Trial Outcomes & Findings for A Study to Evaluate the Effect on Body Weight of Leptin Administered in Conjunction With Pramlintide in Overweight and Obese Subjects (NCT NCT00392925)

NCT ID: NCT00392925

Last Updated: 2015-04-14

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 177 participants
• Primary outcome timeframe: Baseline to Week 16
• Results posted on: 2015-04-14

Participant Flow

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.

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.

Participant milestones

Measure	Non-Randomized From 4 Week Lead-In 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.	Metreleptin 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.	Pramlintide Acetate 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.	Pramlintide Acetate + Metreleptin 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.
4 Week Lead-In Period - Non-Randomized STARTED	177	0	0	0
4 Week Lead-In Period - Non-Randomized COMPLETED	139	0	0	0
4 Week Lead-In Period - Non-Randomized NOT COMPLETED	38	0	0	0
Randomization to Treatment Group Period STARTED	0	27	56	56
Randomization to Treatment Group Period COMPLETED	0	19	37	38
Randomization to Treatment Group Period NOT COMPLETED	0	8	19	18

Reasons for withdrawal

Measure	Non-Randomized From 4 Week Lead-In 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.	Metreleptin 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.	Pramlintide Acetate 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.	Pramlintide Acetate + Metreleptin 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.
4 Week Lead-In Period - Non-Randomized Withdrawal by Subject	11	0	0	0
4 Week Lead-In Period - Non-Randomized Adverse Event	5	0	0	0
4 Week Lead-In Period - Non-Randomized Physician Decision	1	0	0	0
4 Week Lead-In Period - Non-Randomized Lost to Follow-up	5	0	0	0
4 Week Lead-In Period - Non-Randomized did not meet weight loss criteria	16	0	0	0
Randomization to Treatment Group Period Withdrawal by Subject	0	2	6	8
Randomization to Treatment Group Period Adverse Event	0	3	3	5
Randomization to Treatment Group Period Protocol Violation	0	0	2	1
Randomization to Treatment Group Period Lost to Follow-up	0	3	8	4

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Metreleptin n=27 Participants 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.	Pramlintide Acetate n=56 Participants 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.	Pramlintide Acetate + Metreleptin n=56 Participants 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.	Non-Randomized From 4 Week Lead-In n=38 Participants 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 n=177 Participants Total of all reporting groups
Age, Continuous	40.5 years STANDARD_DEVIATION 8.06 • n=5 Participants	38.3 years STANDARD_DEVIATION 9.13 • n=7 Participants	38.5 years STANDARD_DEVIATION 8.42 • n=5 Participants	37.9 years STANDARD_DEVIATION 7.51 • n=4 Participants	38.6 years STANDARD_DEVIATION 8.39 • n=21 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	35 Participants n=7 Participants	35 Participants n=5 Participants	24 Participants n=4 Participants	111 Participants n=21 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	21 Participants n=7 Participants	21 Participants n=5 Participants	14 Participants n=4 Participants	66 Participants n=21 Participants
Region of Enrollment United States	27 participants n=5 Participants	56 participants n=7 Participants	56 participants n=5 Participants	38 participants n=4 Participants	177 participants n=21 Participants
Body Weight at Enrollment	93.80 kg STANDARD_DEVIATION 14.322 • n=5 Participants	91.70 kg STANDARD_DEVIATION 11.085 • n=7 Participants	93.89 kg STANDARD_DEVIATION 12.834 • n=5 Participants	94.54 kg STANDARD_DEVIATION 16.027 • n=4 Participants	93.32 kg STANDARD_DEVIATION 13.246 • n=21 Participants
Body Weight at Baseline	89.83 kg STANDARD_DEVIATION 13.389 • n=5 Participants	88.05 kg STANDARD_DEVIATION 10.507 • n=7 Participants	89.88 kg STANDARD_DEVIATION 12.355 • n=5 Participants	NA kg STANDARD_DEVIATION NA • n=4 Participants	89.13 kg STANDARD_DEVIATION 11.807 • n=21 Participants
Body Mass Index (BMI) at Enrollment	32.0 kg/m^2 STANDARD_DEVIATION 2.15 • n=5 Participants	31.5 kg/m^2 STANDARD_DEVIATION 2.03 • n=7 Participants	32.0 kg/m^2 STANDARD_DEVIATION 2.10 • n=5 Participants	32.5 kg/m^2 STANDARD_DEVIATION 1.95 • n=4 Participants	32.0 kg/m^2 STANDARD_DEVIATION 2.07 • n=21 Participants

PRIMARY outcome

Timeframe: Baseline to Week 16

Population: 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.

