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

Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT00673387
Collaborator
(none)
636
Enrollment
36
Locations
8
Arms
18
Duration (Months)
17.7
Patients Per Site
1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
636 participants
Allocation:
Randomized
Intervention Model:
Factorial Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Examine the Safety, Tolerability, and Effect on Body Weight of Metreleptin Administered in Conjunction With Pramlintide in Obese and Overweight Subjects.
Study Start Date :
Apr 1, 2008
Actual Primary Completion Date :
Apr 1, 2009
Actual Study Completion Date :
Oct 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo-P + Placebo-M

Placebo matched to pramlintide BID plus placebo matched to metreleptin BID

Drug: placebo-P
subcutaneous injection, twice a day
Other Names:
  • Placebo matched to pramlintide

    • Drug: placebo-M
    subcutaneous injection, twice a day
    Other Names:
  • Placebo matched to Metreleptin

    		•
    Experimental: Pramlintide 360 mcg + Placebo-M

    360 mcg pramlintide given twice per day (BID) plus Placebo matched to Metreleptin given BID

    Drug: pramlintide acetate
    subcutaneous injection, twice a day
    Other Names:
  • Smylin

    • Drug: placebo-M
    subcutaneous injection, twice a day
    Other Names:
  • Placebo matched to Metreleptin

    		•
    Experimental: Placebo-P + Metreleptin 5.0 mg

    Placebo matched to pramlintide BID plus metreleptin 5.0 mg BID

    Drug: metreleptin
    subcutaneous injection, twice a day

    Drug: placebo-P
    subcutaneous injection, twice a day
    Other Names:
  • Placebo matched to pramlintide

    		•
    Experimental: Pramlintide 180 mcg + Metreleptin 2.5 mg

    Pramlintide 180 mcg BID plus Metreleptin 2.5 mg BID

    Drug: pramlintide acetate
    subcutaneous injection, twice a day
    Other Names:
  • Smylin

    • Drug: metreleptin
    subcutaneous injection, twice a day
    Experimental: Pramlintide 180 mcg + Metreleptin 5.0 mg

    Pramlintide 180 mcg BID plus Metreleptin 5.0 mg BID

    Drug: pramlintide acetate
    subcutaneous injection, twice a day
    Other Names:
  • Smylin

    • Drug: metreleptin
    subcutaneous injection, twice a day
    Experimental: Pramlintide 360 mcg + Metreleptin 1.25 mg

    Pramlintide 360 mcg BID plus Metreleptin 1.25 mg BID

    Drug: pramlintide acetate
    subcutaneous injection, twice a day
    Other Names:
  • Smylin

    • Drug: metreleptin
    subcutaneous injection, twice a day
    Experimental: Pramlintide 360 mcg + Metreleptin 2.5 mg

    Pramlintide 360 mcg BID plus Metreleptin 2.5 mg BID

    Drug: pramlintide acetate
    subcutaneous injection, twice a day
    Other Names:
  • Smylin

    • Drug: metreleptin
    subcutaneous injection, twice a day
    Experimental: Pramlintide 360 mcg + Metreleptin 5.0 mg

    Pramlintide 360 mcg BID plus Metreleptin 5.0 mg BID

    Drug: pramlintide acetate
    subcutaneous injection, twice a day
    Other Names:
  • Smylin

    • Drug: metreleptin
    subcutaneous injection, twice a day

    Outcome Measures

    Primary Outcome Measures

    1. Least Squares (LS) Mean Percent Change in Body Weight From Baseline to Week 28 - Evaluable Population [Baseline to Week 28]

      Body weight was measured in kilogram (kg). Baseline is defined as Day 1. If Day 1 was missing or after the first dose date of randomized treatment, the last available value prior to Day 1 was used. Drug Randomization stratified by sex and 3 categories baseline BMI (12 arms); 3 treatment arms combined for summaries as single placebo treatment group; 3 combined for summaries as single pramlintide monotherapy treatment group (total: 8 treatment groups).

    Secondary Outcome Measures

    1. Number of Participants Achieving at Least 5% and at Least 10% Body Weight Loss From Baseline to Week 28 - Evaluable Population [Baseline to Week 28]

      Baseline refers to Day 1. If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used.

    2. Mean Absolute Change From Baseline to Weeks 4, 12, 28 in Mean Trough Concentration of Total Leptin - Evaluable Population [Baseline to Week 28]

      Mean fasting plasma total leptin concentration (nanograms per milliliter; ng/mL) change from baseline over time by pooled metreleptin dose (sex, baseline BMI category, and baseline value). Baseline defined as Day 1. If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Evaluable population: all participants who received at least one dose of randomized treatment, had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding. Leptin concentrations measured using a validated immunoenzymetric assay utilizing polyclonal capture antibody, monoclonal detection antibody, and colorimetric readout by Amylin Pharmaceuticals, Inc.

    3. LS Mean Absolute Change in Body Weight From Baseline to Weeks 4, 12, and 28 - Evaluable Population [Baseline to Week 28]

      Least Squares (LS) mean absolute change in Body weight was measured in kilograms (kg). Baseline is defined as Day 1. If Day 1 was missing or after the first dose date of randomized treatment, the last available value prior to Day 1 was used.

    4. LS Mean Change in Waist Circumference From Baseline to Week 12 and Week 28 - Evaluable Population [Baseline to Weeks 12 and Week 28]

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

    5. Geometric Mean of the Total Area Under the Concentration Time Curve (AUC) From Time 0 to Last Quantifiable Concentration (Tlast) for Pramlintide at Weeks 4 and 24 - Evaluable Population Receiving Pramlintide [Week 4 and Week 24]

      Assessment of AUC was over a period of 2 hours following pramlintide administration. AUC (0 to time of last quantifiable concentration (-tlast). For AUC calculation, concentration at -5 min will be considered as 0 h concentration if quantifiable, otherwise, t=0 h. AUC measured as picograms*hour/milliliter (pg*h/mL). Pramlintide concentrations measured using a colorimetric immunoenzymetric assay employing monoclonal antibodies against pramlintide for both capture and detection.

    6. Geometric Mean of AUC From Time 0 to Infinity for Pramlintide at Weeks 4 and 24 - Evaluable Population Treated With Pramlintide [Weeks 4 and 24]

      Assessment of AUC was over a period of 2 hours following pramlintide administration. Area under the concentration curve (AUC) time 0 to infinity (-inf). For AUC calculations, concentration at -5 min will be considered as 0 h concentration if quantifiable. AUC measured in picograms*hour/milliliter (pg*h/mL).

    7. Geometric Mean of the Maximum Observed Plasma Concentration (Cmax) for Pramlintide at Weeks 4 and 24 - Evaluable Population Receiving Pramlintide [Week 4 and Week 24]

      Assessment of Cmax was over a period of 2 hours following pramlintide administration at Weeks 4 and 24. Cmax was measured as picograms/milliliter (pg/mL).

    8. Least Squares (LS) Mean Absolute Change From Baseline to Week 28 in Percent of Body Fat - Evaluable Population [Baseline to Week 28]

      Parameters of body composition were measured with a Dual Energy X-ray absorptiometry (DEXA) scan and reported as a percent (%). Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Absolute change from baseline was defined as percent body fat at Week 28 - percent body fat at baseline.

    9. LS Mean Absolute Change From Baseline to Week 28 in Total Body Fat Mass (k) - Evaluable Population [Baseline to Week 28]

      Parameters of body composition were measured with a Dual Energy X-ray absorptiometry (DEXA) scan. Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Body fat mass was measured in kilogram (k).

    10. LS Mean Absolute Change From Baseline to Week 28 in Fat-free Mass (kg) - Evaluable Population [Baseline to Week 28]

      Parameters of body composition were measured with a Dual Energy X-ray Absorptiometry (DEXA) scan. Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Fat-free mass were measured in kilogram (k).

