Termination - Randomized Population
Description	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). .
Time Frame	Weeks 16, 20, early termination

Outcome Measure Data

Analysis Population Description

All participants who were enrolled and randomized and had ECGs performed at Weeks 16, 20, or early termination. n=number of participants with ECGs at visit by treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	19	39	38
Week 16 (n=19, 39, 38)	0 0%	0 0%	0 0%
Week 20 (n=19, 37, 37)	0 0%	0 0%	0 0%
Early Termination (n=4, 6, 11))	0 0%	0 0%	0 0%

26. Secondary Outcome

Title	Number of Participants With Treatment-emergent Anti-Leptin Antibodies by Week 4, Week 8, Week 12, Week 16 - Intent to Treat Population
Description	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).
Time Frame	Baseline up to Week 16

Outcome Measure Data

Analysis Population Description

The Intent-To-Treat (ITT) Population includes all randomized participants who received at least 1 injection of any component of the randomized study medication; n=number with non-missing data at visit in each treatment group.

Arm/Group Title	Metreleptin	Pramlintide Acetate	Pramlintide Acetate + Metreleptin
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.	Participants self administered subcutaneous (SC) injections of Pramlintide acetate 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.
Measure Participants	22	48	45
Week 4 (n=22, 48, 45)	19 70.4%	3 5.4%	39 69.6%
Week 8 (n=19, 46, 37)	19 70.4%	0 0%	37 66.1%
Week 12 (n=19, 40, 38)	19 70.4%	0 0%	38 67.9%
Week 16 (n=19, 38, 38)	19 70.4%	1 1.8%	38 67.9%

Adverse Events

Time Frame	4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total)
Adverse Event Reporting Description	systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Arm/Group Title	Placebo + Metreleptin		Pramlintide + Placebo		Pramlintide + Metreleptin		Participants Not Randomized to Group After Lead-In Period
Arm/Group Description	Participants self administered subcutaneous (SC) injections of Placebo matched to pramlintide (Placebo-P) BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.		Participants self administered subcutaneous (SC) injections of Pramlintide 360 mcg BID plus Placebo matched to Metreleptin (Placebo-M) BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.		Participants self administered subcutaneous (SC) injections of Pramlintide 360 mcg BID plus Metreleptin 5 mg BID. Dosing for up to 20 weeks. Participants were asked to maintain a 20% caloric deficit during the treatment period.		During the 4-week lead-in period, all participants self administered a subcutaneous injection of pramlintide 180 mcg twice per week (BID) for 2 weeks followed by pramlintide 360 mcg BID for 2 weeks while following a diet aimed at creating a 40% caloric deficit relative to their estimated weight-maintenance energy needs. Participants who lost between 2% and 8% of their enrollment body weight during the lead-in period were randomized at Visit 4 (baseline/Day 1) to 1 of 3 treatment groups (metreleptin, pramlintide, or pramlintide+metreleptin). 38 participants were not Randomized into one of the 3 treatment groups and withdrew from the study.
All Cause Mortality
	Placebo + Metreleptin		Pramlintide + Placebo		Pramlintide + Metreleptin		Participants Not Randomized to Group After Lead-In Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo + Metreleptin		Pramlintide + Placebo		Pramlintide + Metreleptin		Participants Not Randomized to Group After Lead-In Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/27 (3.7%)		0/56 (0%)		2/56 (3.6%)		0/38 (0%)
Cardiac disorders
Myocardial Infarction	0/27 (0%)	0	0/56 (0%)	0	1/56 (1.8%)	1	0/38 (0%)	0
Immune system disorders
Hypersensitivity	0/27 (0%)	0	0/56 (0%)	0	1/56 (1.8%)	1	0/38 (0%)	0
Vascular disorders
Deep vein thrombosis	1/27 (3.7%)	1	0/56 (0%)	0	0/56 (0%)	0	0/38 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo + Metreleptin		Pramlintide + Placebo		Pramlintide + Metreleptin		Participants Not Randomized to Group After Lead-In Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/27 (88.9%)		42/56 (75%)		45/56 (80.4%)		17/38 (44.7%)
Gastrointestinal disorders
Nausea	7/27 (25.9%)	7	8/56 (14.3%)	10	7/56 (12.5%)	8	10/38 (26.3%)	10
Diarrhoea	0/27 (0%)	0	3/56 (5.4%)	3	2/56 (3.6%)	3	2/38 (5.3%)	3
Constipation	1/27 (3.7%)	1	0/56 (0%)	0	3/56 (5.4%)	3	0/38 (0%)	0
Vomiting	2/27 (7.4%)	2	1/56 (1.8%)	1	1/56 (1.8%)	1	3/38 (7.9%)	3
General disorders
Injection Site Bruising	3/27 (11.1%)	3	9/56 (16.1%)	11	11/56 (19.6%)	13	1/38 (2.6%)	1
Injection Site Erythema	5/27 (18.5%)	5	6/56 (10.7%)	8	8/56 (14.3%)	8	0/38 (0%)	0
Injection Site Pruritus	7/27 (25.9%)	7	3/56 (5.4%)	3	8/56 (14.3%)	8	0/38 (0%)	0
Injection Site Urticaria	5/27 (18.5%)	5	0/56 (0%)	0	9/56 (16.1%)	10	0/38 (0%)	0
Injection Site Nodule	4/27 (14.8%)	4	3/56 (5.4%)	3	3/56 (5.4%)	5	0/38 (0%)	0
Injection Site Haemorrhage	1/27 (3.7%)	2	6/56 (10.7%)	7	2/56 (3.6%)	2	0/38 (0%)	0
Injection Site Induration	2/27 (7.4%)	2	0/56 (0%)	0	3/56 (5.4%)	3	0/38 (0%)	0
Injection Site Pain	0/27 (0%)	0	2/56 (3.6%)	2	3/56 (5.4%)	3	2/38 (5.3%)	3
Injection Site Rash	0/27 (0%)	0	0/56 (0%)	0	3/56 (5.4%)	3	0/38 (0%)	0
Immune system disorders
Hypersensitivity	2/27 (7.4%)	2	0/56 (0%)	0	1/56 (1.8%)	2	0/38 (0%)	0
Infections and infestations
Nasopharyngitis	2/27 (7.4%)	2	7/56 (12.5%)	7	3/56 (5.4%)	3	2/38 (5.3%)	2
Influenza	1/27 (3.7%)	1	3/56 (5.4%)	3	2/56 (3.6%)	2	0/38 (0%)	0
Pharyngitis streptococcal	0/27 (0%)	0	3/56 (5.4%)	3	1/56 (1.8%)	1	0/38 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	0/27 (0%)	0	3/56 (5.4%)	3	0/56 (0%)	0	0/38 (0%)	0
Nervous system disorders
Headache	2/27 (7.4%)	2	4/56 (7.1%)	5	3/56 (5.4%)	4	1/38 (2.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.