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

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Mean Absolute Change From Baseline to Week 16 in Body Weight - Evaluable Population	-2.68 kg Standard Error 0.952	-3.30 kg Standard Error 0.698	-6.46 kg Standard Error 0.682	—

SECONDARY outcome

Timeframe: Baseline up to Week 20

Population: 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.

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

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 4 (n=19, 38, 36)	-0.70 percentage of change Standard Error 0.429	-1.55 percentage of change Standard Error 0.310	-2.36 percentage of change Standard Error 0.311	—
LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 8 (n=19, 38, 36)	-2.08 percentage of change Standard Error 0.591	-2.74 percentage of change Standard Error 0.427	-4.81 percentage of change Standard Error 0.429	—
LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 12 (n=19, 38, 36)	-3.17 percentage of change Standard Error 0.796	-3.39 percentage of change Standard Error 0.575	-6.13 percentage of change Standard Error 0.577	—
LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 16 (n=19, 38, 36)	-3.37 percentage of change Standard Error 1.025	-3.85 percentage of change Standard Error 0.740	-7.59 percentage of change Standard Error 0.743	—
LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 20 (n=19, 37, 36)	-3.62 percentage of change Standard Error 1.277	-3.89 percentage of change Standard Error 0.925	-8.21 percentage of change Standard Error 0.926	—

SECONDARY outcome

Timeframe: Baseline to Week 20

Population: 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.

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

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Absolute Change From Baseline to Weeks 4, 8, 12, 20 in Body Weight - Evaluable Population Week 4 (n=19, 38, 36)	-0.66 kg Standard Error 0.387	-1.43 kg Standard Error 0.284	-2.13 kg Standard Error 0.277	—
LS Mean Absolute Change From Baseline to Weeks 4, 8, 12, 20 in Body Weight - Evaluable Population Week 8 (n=19, 38, 36)	-1.66 kg Standard Error 0.540	-2.32 kg Standard Error 0.396	-4.16 kg Standard Error 0.387	—
LS Mean Absolute Change From Baseline to Weeks 4, 8, 12, 20 in Body Weight - Evaluable Population Week 12 (n=19, 38, 36)	-2.59 kg Standard Error 0.742	-2.97 kg Standard Error 0.544	-5.28 kg Standard Error 0.532	—
LS Mean Absolute Change From Baseline to Weeks 4, 8, 12, 20 in Body Weight - Evaluable Population Week 20 (n=19, 37, 36)	-2.80 kg Standard Error 1.199	-3.30 kg Standard Error 0.881	-6.90 kg Standard Error 0.859	—

SECONDARY outcome

Timeframe: Enrollment to Week 20

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 4 (n=19, 38, 36)	-5.22 kg Standard Error 0.483	-5.93 kg Standard Error 0.353	-6.72 kg Standard Error 0.346	—
LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 8 (n=19, 38, 36)	-6.25 kg Standard Error 0.635	-6.85 kg Standard Error 0.464	-8.77 kg Standard Error 0.455	—
LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 12 (n=19, 38, 36)	-7.18 kg Standard Error 0.822	-7.50 kg Standard Error 0.60	-9.89 kg Standard Error 0.590	—
LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 16 (n=19, 38, 36)	-7.28 kg Standard Error 1.028	-7.84 kg Standard Error 0.751	-11.07 kg Standard Error 0.737	—
LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 20(n=19, 37, 36)	-7.41 kg Standard Error 1.262	-7.86 kg Standard Error 0.923	-11.52 kg Standard Error 0.904	—

SECONDARY outcome

Timeframe: Enrollment to Week 20

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 4 (n=19, 38, 36)	-5.46 percentage of change Standard Error 0.512	-6.20 percentage of change Standard Error 0.369	-7.18 percentage of change Standard Error 0.371	—
LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 8 (n=19, 38, 36)	-6.77 percentage of change Standard Error 0.654	-7.33 percentage of change Standard Error 0.473	-9.50 percentage of change Standard Error 0.474	—
LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 12 (n=19, 38, 36)	-7.80 percentage of change Standard Error 0.836	-7.95 percentage of change Standard Error 0.604	-10.75 percentage of change Standard Error 0.606	—
LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 16 (n=19, 38, 36)	-7.99 percentage of change Standard Error 1.058	-8.37 percentage of change Standard Error 0.764	-12.13 percentage of change Standard Error 0.767	—
LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population Week 20 (n=19, 37, 36)	-8.22 percentage of change Standard Error 1.286	-8.42 percentage of change Standard Error 0.931	-12.72 percentage of change Standard Error 0.932	—

SECONDARY outcome

Timeframe: Baseline to Week 20

Population: 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.