    11. LS Mean Absolute Change From Baseline to Week 28 in Fasting Plasma Glucose, Total Cholesterol (TC), Triglycerides, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol - Evaluable Population [Baseline to Week 28]

      Baseline refers to Visit 5 (Day 1). If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Fasting samples were obtained at baseline, Weeks 4, 12, and 28. All parameters were measured in milligrams per deciliter (mg/dL).

    12. Mean Absolute Change From Baseline to Week 28 for Insulin - Evaluable Population [Baseline to Week 28]

      Baseline refers to Visit 5 (Day 1). If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Fasting samples were obtained at baseline, Weeks 4, 12, and 28. Parameter was measured micro international units per milliliter. (µIU/mL).

    13. Mean Absolute Change From Screening to Week 24 in Impact of Weight on Quality of Life Questionnaire-lite Version (IWQOL-Lite) Total Score - Evaluable Population [Screening to Week 24]

      Subjective effects of weight loss were measured using the IWQOL-Lite questionnaire, a 31-item patient reported outcome (PRO) instrument used to assess the effect of weight on physical function, self-esteem, sexual life, public distress, and work. Individual items have a range of 1 to 5 with 5=always true and 1= never true. The total score for the IWQOL-Lite instrument is measured on a scale from 0 (worst) to 100 (best). Higher scores indicate improvement. Values were obtained for this questionnaire on Visit 3 in the screening period.

    14. Mean Absolute Change From Screening to Week 24 in Binge Eating Scale (BES) Total Score - Evaluable Population [Screening to Week 24]

      The Binge Eating Scale (BES) is a 16-item questionnaire that assesses the behavioral and cognitive correlates of binge eating, including participants' perceived self-control over eating behavior using a range of 1 to 4 with 1=positive perceptions and 4= negative perceptions. The minimum and maximum score for the BES instrument is 0 and 55, respectively. The higher the score the worse the outcome. Values were obtained for this questionnaire on Visit 3 in the screening period.

    15. Mean Absolute Change From Screening to Week 24 in Susceptibility to Eating Questionnaire (SEQ) Item Scores - Evaluable Population [Screening to Week 24]

      The eating questionnaire is an exploratory measure of appetite, satiety, and perceived control over portion size using 10 VAS items with each response measured on a 100 mm visual analogue scale (ranges vary from Never to Very Often; Not at All Difficult to Extremely Difficult; Not at all Strong to Very Strong). Lower scores indicate improvement. The Eating Questionnaire instructed participants to rate their responses to these items over the past 7 days. Values were obtained for this questionnaire on Visit 3 in the screening period.

    16. Mean Absolute Change From Screening to Week 24 in Hospital Anxiety and Depression Scale (HADS) Total Scores - Evaluable Population [Screening to Week 24]

      The HADS is a questionnaire that uses 14 items to assess both anxiety and depression over the past week. The odd numbered items constitute the anxiety subscale, and the even numbered items constitute the depression subscale. The individual response scores for each subscale component are added together to obtain the individual subscale scores. The minimum and maximum score for each subscale is 0 and 21, respectively. The higher the score, the worse the outcome. Values were obtained for this questionnaire on Visit 3 in the screening period

    17. Mean Absolute Change From Screening to Week 24 in Summary Scores for Profile of Mood States - Brief (POMS-B) - Evaluable Population [Screening to Week 24]

      The POMS is a mood scale consisting of 65 mood adjectives that assess participants' mood over the past seven days. The POMS-B is an authorized, 30-item brief version of the POMS consisting of five items for each of the six POMS factors. The mood adjectives load onto 6 mood factors, which are as follows: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. Scores range from 0= Not at All to 4=Extremely. The factor scores are added to obtain the total mood disturbance score. A lower total mood disturbance score indicates improvement. Values were obtained for this questionnaire on Visit 3 in the screening period.

    18. Mean Absolute Change From Screening to Week 24 in Minutes to Fall Asleep, Hours of Sleep and The Pittsburgh Sleep Quality Index (PSQI) Global Score - Evaluable Population [Screening to Week 24]

      The Pittsburgh Sleep Quality Index (PSQI) is a questionnaire which assesses sleep quality and sleep disturbances over a period of 1 month. The PSQI provides ratings on seven domains of sleep (subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction). The sum of the individual domains yields a global sleep quality score with a range of 0-21. A PSQI score >5 is indicative of poor sleep, which is characterized by severe difficulties in at least two domains, or moderate difficulties in three or more domains. Values were obtained for this questionnaire on Visit 3 in the screening period.

    19. Mean Absolute Change From Screening to Week 24 in the Epworth Sleepiness Scale (ESS) Total Score - Evaluable Population [Screening to Week 24]

      The Epworth Sleepiness Scale (ESS) is an eight-item questionnaire that assesses sleep propensity in daily situations of increasing sleepiness on a four-point scale with 0=would never doze and 3=high chance of dozing. Lower scores indicate improvement. Values were obtained for this questionnaire on Visit 3 in the screening period

    20. Number of Hematology and Urinalysis Laboratory Values of Potential Clinical Importance Observed From Screening to Week 28 - Intent to Treat Population [Screening to Week 28]

      Criteria for laboratory values of potential clinical importance for obese and overweight (BMI >= 25 kg/m^2) participants: Platelets high (H) >500,000/µL; low (L) <75,000/µL. Hematocrit males <36%, females <30%. Hemoglobin males <12 g/dL, females <10 g/dL. White blood cell count (WBC) H >18,000/µL; L <1,500/µL. Urine protein H >= 3+ or >= 500 mg/dL. Urine glucose H >= 3+ or >= 500 mg/dL. Urine ketones >= 3+ or Large. Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28. Numbers of values are cumulative across the study.

    21. Number of Chemistry Laboratory Values of Potential Clinical Importance Observed From Screening to Week 28 - Intent to Treat Population [Screening to Week 28]

      Obtained at: Screening, Days -7, 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28. Numbers of laboratory values are cumulative across the study. Criteria for values of potential clinical importance for obese and overweight (BMI>=25 kg/m^2) participants: Total bilirubin High (H) > 2 mg/dL; Plasma/serum glucose fasting or non-fasting H > 200 mg/dL, low (L) < 60 mg/dL; Albumin L <2.5 g/dL; Creatine kinase H > 3*Upper limit of Normal (ULN); Sodium L <130 milliequivalents per liter (mEq/L), H > 150 mEq/L; potassium L<3.0 mEq/L, H> 5.5 mEq/L;bicarbonate L<18 mEq/L, H>35 mEq/L;calcium L <8mg/dL, H> 11 mg/dL; triglycerides H> 500 mg/dL; Cholesterol L < 100 mg/dL, H > 350 mg/dL; Alkaline phosphatase H > 3*ULN; Gamma-glutamyltransferase H>3*ULN; creatinine males > 1.6 mg/dL, females > 1.4 mg/dL; alanine aminotransferase H > 3*ULN; aspartate aminotransferase H > 3*ULN; urea nitrogen H > 45 mg/dL; uric acid males > 10.0 mg/dL, females > 8.0 mg/dL; Phosphorus L < 1.0 mg/dL H > 6.0 mg/dL.

    22. Mean Change in Systolic and Diastolic Blood Pressure From Baseline to Week 28 - Intent to Treat Population [Baseline to Week 28]

      Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Blood pressure was taken while the participant was sitting and was measured in millimeters of mercury (mm Hg). Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28

    23. Mean Change in Heart Rate From Baseline to Week 28 - Intent to Treat Population [Baseline to Week 28]

      Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Heart rate was measured while the participant was sitting and was measured in beats per minute (bpm). Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28.

    24. Number of Participants With Treatment-emergent Positive Anti-leptin Antibody Titers at Week 28 - Intent to Treat Population [Baseline to Week 28]

      Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Serum titer determinations for antibodies to metreleptin were made using a validated electrochemical luminescence (ECLA) bridging assay. Antibody titers were assessed according to the following dilutions: 0, 5, 25, 125, 625, 3125, 15625, and 78125. Participants were considered to have a positive titer to treatment-emergent antibodies to metreleptin at a given visit if they had a titer >=5 following a negative or missing titer at baseline or if they had a titer that had increased by at least 2 dilutions from a detectable level at baseline.