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).

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Initial, Late, and Overall Rates of LS Mean Absolute Change in Body Weight From Day 1 to Week 20 - Evaluable Population Initial rate of absolute change	-0.23 kg/week Standard Error 0.060	-0.25 kg/week Standard Error 0.044	-0.46 kg/week Standard Error 0.043	—
Initial, Late, and Overall Rates of LS Mean Absolute Change in Body Weight From Day 1 to Week 20 - Evaluable Population Late rate of absolute change	-0.02 kg/week Standard Error 0.079	-0.05 kg/week Standard Error 0.058	-0.20 kg/week Standard Error 0.057	—
Initial, Late, and Overall Rates of LS Mean Absolute Change in Body Weight From Day 1 to Week 20 - Evaluable Population Overall rate of absolute change	-0.16 kg/week Standard Error 0.059	-0.17 kg/week Standard Error 0.043	-0.36 kg/week Standard Error 0.042	—

SECONDARY outcome

Timeframe: Baseline to Weeks 16 and Weeks 20

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
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 Weight Loss of 5% or more Week 16 (n=19, 38, 36)	5 participants	13 participants	22 participants	—
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 Weight Loss of 5% or more Week 20(n=19, 37, 36)	6 participants	14 participants	25 participants	—
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 5% Loss Week 16 Sustained (n=19, 38, 36)	5 participants	12 participants	21 participants	—
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 Weight Loss of 10% or more Week 16(n=19, 38, 36)	1 participants	1 participants	9 participants	—
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 Weight Loss of 10% or more Week 20(n=19, 37, 36)	2 participants	2 participants	11 participants	—
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 10% Loss Week 16 Sustained (n=19, 38, 36)	1 participants	1 participants	9 participants	—

SECONDARY outcome

Timeframe: Enrollment to Baseline

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=93 Participants 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.	Pramlintide Acetate 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.	Pramlintide Acetate + Metreleptin 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Percent Change in Weight From Enrollment to Baseline and LS Mean Percent Change in Excess Weight From Enrollment to Baseline - Evaluable Population Percent Change in Weight from Enrollment	-4.42 percentage of change Standard Error 0.171	—	—	—
LS Mean Percent Change in Weight From Enrollment to Baseline and LS Mean Percent Change in Excess Weight From Enrollment to Baseline - Evaluable Population Percent Change in Excess Weight from Enrollment	-25.24 percentage of change Standard Error 1.085	—	—	—

SECONDARY outcome

Timeframe: Enrollment to Week 20

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 4 (n=19, 38, 36)	-5.49 cm Standard Error 0.940	-6.78 cm Standard Error 0.679	-7.28 cm Standard Error 0.682	—
LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 8 (n=19, 38, 36)	-5.74 cm Standard Error 0.974	-7.76 cm Standard Error 0.703	-8.75 cm Standard Error 0.706	—
LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 12 (n=19, 38, 36)	-7.06 cm Standard Error 1.077	-8.46 cm Standard Error 0.778	-9.88 cm Standard Error 0.782	—
LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 16 (n=19, 38, 36)	-6.84 cm Standard Error 1.281	-9.00 cm Standard Error 0.925	-10.66 cm Standard Error 0.929	—
LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 20 (n=19, 37, 36)	-7.99 cm Standard Error 1.509	-9.17 cm Standard Error 1.092	-11.61 cm Standard Error 1.094	—

SECONDARY outcome

Timeframe: Baseline to Week 20

Population: 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.

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

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 12 (n=19, 38, 36)	-2.63 cm Standard Error 0.941	-4.22 cm Standard Error 0.679	-5.54 cm Standard Error 0.683	—
LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 4 (n=19, 38, 36)	-1.08 cm Standard Error 0.868	-2.55 cm Standard Error 0.626	-2.95 cm Standard Error 0.630	—
LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 8 (n=19, 38, 36)	-1.29 cm Standard Error 0.833	-3.51 cm Standard Error 0.601	-4.39 cm Standard Error 0.605	—
LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 16 (n=19, 38, 36)	-2.40 cm Standard Error 1.177	-4.75 cm Standard Error 0.849	-6.30 cm Standard Error 0.854	—
LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population Week 20 (n=19, 37, 36)	-3.60 cm Standard Error 1.421	-4.90 cm Standard Error 1.029	-7.28 cm Standard Error 1.031	—

SECONDARY outcome

Timeframe: Screening up to Week 20

Population: 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.