    25. Mean Change From Screening to Week 28 in Electrocardiogram Parameters - Intent to Treat Population [Screening to Week 28 (or study termination)]

      A 12-Lead electrocardiogram (ECG) was obtained at Screening, Day 1, Weeks 1, 12, 28 (study termination). The PR interval, which is time from beginning of the P wave to the beginning of the QRS complex (Note: QRS complex is a name for the combination of 3 of the graphical deflections seen in an ECG); QRS interval (time from the beginning to the end of the QRS complex); QT interval (measure between Q wave and T wave in the heart's electrical cycle); and QT interval corrected for heart rate using Fridericia's formula (QTcF) were measured in milliseconds (msec).

    26. Mean Change From Screening to Week 28 in the Electrocardiogram Parameter of Heart Rate - Intent to Treat Population [Screening to Week 28 (or early termination)]

      A 12-Lead electrocardiogram (ECG) was obtained at Screening (visit 2), Day 1, Weeks 1, 12, 28 (study termination). Heart Rate was measured in beats per min (bpm).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • 18 to 65 years old.

    • Is obese (Body Mass Index [BMI]>=30kg/m2 and <=35kg/m2); or overweight (BMI>=27kg/m2 and <30kg/m2.

    • Has stable body weight, i.e., not varying by >3% within 3 months prior to study.

    • Has not been treated over the past 3 months or is currently treated with any of the following medications: Oral contraceptives (female subjects); Hormone replacement therapy (female subjects); Metformin for the treatment of polycystic ovary syndrome (female subjects); Antihypertensive agents; Lipid-lowering agents; Thyroid replacement therapy; selective serotonin reuptake inhibitors (SSRIs).

    • Is comfortable with having repeated telephone contacts with a lifestyle counselor during the study.

    • Is a nonsmoker (has not smoked for at least 6 months prior to the study).

    Exclusion Criteria:

    • Has a medical history (e.g., morbid childhood obesity) and/or physical characteristics suggestive of genetic obesity or syndromatic obesity (e.g., Prader-Willi syndrome, Bardet-Biedl syndrome).

    • Is currently enrolled or plans to enroll in a diet, weight loss, or exercise program with the specific intent of losing weight (subjects who have been following an exercise regimen resulting in stable weight maintenance for at least 2 months prior to enrollment are eligible for study inclusion)

    • Has been treated over the past 2 months, is currently treated, or is expected to require or undergo treatment with *antiobesity agents (prescription or over-the-counter), *antipsychotic agents, *antiepileptic agents, *antidepressant agents, *drugs that directly affect gastrointestinal motility, *antidiabetic medications.

    • Has previously received treatment with metreleptin or pramlintide in a clinical study or has received prior treatment with pramlintide (SYMLIN®).

    • Has received any investigational drug within 30 days or within a period corresponding to 5 half-lives of that drug, whichever is greater, prior to this study starting.

    • Has had a major surgery or a blood transfusion, or has donated blood over the past 2 months or is planning to donate blood during the study.

    • Has had liposuction, abdominoplasty, or similar procedure over the past year or is planning to have such a procedure during the study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Birmingham Alabama United States
    2 Research Site Chandler Arizona United States
    3 Research Site Santa Rosa California United States
    4 Research Site Walnut Creek California United States
    5 Research Site Denver Colorado United States
    6 Research Site Jacksonville Florida United States
    7 Research Site Miami Florida United States
    8 Research Site Pembrook Pines Florida United States
    9 Research Site Plantation Florida United States
    10 Research Site Atlanta Georgia United States
    11 Research Site Chicago Illinois United States
    12 Research Site Springfield Illinois United States
    13 Research Site Overland Park Kansas United States
    14 Research Site Baton Rouge Louisiana United States
    15 Research Site Auburn Maine United States
    16 Research Site Boston Massachusetts United States
    17 Research Site Edina Minnesota United States
    18 Research Site St. Louis Missouri United States
    19 Research Site Butte Montana United States
    20 Research Site New York City New York United States
    21 Research Site Statesville North Carolina United States
    22 Research Site Cincinnati Ohio United States
    23 Research Site Columbus Ohio United States
    24 Research Site Eugene Oregon United States
    25 Research Site Medford Oregon United States
    26 Research Site Anderson South Carolina United States
    27 Research Site Greer South Carolina United States
    28 Research Site Mt. Pleasant South Carolina United States
    29 Research Site Nashville Tennessee United States
    30 Research Site Austin Texas United States
    31 Research Site Dallas Texas United States
    32 Research Site San Antonio Texas United States
    33 Research Site Salt Lake City Utah United States
    34 Research Site Norfolk Virginia United States
    35 Research Site Belingham Washington United States
    36 Research Site Olympia Washington United States

    Sponsors and Collaborators

    • AstraZeneca

    Investigators

    • Study Director: Vice President Research and Development, MD, Amylin Pharmaceuticals, LLC.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT00673387
    Other Study ID Numbers:
    • DFA102
    First Posted:
    May 7, 2008
    Last Update Posted:
    Apr 15, 2015
    Last Verified:
    Mar 1, 2015
    Keywords provided by AstraZeneca
    overweight
    obesity
    pramlintide
    metreleptin
    Amylin
    Additional relevant MeSH terms:
    Overweight
    Body Weight
    Pramlintide
    Islet Amyloid Polypeptide

    Study Results

    Participant Flow

    Recruitment Details First participant dosed/lead in: 06 May 2008; last participant's final visit: 07 April 2009. Study conducted in 42 clinics in participants who were either obese (body mass index (BMI) greater than, equal to (>=) 30 kg/m^2 and less than equal to (<=) 45 kg/m^2) or overweight (>= 27 kg/m^2 and < 30 kg/m^2).
    Pre-assignment Detail Participants enrolled, not randomized /treated (28): withdrew consent (10), adverse event (1), investigator decision (7), protocol violation (4), lost to follow up (5), administrative (1). 1 Week Lead-in Period: all arms received placebo matched to metreleptin and matched to pramlintide, BID (single blind); 28 week double blind Treatment Period.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered twice a day (BID) for 28 weeks, subcutaneous (SC) placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Period Title: Overall Study
    STARTED 75 77 72 75 78 78 78 75
    COMPLETED 46 54 41 49 48 44 48 40
    NOT COMPLETED 29 23 31 26 30 34 30 35

    Baseline Characteristics

    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg Total
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Total of all reporting groups
    Overall Participants 75 77 72 75 78 78 78 75 608
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    41.9
    (11.35)
    42.0
    (11.42)
    45.9
    (10.92)
    45.8
    (10.80)
    46.8
    (10.54)
    44.4
    (10.87)
    45.2
    (10.07)
    44.7
    (11.32)
    44.6
    (10.98)
    Sex: Female, Male (Count of Participants)
    Female
    53
    70.7%
    54
    70.1%
    53
    73.6%
    53
    70.7%
    54
    69.2%
    54
    69.2%
    55
    70.5%
    52
    69.3%
    428
    70.4%
    Male
    22
    29.3%
    23
    29.9%
    19
    26.4%
    22
    29.3%
    24
    30.8%
    24
    30.8%
    23
    29.5%
    23
    30.7%
    180
    29.6%
    Region of Enrollment (participants) [Number]
    United States
    75
    100%
    77
    100%
    72
    100%
    75
    100%
    78
    100%
    78
    100%
    78
    100%
    75
    100%
    608
    100%
    Body Mass Index ((kg/m^2)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [(kg/m^2)]
    36.88
    (4.473)
    36.93
    (4.389)
    36.62
    (4.478)
    36.88
    (4.336)
    36.65
    (4.379)
    36.80
    (4.260)
    36.96
    (4.406)
    36.68
    (4.504)
    36.80
    (4.379)

    Outcome Measures

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

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes all intent to treat participants (received at least one dose of randomized treatment) who had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 47 51 41 47 46 45 45 38
    Least Squares Mean (95% Confidence Interval) [Percentage change in kg]
    -2.01
    -5.47
    -5.83
    -6.85
    -6.61
    -6.39
    -6.98
    -7.02
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 2.5 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion.
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 5.0 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 1.25 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 2.5 mg
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 5.0 mg
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0001
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Pramlintide 360 mcg, Pramlintide 180 mcg + Metreleptin 2.5 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2510
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Pramlintide 360 mcg, Pramlintide 180 mcg + Metreleptin 5.0 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3433
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Pramlintide 360 mcg, Pramlintide 360 mcg + Metreleptin 1.25 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4503
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Pramlintide 360 mcg, Pramlintide 360 mcg + Metreleptin 2.5 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2122
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Pramlintide 360 mcg, Pramlintide 360 mcg + Metreleptin 5.0 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2232
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Metreleptin 5.0 mg, Pramlintide 180 mcg + Metreleptin 2.5 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4207
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion.
    Method t-test, 2 sided
    Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Metreleptin 5.0 mg, Pramlintide 180 mcg + Metreleptin 5.0 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5375
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion.
    Method t-test, 2 sided
    Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Metreleptin 5.0 mg, Pramlintide 360 mcg + Metreleptin 1.25 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6633
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Metreleptin 5.0 mg, Pramlintide 360 mcg + Metreleptin 2.5 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3667
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion
    Method t-test, 2 sided
    Comments
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection Metreleptin 5.0 mg, Pramlintide 360 mcg + Metreleptin 5.0 mg
    Comments When multiplicity not considered, sample size of 50 participants per arm (after dropouts) was considered adequate to detect a difference of 4.5% in mean body weight change from baseline to Week 28 between one effective pramlintide + metreleptin combination treatment group versus the placebo, Pramlintide 360 mcg BID + Placebo-M, or Metreleptin 5.0 mg BID + Placebo-P treatment arms with approximately 90% power, assuming a common within-treatment standard deviation of 6.858%.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3720
    Comments unadjusted for multiple comparisons; significance level of 0.0492 based on the Haybittle-Peto Criterion.
    Method t-test, 2 sided
    Comments
    2. Secondary Outcome
    Title Number of Participants Achieving at Least 5% and at Least 10% Body Weight Loss From Baseline to Week 28 - Evaluable Population
    Description Baseline refers to Day 1. If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used.
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes all intent to treat participants (received at least one dose of randomized treatment) who had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 47 51 41 47 46 45 45 38
    Weight Loss >=5%
    10
    13.3%
    27
    35.1%
    18
    25%
    27
    36%
    27
    34.6%
    23
    29.5%
    29
    37.2%
    25
    33.3%
    Weight Loss >=5% and <10%
    7
    9.3%
    14
    18.2%
    6
    8.3%
    14
    18.7%
    15
    19.2%
    15
    19.2%
    15
    19.2%
    12
    16%
    Weight Loss >=10%
    3
    4%
    13
    16.9%
    12
    16.7%
    13
    17.3%
    12
    15.4%
    8
    10.3%
    14
    17.9%
    13
    17.3%
    Weight Gain
    17
    22.7%
    7
    9.1%
    7
    9.7%
    4
    5.3%
    8
    10.3%
    5
    6.4%
    4
    5.1%
    3
    4%
    No Weight Change or Weight Loss <5%
    20
    26.7%
    17
    22.1%
    16
    22.2%
    16
    21.3%
    11
    14.1%
    17
    21.8%
    12
    15.4%
    10
    13.3%
    3. Secondary Outcome
    Title Mean Absolute Change From Baseline to Weeks 4, 12, 28 in Mean Trough Concentration of Total Leptin - Evaluable Population
    Description Mean fasting plasma total leptin concentration (nanograms per milliliter; ng/mL) change from baseline over time by pooled metreleptin dose (sex, baseline BMI category, and baseline value). Baseline defined as Day 1. If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Evaluable population: all participants who received at least one dose of randomized treatment, had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding. Leptin concentrations measured using a validated immunoenzymetric assay utilizing polyclonal capture antibody, monoclonal detection antibody, and colorimetric readout by Amylin Pharmaceuticals, Inc.
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Number analyzed (n) at baseline above. Week 4: n=41 45,46, 45, 45, 38; Week 8: n=41,45,46,44,45,37; Week 12: n=41, 46, 46, 45,45,38; Week 16: n=41,47,46,45,45,38; Week 20: n=41, 45,45,45,45,38; Week 24: n=40, 43, 46, 42, 44,38; Week 28: n=41, 45, 45, 44, 43, 36. Leptin concentration for placebo and pramlintide plus placebo groups not presented.
    Arm/Group Title Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 41 47 46 45 45 38
    Change from baseline at Week 4
    53.26
    (64.542)
    31.00
    (73.953)
    47.82
    (76.469)
    -2.36
    (16.918)
    14.66
    (48.212)
    49.16
    (70.881)
    Change from baseline at Week 12
    386.48
    (408.472)
    167.62
    (147.512)
    353.61
    (265.727)
    53.76
    (68.627)
    165.65
    (173.851)
    399.74
    (378.120)
    Change from baseline at Week 28
    557.22
    (604.617)
    373.64
    (465.511)
    487.17
    (625.071)
    105.96
    (143.680)
    266.02
    (210.412)
    393.06
    (381.428)
    4. Secondary Outcome
    Title LS Mean Absolute Change in Body Weight From Baseline to Weeks 4, 12, and 28 - Evaluable Population
    Description Least Squares (LS) mean absolute change in Body weight was measured in kilograms (kg). Baseline is defined as Day 1. If Day 1 was missing or after the first dose date of randomized treatment, the last available value prior to Day 1 was used.
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes all intent to treat participants (received at least one dose of randomized treatment) who had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 47 51 41 47 46 45 45 38
    Change at Week 4
    -1.81
    -2.85
    -2.54
    -2.94
    -2.40
    -2.62
    -3.21
    -3.32
    Change at Week 12
    -3.39
    -4.90
    -5.13
    -5.52
    -4.53
    -5.52
    -5.88
    -6.12
    Change at Week 28
    -2.04
    -5.66
    -6.18
    -6.96
    -6.55
    -6.38
    -7.18
    -6.97
    5. Secondary Outcome
    Title LS Mean Change in Waist Circumference From Baseline to Week 12 and Week 28 - Evaluable Population
    Description Waist circumference was measured at baseline (Day 1), Weeks 12, 28 (or at early termination) in centimeters (cm).
    Time Frame Baseline to Weeks 12 and Week 28