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).

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=37 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Absolute Change in Hip Circumference From Screening up to Week 20 - Evaluable Population	-6.36 cm Standard Error 1.475	-8.07 cm Standard Error 1.082	-10.27 cm Standard Error 1.070	—

SECONDARY outcome

Timeframe: Enrollment up to Week 16

Population: 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.

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).

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population Obese BMI at Enrollment	14 participants	30 participants	27 participants	—
Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population Continued Obese BMI at Week 16	9 participants	11 participants	11 participants	—
Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population Decreased BMI to Overweight at Week 16	5 participants	19 participants	16 participants	—
Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population Decreased BMI to Normal at Week 16	1 participants	0 participants	4 participants	—
Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population Overweight BMI at Enrollment	5 participants	8 participants	9 participants	—
Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population Continued Overweight BMI at Week 16	4 participants	8 participants	5 participants	—

SECONDARY outcome

Timeframe: Enrollment up to Week 20

Population: 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.

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).

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=37 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population Obese BMI at Enrollment	14 participants	29 participants	27 participants	—
Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population Continued Obese BMI at Week 20	7 participants	10 participants	10 participants	—
Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population Greater Obesity at Week 20	1 participants	0 participants	0 participants	—
Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population Decreased BMI to Overweight at Week 20	6 participants	19 participants	17 participants	—
Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population Decreased BMI to Normal at Week 20	1 participants	0 participants	4 participants	—
Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population Overweight BMI at Enrollment	5 participants	8 participants	9 participants	—
Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population Continued Overweight BMI at Week 20	4 participants	8 participants	5 participants	—

SECONDARY outcome

Timeframe: Enrollment to Week 16

Population: 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.

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).

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population Glucose (n=19, 35, 35)	-2.21 mg/dL Standard Deviation 8.574	-1.86 mg/dL Standard Deviation 10.347	-3.00 mg/dL Standard Deviation 7.412	—
Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population Total Cholesterol (n=19, 38, 36)	2.68 mg/dL Standard Deviation 25.164	-10.76 mg/dL Standard Deviation 20.285	-20.64 mg/dL Standard Deviation 25.798	—
Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population HDL cholesterol (n=19, 38, 36)	1.74 mg/dL Standard Deviation 6.358	1.63 mg/dL Standard Deviation 7.321	-0.64 mg/dL Standard Deviation 7.761	—
Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population LDL cholesterol (n=19, 38, 36)	1.11 mg/dL Standard Deviation 22.266	-5.50 mg/dL Standard Deviation 18.064	-13.25 mg/dL Standard Deviation 17.986	—
Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population Triglycerides (n=19, 37, 35)	30.37 mg/dL Standard Deviation 77.920	1.57 mg/dL Standard Deviation 75.063	-9.54 mg/dL Standard Deviation 53.844	—

SECONDARY outcome

Timeframe: Enrollment to Week 16

Population: 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.

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]).

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Mean Absolute Change From Enrollment to Baseline, Weeks 4 and 16 in Fasting Total Leptin Concentration - Evaluable Population Baseline (Day 1) (n=18, 38, 35)	-6.16 ng/mL Standard Deviation 6.919	-7.98 ng/mL Standard Deviation 6.932	-7.23 ng/mL Standard Deviation 8.157	—
Mean Absolute Change From Enrollment to Baseline, Weeks 4 and 16 in Fasting Total Leptin Concentration - Evaluable Population Week 4 (n=19, 38, 36)	53.54 ng/mL Standard Deviation 98.124	-6.56 ng/mL Standard Deviation 7.766	18.94 ng/mL Standard Deviation 38.475	—
Mean Absolute Change From Enrollment to Baseline, Weeks 4 and 16 in Fasting Total Leptin Concentration - Evaluable Population Week 16 (n=19, 38, 36)	375.28 ng/mL Standard Deviation 340.885	-3.58 ng/mL Standard Deviation 13.296	262.61 ng/mL Standard Deviation 268.501	—

SECONDARY outcome

Timeframe: Enrollment to Week 16

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=18 Participants 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.	Pramlintide Acetate n=37 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Amylin -Evaluable Population Baseline (Day 1) (n=18, 37, 36)	-0.89 pM Standard Deviation 4.258	-2.18 pM Standard Deviation 5.641	-3.28 pM Standard Deviation 4.378	—
Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Amylin -Evaluable Population Week 16 (n=18, 34, 36)	-3.31 pM Standard Deviation 4.731	-1.60 pM Standard Deviation 5.720	-2.17 pM Standard Deviation 12.416	—

SECONDARY outcome

Timeframe: Enrollment to Week 16

Population: 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.