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of randomized treatment and who had adequate exposure to treatment and complied with the protocol as assessed prior to database lock/unblinding. Numbers (n) analyzed Week 12 n=45,51,41,47,45,45,45,38 in each treatment group respectively; Week 28 n= 44, 51, 41, 46, 45, 44, 43, 38 in each group, respectively.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 45 51 41 47 45 45 45 38
    Change at Week 12
    -3.03
    (0.851)
    -3.40
    (0.799)
    -3.41
    (0.895)
    -4.91
    (0.846)
    -4.29
    (0.876)
    -3.32
    (0.853)
    -4.63
    (0.855)
    -5.23
    (0.916)
    Change at Week 28
    -2.54
    (1.038)
    -3.95
    (0.965)
    -3.86
    (1.081)
    -5.48
    (1.032)
    -5.75
    (1.058)
    -4.70
    (1.043)
    -5.52
    (1.057)
    -6.53
    (1.107)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 2.5 mg
    Comments Change at Week 28 based on a general linear model with factors for treatment group, sex, baseline BMI category, and baseline value as a covariate
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0404
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 5.0 mg
    Comments Change at Week 28 based on a general linear model with factors for treatment group, sex, baseline BMI category, and baseline value as a covariate.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0265
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 1.25 mg
    Comments Change at Week 28 based on a general linear model with factors for treatment group, sex, baseline BMI category, and baseline value as a covariate.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1357
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 2.5 mg
    Comments Change at Week 28 based on a general linear model with factors for treatment group, sex, baseline BMI category, and baseline value as a covariate.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0409
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 5.0 mg
    Comments Change at Week 28 based on a general linear model with factors for treatment group, sex, baseline BMI category, and baseline value as a covariate.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0082
    Comments
    Method t-test, 2 sided
    Comments
    6. Secondary Outcome
    Title Geometric Mean of the Total Area Under the Concentration Time Curve (AUC) From Time 0 to Last Quantifiable Concentration (Tlast) for Pramlintide at Weeks 4 and 24 - Evaluable Population Receiving Pramlintide
    Description Assessment of AUC was over a period of 2 hours following pramlintide administration. AUC (0 to time of last quantifiable concentration (-tlast). For AUC calculation, concentration at -5 min will be considered as 0 h concentration if quantifiable, otherwise, t=0 h. AUC measured as picograms*hour/milliliter (pg*h/mL). Pramlintide concentrations measured using a colorimetric immunoenzymetric assay employing monoclonal antibodies against pramlintide for both capture and detection.
    Time Frame Week 4 and Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population: participants received at least one dose of randomized treatment, had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding. Number (n) analyzed at Week 4:n=46, 40,41, 40,40,33 in each arm respectively;Week 24:n=48, 38, 44, 40, 35, 36.
    Arm/Group Title Pramlintide 360 mcg + Placebo-M Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 48 40 44 40 40 36
    Week 4 AUC (0-tlast)
    1862.5
    (176.83)
    878.8
    (87.34)
    967.5
    (68.59)
    1788.2
    (165.32)
    1920.1
    (143.54)
    2060.4
    (168.92)
    Week 24 AUC (0-tlast)
    1968.4
    (135.60)
    1033.8
    (102.19)
    953.7
    (76.19)
    1536.3
    (103.90)
    1990.2
    (160.49)
    1915.3
    (158.77)
    7. Secondary Outcome
    Title Geometric Mean of AUC From Time 0 to Infinity for Pramlintide at Weeks 4 and 24 - Evaluable Population Treated With Pramlintide
    Description Assessment of AUC was over a period of 2 hours following pramlintide administration. Area under the concentration curve (AUC) time 0 to infinity (-inf). For AUC calculations, concentration at -5 min will be considered as 0 h concentration if quantifiable. AUC measured in picograms*hour/milliliter (pg*h/mL).
    Time Frame Weeks 4 and 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population: participants received at least one dose of randomized treatment, had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding. Number (n) analyzed at Week 4: n=39,36,37,36,35,31 in each arm, respectively; Week 24 n=46, 35, 42, 39, 33, 35 in each arm, respectively.
    Arm/Group Title Pramlintide 360 mcg + Placebo-M Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 36 42 39 35 35
    Week 4 AUC (0-inf)
    2662.7
    (230.34)
    989.3
    (96.05)
    1240.7
    (106.08)
    2159.0
    (238.45)
    2311.3
    (211.63)
    2511.4
    (241.16)
    Week 24 AUC (0-inf)
    2499.5
    (215.51)
    1175.1
    (116.89)
    1216.7
    (102.07)
    1907.5
    (153.91)
    2411.8
    (218.29)
    2349.3
    (210.77)
    8. Secondary Outcome
    Title Geometric Mean of the Maximum Observed Plasma Concentration (Cmax) for Pramlintide at Weeks 4 and 24 - Evaluable Population Receiving Pramlintide
    Description Assessment of Cmax was over a period of 2 hours following pramlintide administration at Weeks 4 and 24. Cmax was measured as picograms/milliliter (pg/mL).
    Time Frame Week 4 and Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population: participants received at least one dose of randomized treatment, had adequate exposure to treatment and complied with the protocol as assessed prior to database lock and unblinding. Number (n) analyzed at Week 4 n=46,40,41,40,40,33 in each arm, respectively; Week 24 n=48,38, 44,40,35,36 in each arm, respectively.
    Arm/Group Title Pramlintide 360 mcg + Placebo-M Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 48 40 44 40 40 36
    Week 4 Cmax
    1759.0
    (168.40)
    876.7
    (77.37)
    897.3
    (51.16)
    1783.8
    (144.34)
    1851.3
    (118.87)
    2096.4
    (149.65)
    Week 24 Cmax
    1985.8
    (118.31)
    1048.1
    (76.86)
    925.5
    (64.16)
    1573.5
    (100.69)
    2032.0
    (152.70)
    1972.2
    (159.33)
    9. Secondary Outcome
    Title Least Squares (LS) Mean Absolute Change From Baseline to Week 28 in Percent of Body Fat - Evaluable Population
    Description Parameters of body composition were measured with a Dual Energy X-ray absorptiometry (DEXA) scan and reported as a percent (%). Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Absolute change from baseline was defined as percent body fat at Week 28 - percent body fat at baseline.
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Number analyzed (n) were of evaluable participants with valid DEXA scan at Week 28.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 36 51 38 40 42 39 40 35
    Least Squares Mean (Standard Error) [percentage of body fat]
    -0.95
    (0.501)
    -1.77
    (0.421)
    -1.94
    (0.492)
    -2.32
    (0.480)
    -2.21
    (0.475)
    -2.21
    (0.497)
    -1.56
    (0.482)
    -2.46
    (0.515)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 2.5 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0464
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 5.0 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0647
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 1.25 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0690
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 2.5 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3717
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 5.0 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0327
    Comments
    Method t-test, 2 sided
    Comments
    10. Secondary Outcome
    Title LS Mean Absolute Change From Baseline to Week 28 in Total Body Fat Mass (k) - Evaluable Population
    Description Parameters of body composition were measured with a Dual Energy X-ray absorptiometry (DEXA) scan. Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Body fat mass was measured in kilogram (k).
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Number analyzed (n) were of evaluable participants with valid DEXA scan at Week 28.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 36 51 38 40 42 39 40 35
    Least Squares Mean (Standard Error) [kg]
    -1.96
    (0.0779)
    -4.28
    (0.661)
    -4.57
    (0.763)
    -4.98
    (0.746)
    -4.97
    (0.734)
    -5.03
    (0.755)
    -4.35
    (0.748)
    -5.51
    (0.792)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 2.5 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0049
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 5.0 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0047
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 1.25 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0046
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 2.5 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0257
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 5.0 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0014
    Comments
    Method t-test, 2 sided
    Comments
    11. Secondary Outcome
    Title LS Mean Absolute Change From Baseline to Week 28 in Fat-free Mass (kg) - Evaluable Population
    Description Parameters of body composition were measured with a Dual Energy X-ray Absorptiometry (DEXA) scan. Data from the first valid DEXA scan obtained no later than 7 days after the first randomized dose was considered as valid baseline values; data from the last valid DEXA scan obtained no later than 10 days after last clinical visit or no later than 14 days after last dose of randomized study medication was considered as valid study termination values. Fat-free mass were measured in kilogram (k).
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Number analyzed (n) were of evaluable participants with valid DEXA scan at Week 28.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 36 51 38 40 42 39 40 35
    Least Squares Mean (Standard Error) [kg]
    -0.69
    (0.393)
    -1.62
    (0.337)
    -1.80
    (0.389)
    -1.90
    (0.377)
    -1.99
    (0.373)
    -2.02
    (0.391)
    -2.11
    (0.380)
    -2.29
    (0.399)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 2.5 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0222
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 180 mcg + Metreleptin 5.0 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0128
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 1.25 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0122
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 2.5 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0073
    Comments
    Method t-test, 2 sided
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, Pramlintide 360 mcg + Metreleptin 5.0 mg
    Comments Based on a general linear model general linear model that includes baseline value and factors for treatment group, sex, baseline BMI category (<35 kg/m2, 35 to <40 kg/m2, ≥40 kg/m2).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0034
    Comments
    Method t-test, 2 sided
    Comments
    12. Secondary Outcome
    Title LS Mean Absolute Change From Baseline to Week 28 in Fasting Plasma Glucose, Total Cholesterol (TC), Triglycerides, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol - Evaluable Population
    Description Baseline refers to Visit 5 (Day 1). If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Fasting samples were obtained at baseline, Weeks 4, 12, and 28. All parameters were measured in milligrams per deciliter (mg/dL).
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable population: received at least one dose of randomized treatment, had adequate exposure to treatment, complied with the protocol as assessed prior to database lock and unblinding. Number analyzed (n) presented above for TC, LDL and HDL cholesterol. Glucose n= 43, 50, 41, 46, 45, 43,44,36; Triglycerides n= 44,50,41,46,45,44,44.38.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 44 50 39 46 45 44 44 37
    Fasting Plasma Glucose
    -1.3
    (1.35)
    -1.8
    (1.25)
    -1.8
    (1.39)
    -2.5
    (1.32)
    -1.2
    (1.34)
    -1.0
    (1.36)
    -1.7
    (1.35)
    -1.3
    (1.47)
    Total Cholesterol
    4.3
    (3.57)