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)

Outcome measures

Measure	Metreleptin n=17 Participants 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.	Pramlintide Acetate n=35 Participants 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.	Pramlintide Acetate + Metreleptin n=34 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Insulin - Evaluable Population Baseline (Day 1) (n=17, 35, 34)	0.00 µIU/mL Standard Deviation 4.108	-1.14 µIU/mL Standard Deviation 4.095	-0.68 µIU/mL Standard Deviation 4.183	—
Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Insulin - Evaluable Population Week 16 (n=18, 34, 35)	-0.61 µIU/mL Standard Deviation 4.877	-0.65 µIU/mL Standard Deviation 4.792	-2.80 µIU/mL Standard Deviation 3.385	—

SECONDARY outcome

Timeframe: Enrollment to Week 16

Population: 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

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.

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcome (PRO) Instruments Measuring Quality of Life and Mood - Evaluable Population POMS Total Mood Disturbance Score(n=19, 38, 36)	-2.8 units on a scale Standard Error 6.17	-4.5 units on a scale Standard Error 4.45	-6.0 units on a scale Standard Error 4.50	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcome (PRO) Instruments Measuring Quality of Life and Mood - Evaluable Population IWQOL-Lite Total Score(n=19, 38, 36)	12.14 units on a scale Standard Error 2.553	11.92 units on a scale Standard Error 1.843	12.49 units on a scale Standard Error 1.863	—

SECONDARY outcome

Timeframe: Enrollment to Week 16

Population: 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.

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;

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population BES Total Score (n=17, 36, 34)	-5.5 units on a scale Standard Error 1.27	-3.8 units on a scale Standard Error 0.87	-6.4 units on a scale Standard Error 0.89	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ Food Craving Frequency(n=19, 38, 36)	-21.8 units on a scale Standard Error 5.32	-19.5 units on a scale Standard Error 3.84	-24.6 units on a scale Standard Error 3.86	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ Strength of Food Cravings(n=19, 38, 36)	-16.8 units on a scale Standard Error 5.39	-11.5 units on a scale Standard Error 3.88	-19.8 units on a scale Standard Error 3.91	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ Difficult to Control Eating(n=19, 38, 36)	-23.0 units on a scale Standard Error 5.77	-20.9 units on a scale Standard Error 4.17	-29.3 units on a scale Standard Error 4.19	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ Difficult to Resist Food Cravings(n=19, 38, 36	-22.7 units on a scale Standard Error 5.47	-18.6 units on a scale Standard Error 3.95	-30.2 units on a scale Standard Error 3.97	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ Response to Food Cravings(n=19, 38, 36)	-22.0 units on a scale Standard Error 5.30	-22.6 units on a scale Standard Error 3.83	-33.4 units on a scale Standard Error 3.85	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ Control Portion Sizes(n=19, 38, 36)	-24.8 units on a scale Standard Error 5.26	-27.5 units on a scale Standard Error 3.78	-33.1 units on a scale Standard Error 3.78	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ How Hungry(n=19, 38, 36)	-21.1 units on a scale Standard Error 5.20	-18.5 units on a scale Standard Error 3.77	-28.5 units on a scale Standard Error 3.77	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ How Full After Meal(n=19, 38, 36)	-3.0 units on a scale Standard Error 5.20	2.8 units on a scale Standard Error 3.76	-4.6 units on a scale Standard Error 3.77	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ Thoughts of Food(n=19, 38, 36)	-20.4 units on a scale Standard Error 5.62	-11.6 units on a scale Standard Error 4.07	-21.5 units on a scale Standard Error 4.07	—
LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population SEQ How Pleasant Meals(n=19, 38, 36)	-3.2 units on a scale Standard Error 4.73	-0.8 units on a scale Standard Error 3.42	-6.5 units on a scale Standard Error 3.44	—

SECONDARY outcome

Timeframe: Enrollment to Week 16

Population: 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).

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.

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=38 Participants 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.	Pramlintide Acetate + Metreleptin n=36 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
LS Mean Absolute Change From Enrollment to Week 16 in Hospital Anxiety and Depression Scale (HADS) - Evaluable Population Anxiety Total (n=19, 38, 36)	-0.7 units on a scale Standard Error 0.71	-0.1 units on a scale Standard Error 0.51	-0.3 units on a scale Standard Error 0.51	—
LS Mean Absolute Change From Enrollment to Week 16 in Hospital Anxiety and Depression Scale (HADS) - Evaluable Population Depression Total (n=19, 38, 36)	-0.7 units on a scale Standard Error 0.56	-0.5 units on a scale Standard Error 0.40	-0.5 units on a scale Standard Error 0.40	—

SECONDARY outcome

Timeframe: Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=27 Participants 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.	Pramlintide Acetate n=56 Participants 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.	Pramlintide Acetate + Metreleptin n=56 Participants 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.	Non-Randomized From 4 Week Lead-In n=38 Participants 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.
Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population Systolic BP Change up to Week -2(n=27,56,56,23)	-1.2 mm Hg Standard Deviation 8.06	-3.5 mm Hg Standard Deviation 8.74	-2.8 mm Hg Standard Deviation 9.08	0.9 mm Hg Standard Deviation 9.94
Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population Diastolic BP Change up to Week -2(n=27,56,56,23)	-3.7 mm Hg Standard Deviation 6.10	-1.8 mm Hg Standard Deviation 6.51	-1.9 mm Hg Standard Deviation 7.06	-0.6 mm Hg Standard Deviation 6.08
Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population Systolic BP Change to Week 16(n=19,39,38)	-6.3 mm Hg Standard Deviation 7.98	-4.5 mm Hg Standard Deviation 9.41	-1.6 mm Hg Standard Deviation 10.06	NA mm Hg Standard Deviation NA Non-randomized participants (total of 38) are those who left the study before being randomized to a treatment group. These 38 participants received pramlintide in the Lead-In Period.
Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population Diastolic BP Change to Week 16(n=19,39,38)	-3.7 mm Hg Standard Deviation 6.88	-2.6 mm Hg Standard Deviation 7.16	0.3 mm Hg Standard Deviation 8.57	NA mm Hg Standard Deviation NA Non-randomized participants (total of 38) are those who left the study before being randomized to a treatment group. These 38 participants received pramlintide in the Lead-In Period.
Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population Systolic BP Change to Week 20(n=19,37,38)	-1.2 mm Hg Standard Deviation 11.28	-3.9 mm Hg Standard Deviation 9.64	-1.9 mm Hg Standard Deviation 8.76	NA mm Hg Standard Deviation NA Non-randomized participants (total of 38) are those who left the study before being randomized to a treatment group. These 38 participants received pramlintide in the Lead-In Period.
Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population Diastolic BP Change to Week 20(n=19,37,38)	-1.5 mm Hg Standard Deviation 8.12	-1.0 mm Hg Standard Deviation 8.15	1.8 mm Hg Standard Deviation 7.59	NA mm Hg Standard Deviation NA Non-randomized participants (total of 38) are those who left the study before being randomized to a treatment group. These 38 participants received pramlintide in the Lead-In Period.

SECONDARY outcome

Timeframe: Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=27 Participants 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.	Pramlintide Acetate n=56 Participants 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.	Pramlintide Acetate + Metreleptin n=56 Participants 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.	Non-Randomized From 4 Week Lead-In n=38 Participants 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.
Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Heart Rate - Enrolled Population Week -2 (n=27,56,56,23)	-1.3 beats/min Standard Deviation 10.76	-0.8 beats/min Standard Deviation 7.82	-1.1 beats/min Standard Deviation 8.83	1.3 beats/min Standard Deviation 12.05
Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Heart Rate - Enrolled Population Week 16 (n=19, 39, 38)	-0.2 beats/min Standard Deviation 11.09	-2.1 beats/min Standard Deviation 7.58	-4.2 beats/min Standard Deviation 9.47	NA beats/min Standard Deviation NA Non-randomized participants (total of 38) are those who left the study before being randomized to a treatment group. These 38 participants received pramlintide in the Lead-In Period.
Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Heart Rate - Enrolled Population Week 20 (n=19, 37, 38)	-0.2 beats/min Standard Deviation 8.90	-1.6 beats/min Standard Deviation 6.50	-3.8 beats/min Standard Deviation 10.21	NA beats/min Standard Deviation NA Non-randomized participants (total of 38) are those who left the study before being randomized to a treatment group. These 38 participants received pramlintide in the Lead-In Period.