    -7.1
    (3.35)
    -3.7
    (3.82)
    -2.1
    (3.54)
    -2.5
    (3.60)
    -0.6
    (3.60)
    -4.0
    (3.61)
    -1.3
    (3.88)
    Triglycerides
    -0.1
    (8.25)
    -8.6
    (7.73)
    -13.0
    (8.66)
    -1.4
    (8.17)
    -10.9
    (8.29)
    11.1
    (8.34)
    -9.2
    (8.35)
    0.9
    (8.86)
    LDL Cholesterol
    4.3
    (2.82)
    -3.5
    (2.65)
    -2.3
    (3.02)
    -3.7
    (2.80)
    -0.0
    (2.85)
    -2.7
    (2.85)
    -3.7
    (2.86)
    -1.2
    (3.08)
    HDL Cholesterol
    1.5
    (0.96)
    0.6
    (0.90)
    2.6
    (1.03)
    0.7
    (0.95)
    1.0
    (0.96)
    2.9
    (0.97)
    0.97
    (0.97)
    1.05
    (1.05)
    13. Secondary Outcome
    Title Mean Absolute Change From Baseline to Week 28 for Insulin - Evaluable Population
    Description Baseline refers to Visit 5 (Day 1). If Day 1 value is missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 is used. Fasting samples were obtained at baseline, Weeks 4, 12, and 28. Parameter was measured micro international units per milliliter. (µIU/mL).
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 42 49 40 44 45 43 43 36
    Least Squares Mean (Standard Error) [µIU/mL]
    1.1
    (1.01)
    -0.4
    (0.94)
    -1.6
    (1.0)
    -1.0
    (1.00)
    -2.5
    (0.99)
    -1.4
    (1.00)
    -0.8
    (1.01)
    -0.5
    (1.08)
    14. Secondary Outcome
    Title Mean Absolute Change From Screening to Week 24 in Impact of Weight on Quality of Life Questionnaire-lite Version (IWQOL-Lite) Total Score - Evaluable Population
    Description Subjective effects of weight loss were measured using the IWQOL-Lite questionnaire, a 31-item patient reported outcome (PRO) instrument used to assess the effect of weight on physical function, self-esteem, sexual life, public distress, and work. Individual items have a range of 1 to 5 with 5=always true and 1= never true. The total score for the IWQOL-Lite instrument is measured on a scale from 0 (worst) to 100 (best). Higher scores indicate improvement. Values were obtained for this questionnaire on Visit 3 in the screening period.
    Time Frame Screening to Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Missing item responses may be imputed for each subject as appropriate before summarization.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 51 41 47 46 44 45 35
    Mean (Standard Deviation) [units on a scale]
    10.52
    (12.480)
    10.31
    (11.629)
    11.09
    (13.503)
    10.14
    (10.957)
    16.15
    (15.193)
    13.84
    (11.535)
    13.44
    (11.175)
    11.68
    (10.271)
    15. Secondary Outcome
    Title Mean Absolute Change From Screening to Week 24 in Binge Eating Scale (BES) Total Score - Evaluable Population
    Description The Binge Eating Scale (BES) is a 16-item questionnaire that assesses the behavioral and cognitive correlates of binge eating, including participants' perceived self-control over eating behavior using a range of 1 to 4 with 1=positive perceptions and 4= negative perceptions. The minimum and maximum score for the BES instrument is 0 and 55, respectively. The higher the score the worse the outcome. Values were obtained for this questionnaire on Visit 3 in the screening period.
    Time Frame Screening to Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Missing item responses may be imputed for each subject as appropriate before summarization.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 49 41 47 46 43 45 36
    Mean (Standard Deviation) [units on a scale]
    -3.0
    (6.31)
    -3.4
    (6.96)
    -4.0
    (6.21)
    -4.4
    (6.45)
    -6.6
    (8.28)
    -3.5
    (5.87)
    -5.9
    (7.44)
    -5.2
    (6.17)
    16. Secondary Outcome
    Title Mean Absolute Change From Screening to Week 24 in Susceptibility to Eating Questionnaire (SEQ) Item Scores - Evaluable Population
    Description The eating questionnaire is an exploratory measure of appetite, satiety, and perceived control over portion size using 10 VAS items with each response measured on a 100 mm visual analogue scale (ranges vary from Never to Very Often; Not at All Difficult to Extremely Difficult; Not at all Strong to Very Strong). Lower scores indicate improvement. The Eating Questionnaire instructed participants to rate their responses to these items over the past 7 days. Values were obtained for this questionnaire on Visit 3 in the screening period.
    Time Frame Screening to Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Missing item responses may be imputed for each subject as appropriate before summarization.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 51 41 47 45 44 45 36
    Frequency of Food Cravings
    -9.0
    (25.85)
    -6.6
    (27.17)
    -4.0
    (24.28)
    -14.1
    (24.55)
    -19.8
    (31.06)
    -15.7
    (21.76)
    -18.5
    (27.69)
    -13.5
    (29.56)
    Strength of Food Cravings
    -5.1
    (27.60)
    -6.1
    (26.86)
    -1.1
    (24.97)
    -13.9
    (25.45)
    -13.8
    (28.02)
    -12.9
    (19.19)
    -19.6
    (25.66)
    -15.2
    (32.56)
    Difficult to Control Eating
    -8.1
    (27.45)
    -15.2
    (26.37)
    -9.5
    (27.44)
    -19.7
    (23.00)
    -27.3
    (27.02)
    -18.3
    (19.46)
    -26.3
    (28.89)
    -18.0
    (35.40)
    Difficult to Resist Food Cravings
    -11.4
    (30.32)
    -11.1
    (24.52)
    9.6
    (25.02)
    -19.5
    (26.28)
    -21.8
    (28.65)
    -19.0
    (26.49)
    -28.0
    (29.90)
    -18.2
    (29.80)
    Eating in Response to Food Cravings
    -11.1
    (28.41)
    -12.2
    (25.14)
    -12.6
    (27.34)
    -15.4
    (22.17)
    -22.2
    (32.94)
    -18.5
    (24.95)
    -22.9
    (27.85)
    -15.9
    (27.04)
    Difficult to Control Portion Sizes
    -10.8
    (23.37)
    -16.9
    (29.58)
    -27.6
    (30.70)
    -19.6
    (21.19)
    -25.2
    (28.00)
    -20.8
    (21.18)
    -24.0
    (26.91)
    -27.6
    (34.18)
    How Hungry
    -0.1
    (20.59)
    -9.7
    (22.92)
    -17.5
    (23.18)
    -16.4
    (24.00)
    -17.0
    (24.09)
    -17.5
    (22.53)
    -19.2
    (24.64)
    -19.9
    (31.32)
    How Full After Meals
    -5.8
    (25.37)
    0.5
    (25.05)
    -7.6
    (19.94)
    -3.8
    (26.19)
    -8.8
    (31.83)
    -6.5
    (26.46)
    -4.2
    (27.71)
    1.1
    (23.42)
    Thoughts of Food
    -2.7
    (21.70)
    -10.7
    (25.84)
    -10.6
    (30.04)
    -9.4
    (22.33)
    -16.7
    (27.75)
    -12.0
    (20.98)
    -20.0
    (27.90)
    -5.6
    (30.73)
    How Pleasant Meals
    -6.1
    (19.72)
    -2.3
    (24.55)
    -2.1
    (21.00)
    1.2
    (27.11)
    -1.2
    (25.96)
    3.7
    (24.87)
    5.3
    (22.41)
    -2.1
    (28.08)
    17. Secondary Outcome
    Title Mean Absolute Change From Screening to Week 24 in Hospital Anxiety and Depression Scale (HADS) Total Scores - Evaluable Population
    Description The HADS is a questionnaire that uses 14 items to assess both anxiety and depression over the past week. The odd numbered items constitute the anxiety subscale, and the even numbered items constitute the depression subscale. The individual response scores for each subscale component are added together to obtain the individual subscale scores. The minimum and maximum score for each subscale is 0 and 21, respectively. The higher the score, the worse the outcome. Values were obtained for this questionnaire on Visit 3 in the screening period
    Time Frame Screening to Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Missing item responses may be imputed for each subject as appropriate before summarization.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 51 41 47 46 44 45 36
    Anxiety Total Scores
    0.02
    (0.475)
    0.08
    (0.274)
    -0.56
    (0.342)
    -0.11
    (0.431)
    -0.43
    (0.373)
    -0.59
    (0.370)
    -0.58
    (0.429)
    0.06
    (0.465)
    Depression Total Scores
    -0.85
    (0.435)
    -0.76
    (0.357)
    -0.98
    (0.394)
    -0.66
    (0.332)
    -1.37
    (0.387)
    -1.23
    (0.416)
    -1.02
    (0.294)
    0.00
    (0.481)
    18. Secondary Outcome
    Title Mean Absolute Change From Screening to Week 24 in Summary Scores for Profile of Mood States - Brief (POMS-B) - Evaluable Population
    Description The POMS is a mood scale consisting of 65 mood adjectives that assess participants' mood over the past seven days. The POMS-B is an authorized, 30-item brief version of the POMS consisting of five items for each of the six POMS factors. The mood adjectives load onto 6 mood factors, which are as follows: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. Scores range from 0= Not at All to 4=Extremely. The factor scores are added to obtain the total mood disturbance score. A lower total mood disturbance score indicates improvement. Values were obtained for this questionnaire on Visit 3 in the screening period.
    Time Frame Screening to Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Missing item responses may be imputed for each subject as appropriate before summarization.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 51 41 47 46 43 45 35
    Tension - Anxiety
    0.35
    (0.518)
    0.39
    (0.308)
    -0.17
    (0.389)
    0.87
    (0.518)
    -0.30
    (0.408)
    -0.21
    (0.358)
    0.00
    (0.423)
    0.66
    (0.583)
    Depression - Dejection
    0.41
    (0.628)
    0.27
    (0.489)
    0.44
    (0.466)
    0.64
    (0.410)
    0.26
    (0.464)
    0.37
    (0.381)
    -0.29
    (0.348)
    0.23
    (0.666)
    Anger - Hostility
    0.04
    (0.577)
    0.16
    (0.418)
    -0.22
    (0.468)
    0.53
    (0.489)
    -0.30
    (0.409)
    -0.05
    (0.410)
    -0.18
    (0.476)
    0.71
    (0.515)
    Vigor - Activity
    1.11
    (0.534)
    0.27
    (0.681)
    0.78
    (0.670)
    1.04
    (0.603)
    1.20
    (0.632)
    0.95
    (0.773)
    1.13
    (0.641)
    1.29
    (0.787)
    Fatigue - Inertia
    -1.22
    (0.852)
    -0.53
    (0.709)
    -1.10
    (0.688)
    0.02
    (0.660)
    -0.30
    (0.676)
    -1.49
    (0.626)
    -0.82
    (0.667)
    0.09
    (0.779)
    Confusion - Bewilderment
    0.43
    (0.471)
    0.51
    (0.334)
    0.17
    (0.296)
    0.40
    (0.387)
    0.20
    (0.400)
    0.05
    (0.286)
    0.02
    (0.280)
    0.00
    (0.393)
    19. Secondary Outcome
    Title Mean Absolute Change From Screening to Week 24 in Minutes to Fall Asleep, Hours of Sleep and The Pittsburgh Sleep Quality Index (PSQI) Global Score - Evaluable Population
    Description The Pittsburgh Sleep Quality Index (PSQI) is a questionnaire which assesses sleep quality and sleep disturbances over a period of 1 month. The PSQI provides ratings on seven domains of sleep (subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction). The sum of the individual domains yields a global sleep quality score with a range of 0-21. A PSQI score >5 is indicative of poor sleep, which is characterized by severe difficulties in at least two domains, or moderate difficulties in three or more domains. Values were obtained for this questionnaire on Visit 3 in the screening period.
    Time Frame Screening to Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Missing item responses may be imputed for each subject as appropriate before summarization.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 51 41 47 46 45 45 38
    Minutes to Fall Asleep
    -0.5
    (11.17)
    1.3
    (17.83)
    -2.1
    (14.81)
    -4.3
    (15.09)
    -4.6
    (12.00)
    -4.3
    (19.50)
    -1.0
    (14.74)
    2.7
    (16.04)
    Hours Asleep
    0.1
    (0.80)
    0.1
    (0.91)
    -0.1
    (0.76)
    0.2
    (1.09)
    0.1
    (1.15)
    0.2
    (1.01)
    0.2
    (1.18)
    -0.4
    (1.06)
    PSQI Global Score
    -0.9
    (2.18)
    -0.3
    (2.46)
    -0.3
    (2.81)
    -0.8
    (2.43)
    -0.9
    (2.92)
    -1.0
    (2.57)
    -1.0
    (2.44)
    -0.1
    (2.64)
    20. Secondary Outcome
    Title Mean Absolute Change From Screening to Week 24 in the Epworth Sleepiness Scale (ESS) Total Score - Evaluable Population
    Description The Epworth Sleepiness Scale (ESS) is an eight-item questionnaire that assesses sleep propensity in daily situations of increasing sleepiness on a four-point scale with 0=would never doze and 3=high chance of dozing. Lower scores indicate improvement. Values were obtained for this questionnaire on Visit 3 in the screening period
    Time Frame Screening to Week 24