SECONDARY outcome

Timeframe: Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)

Population: 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.

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.

Outcome measures

Measure	Metreleptin n=27 Participants 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.	Pramlintide Acetate n=56 Participants 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.	Pramlintide Acetate + Metreleptin n=56 Participants 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.	Non-Randomized From 4 Week Lead-In n=37 Participants 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.
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population Bicarbonate (n=27, 55, 56, 37)	3 laboratory values	7 laboratory values	4 laboratory values	0 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population CPK (n=27, 56, 56, 37)	0 laboratory values	1 laboratory values	6 laboratory values	0 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population ALT (n=27, 56, 56, 37)	0 laboratory values	1 laboratory values	0 laboratory values	0 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population AST (n=27, 56, 56, 37)	0 laboratory values	1 laboratory values	0 laboratory values	0 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population GGT (n=27, 56, 56, 37)	1 laboratory values	2 laboratory values	0 laboratory values	0 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population Phosphorus (n=27, 56, 56, 37)	0 laboratory values	0 laboratory values	0 laboratory values	1 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population Potassium (n=27, 56, 56, 37)	0 laboratory values	1 laboratory values	0 laboratory values	2 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population Sodium (n=27, 56, 56, 37)	0 laboratory values	1 laboratory values	0 laboratory values	0 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population Total bilirubin (n=27, 56, 56, 37)	0 laboratory values	1 laboratory values	0 laboratory values	0 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population Triglycerides (n=27, 56, 56, 37)	1 laboratory values	0 laboratory values	0 laboratory values	0 laboratory values
Number of Chemistry Values of Potential Clinical Importance - Enrolled Population Uric Acid (n=27, 56, 56, 37)	1 laboratory values	0 laboratory values	0 laboratory values	0 laboratory values

SECONDARY outcome

Timeframe: Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group)

Population: 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

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.

Outcome measures

Measure	Metreleptin n=27 Participants 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.	Pramlintide Acetate n=56 Participants 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.	Pramlintide Acetate + Metreleptin n=56 Participants 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.	Non-Randomized From 4 Week Lead-In n=38 Participants 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.
Number of Hematology and Urinalysis Values of Potential Clinical Importance - Enrolled Population Hematocrit (n=27, 55, 54, 35)	0 participants	3 participants	1 participants	0 participants
Number of Hematology and Urinalysis Values of Potential Clinical Importance - Enrolled Population Hemoglobin (n=27, 56, 54, 36)	0 participants	2 participants	1 participants	0 participants
Number of Hematology and Urinalysis Values of Potential Clinical Importance - Enrolled Population Urine Protein Positive (n=27, 56, 56, 37)	0 participants	1 participants	4 participants	0 participants

SECONDARY outcome

Timeframe: Weeks 16, 20, early termination

Population: 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.

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). .

Outcome measures

Measure	Metreleptin n=19 Participants 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.	Pramlintide Acetate n=39 Participants 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.	Pramlintide Acetate + Metreleptin n=38 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Number of Participants With Clinically Significant Abnormal ECG at Weeks 16, 20, or Early Termination - Randomized Population Week 16 (n=19, 39, 38)	0 participants	0 participants	0 participants	—
Number of Participants With Clinically Significant Abnormal ECG at Weeks 16, 20, or Early Termination - Randomized Population Week 20 (n=19, 37, 37)	0 participants	0 participants	0 participants	—
Number of Participants With Clinically Significant Abnormal ECG at Weeks 16, 20, or Early Termination - Randomized Population Early Termination (n=4, 6, 11))	0 participants	0 participants	0 participants	—

SECONDARY outcome

Timeframe: Baseline up to Week 16

Population: 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.

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).