    Outcome Measure Data

    Analysis Population Description
    Evaluable population includes participants received at least one dose of randomized treatment, had adequate exposure to treatment, and complied with the protocol as assessed prior to database lock and unblinding. Missing item responses may be imputed for each subject as appropriate before summarization.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 45 51 41 47 46 44 45 36
    Mean (Standard Error) [units on a scale]
    -0.69
    (0.552)
    -0.63
    (0.450)
    0.12
    (0.621)
    -1.32
    (0.319)
    -1.80
    (0.426)
    -1.05
    (0.662)
    -1.80
    (0.448)
    -0.42
    (0.522)
    21. Secondary Outcome
    Title Number of Hematology and Urinalysis Laboratory Values of Potential Clinical Importance Observed From Screening to Week 28 - Intent to Treat Population
    Description Criteria for laboratory values of potential clinical importance for obese and overweight (BMI >= 25 kg/m^2) participants: Platelets high (H) >500,000/µL; low (L) <75,000/µL. Hematocrit males <36%, females <30%. Hemoglobin males <12 g/dL, females <10 g/dL. White blood cell count (WBC) H >18,000/µL; L <1,500/µL. Urine protein H >= 3+ or >= 500 mg/dL. Urine glucose H >= 3+ or >= 500 mg/dL. Urine ketones >= 3+ or Large. Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28. Numbers of values are cumulative across the study.
    Time Frame Screening to Week 28

    Outcome Measure Data

    Analysis Population Description
    Intent to treat population included all randomized participants who received at least one injection of study medication.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered twice a day (BID) for 28 weeks, subcutaneous (SC) placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 75 77 72 75 78 78 78 75
    Hematocrit
    4
    0
    0
    0
    0
    1
    4
    3
    Hemoglobin
    7
    0
    0
    0
    0
    5
    7
    4
    Platelet Count
    0
    0
    1
    1
    0
    0
    10
    0
    White Blood Cell Count
    0
    0
    0
    0
    0
    0
    0
    0
    Urine Glucose
    0
    1
    0
    0
    0
    0
    0
    0
    Urine Ketones
    0
    0
    0
    0
    0
    0
    1
    1
    Urine protein
    1
    2
    0
    2
    3
    4
    2
    1
    22. Secondary Outcome
    Title Number of Chemistry Laboratory Values of Potential Clinical Importance Observed From Screening to Week 28 - Intent to Treat Population
    Description Obtained at: Screening, Days -7, 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28. Numbers of laboratory values are cumulative across the study. Criteria for values of potential clinical importance for obese and overweight (BMI>=25 kg/m^2) participants: Total bilirubin High (H) > 2 mg/dL; Plasma/serum glucose fasting or non-fasting H > 200 mg/dL, low (L) < 60 mg/dL; Albumin L <2.5 g/dL; Creatine kinase H > 3*Upper limit of Normal (ULN); Sodium L <130 milliequivalents per liter (mEq/L), H > 150 mEq/L; potassium L<3.0 mEq/L, H> 5.5 mEq/L;bicarbonate L<18 mEq/L, H>35 mEq/L;calcium L <8mg/dL, H> 11 mg/dL; triglycerides H> 500 mg/dL; Cholesterol L < 100 mg/dL, H > 350 mg/dL; Alkaline phosphatase H > 3*ULN; Gamma-glutamyltransferase H>3*ULN; creatinine males > 1.6 mg/dL, females > 1.4 mg/dL; alanine aminotransferase H > 3*ULN; aspartate aminotransferase H > 3*ULN; urea nitrogen H > 45 mg/dL; uric acid males > 10.0 mg/dL, females > 8.0 mg/dL; Phosphorus L < 1.0 mg/dL H > 6.0 mg/dL.
    Time Frame Screening to Week 28

    Outcome Measure Data

    Analysis Population Description
    Intent to treat population included all randomized participants who received at least one injection of study medication.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered twice a day (BID) for 28 weeks, subcutaneous (SC) placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 75 77 72 75 78 78 78 75
    alanine aminotransferase
    0
    8
    1
    0
    0
    0
    0
    3
    aspartate aminotransferase
    0
    2
    0
    0
    1
    0
    0
    2
    Bicarbonate
    0
    5
    1
    5
    1
    0
    0
    1
    Gamma-glutamyltransferase
    17
    3
    5
    1
    13
    0
    0
    6
    Creatine kinase
    18
    4
    4
    9
    8
    4
    2
    2
    Calcium
    2
    2
    2
    7
    1
    0
    13
    0
    Potassium
    0
    1
    0
    1
    2
    1
    2
    6
    Sodium
    2
    4
    2
    4
    2
    0
    3
    0
    Creatinine
    0
    0
    0
    1
    2
    0
    0
    3
    Total Bilirubin
    1
    0
    0
    0
    0
    0
    0
    1
    Uric Acid
    4
    10
    5
    11
    19
    21
    9
    25
    Alkaline Phosphatase
    0
    0
    0
    1
    0
    0
    0
    0
    Blood urea nitrogen
    0
    0
    0
    0
    0
    0
    0
    2
    23. Secondary Outcome
    Title Mean Change in Systolic and Diastolic Blood Pressure From Baseline to Week 28 - Intent to Treat Population
    Description Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Blood pressure was taken while the participant was sitting and was measured in millimeters of mercury (mm Hg). Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Intent to treat population included all randomized participants who received at least one injection of study medication.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered twice a day (BID) for 28 weeks, subcutaneous (SC) placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 75 77 72 75 78 78 78 75
    Systolic Blood Pressure
    2.4
    (10.65)
    -0.9
    (11.9)
    -3.4
    (12.54)
    -3.2
    (10.84)
    0.4
    (11.84)
    -2.0
    (12.47)
    -1.2
    (10.78)
    -1.5
    (12.54)
    Diastolic Blood Pressure
    1.2
    (7.31)
    -1.7
    (6.83)
    -2.6
    (7.21)
    -0.4
    (8.07)
    -1.0
    (6.99)
    -1.3
    (7.96)
    -1.8
    (6.77)
    -0.1
    (9.93)
    24. Secondary Outcome
    Title Mean Change in Heart Rate From Baseline to Week 28 - Intent to Treat Population
    Description Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Heart rate was measured while the participant was sitting and was measured in beats per minute (bpm). Values obtained at Screening, Day -7, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28.
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Intent to treat population included all randomized participants who received at least one injection of study medication.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered twice a day (BID) for 28 weeks, subcutaneous (SC) placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 74 77 72 75 78 78 78 75
    Mean (Standard Deviation) [bpm]
    1.6
    (9.29)
    -1.3
    (7.70)
    -2.6
    (6.66)
    -1.4
    (8.40)
    -2.1
    (7.38)
    -0.5
    (9.34)
    -2.4
    (7.54)
    -0.1
    (10.80)
    25. Secondary Outcome
    Title Number of Participants With Treatment-emergent Positive Anti-leptin Antibody Titers at Week 28 - Intent to Treat Population
    Description Baseline refers to Day 1. If Day 1 value was missing or after the first dose date of randomized study medication, the last available value on or prior to Day 1 was used. Serum titer determinations for antibodies to metreleptin were made using a validated electrochemical luminescence (ECLA) bridging assay. Antibody titers were assessed according to the following dilutions: 0, 5, 25, 125, 625, 3125, 15625, and 78125. Participants were considered to have a positive titer to treatment-emergent antibodies to metreleptin at a given visit if they had a titer >=5 following a negative or missing titer at baseline or if they had a titer that had increased by at least 2 dilutions from a detectable level at baseline.
    Time Frame Baseline to Week 28

    Outcome Measure Data

    Analysis Population Description
    Intent to treat population included all randomized participants who received at least one injection of study medication.
    Arm/Group Title Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 45 49 50 44 50 43
    Number [participants]
    43
    57.3%
    49
    63.6%
    48
    66.7%
    42
    56%
    50
    64.1%
    42
    53.8%
    26. Secondary Outcome
    Title Mean Change From Screening to Week 28 in Electrocardiogram Parameters - Intent to Treat Population
    Description A 12-Lead electrocardiogram (ECG) was obtained at Screening, Day 1, Weeks 1, 12, 28 (study termination). The PR interval, which is time from beginning of the P wave to the beginning of the QRS complex (Note: QRS complex is a name for the combination of 3 of the graphical deflections seen in an ECG); QRS interval (time from the beginning to the end of the QRS complex); QT interval (measure between Q wave and T wave in the heart's electrical cycle); and QT interval corrected for heart rate using Fridericia's formula (QTcF) were measured in milliseconds (msec).
    Time Frame Screening to Week 28 (or study termination)

    Outcome Measure Data

    Analysis Population Description
    Intent to treat population included all randomized participants who received at least one