Outcome measures

Measure	Metreleptin n=22 Participants 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.	Pramlintide Acetate n=48 Participants 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.	Pramlintide Acetate + Metreleptin n=45 Participants 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.	Non-Randomized From 4 Week Lead-In 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.
Number of Participants With Treatment-emergent Anti-Leptin Antibodies by Week 4, Week 8, Week 12, Week 16 - Intent to Treat Population Week 4 (n=22, 48, 45)	19 participants	3 participants	39 participants	—
Number of Participants With Treatment-emergent Anti-Leptin Antibodies by Week 4, Week 8, Week 12, Week 16 - Intent to Treat Population Week 8 (n=19, 46, 37)	19 participants	0 participants	37 participants	—
Number of Participants With Treatment-emergent Anti-Leptin Antibodies by Week 4, Week 8, Week 12, Week 16 - Intent to Treat Population Week 12 (n=19, 40, 38)	19 participants	0 participants	38 participants	—
Number of Participants With Treatment-emergent Anti-Leptin Antibodies by Week 4, Week 8, Week 12, Week 16 - Intent to Treat Population Week 16 (n=19, 38, 38)	19 participants	1 participants	38 participants	—

Adverse Events

Placebo + Metreleptin

Serious events: 1 serious events

Other events: 24 other events

Deaths: 0 deaths

Pramlintide + Placebo

Serious events: 0 serious events

Other events: 42 other events

Deaths: 0 deaths

Pramlintide + Metreleptin

Serious events: 2 serious events

Other events: 45 other events

Deaths: 0 deaths

Participants Not Randomized to Group After Lead-In Period

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo + Metreleptin n=27 participants at risk 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.	Pramlintide + Placebo n=56 participants at risk 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.	Pramlintide + Metreleptin n=56 participants at risk 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.	Participants Not Randomized to Group After Lead-In Period n=38 participants at risk 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.
Cardiac disorders Myocardial Infarction	0.00% 0/27 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	1.8% 1/56 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Immune system disorders Hypersensitivity	0.00% 0/27 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	1.8% 1/56 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Vascular disorders Deep vein thrombosis	3.7% 1/27 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.

Other adverse events

Measure	Placebo + Metreleptin n=27 participants at risk 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.	Pramlintide + Placebo n=56 participants at risk 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.	Pramlintide + Metreleptin n=56 participants at risk 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.	Participants Not Randomized to Group After Lead-In Period n=38 participants at risk 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.
General disorders Injection Site Bruising	11.1% 3/27 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	16.1% 9/56 • Number of events 11 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	19.6% 11/56 • Number of events 13 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	2.6% 1/38 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Gastrointestinal disorders Nausea	25.9% 7/27 • Number of events 7 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	14.3% 8/56 • Number of events 10 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	12.5% 7/56 • Number of events 8 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	26.3% 10/38 • Number of events 10 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
General disorders Injection Site Erythema	18.5% 5/27 • Number of events 5 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	10.7% 6/56 • Number of events 8 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	14.3% 8/56 • Number of events 8 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
General disorders Injection Site Pruritus	25.9% 7/27 • Number of events 7 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	14.3% 8/56 • Number of events 8 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
General disorders Injection Site Urticaria	18.5% 5/27 • Number of events 5 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	16.1% 9/56 • Number of events 10 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
General disorders Injection Site Nodule	14.8% 4/27 • Number of events 4 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 5 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Infections and infestations Nasopharyngitis	7.4% 2/27 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	12.5% 7/56 • Number of events 7 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.3% 2/38 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Nervous system disorders Headache	7.4% 2/27 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	7.1% 4/56 • Number of events 5 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 4 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	2.6% 1/38 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
General disorders Injection Site Haemorrhage	3.7% 1/27 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	10.7% 6/56 • Number of events 7 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	3.6% 2/56 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Gastrointestinal disorders Diarrhoea	0.00% 0/27 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	3.6% 2/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.3% 2/38 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Infections and infestations Influenza	3.7% 1/27 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	3.6% 2/56 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
General disorders Injection Site Induration	7.4% 2/27 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
General disorders Injection Site Pain	0.00% 0/27 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	3.6% 2/56 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.3% 2/38 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Gastrointestinal disorders Constipation	3.7% 1/27 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Immune system disorders Hypersensitivity	7.4% 2/27 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	1.8% 1/56 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Infections and infestations Pharyngitis streptococcal	0.00% 0/27 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	1.8% 1/56 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Gastrointestinal disorders Vomiting	7.4% 2/27 • Number of events 2 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	1.8% 1/56 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	1.8% 1/56 • Number of events 1 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	7.9% 3/38 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/27 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.
General disorders Injection Site Rash	0.00% 0/27 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/56 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	5.4% 3/56 • Number of events 3 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.	0.00% 0/38 • 4 Week Lead-in Period and 20 weeks Randomized Treatment Period (24 weeks total) systematic assessment for administration site adverse events and non-systematic assessment for all other adverse events.

Additional Information

Peter Ohman, Medical Science Director

AstraZeneca

Email: ClinicalTrialTransparency@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER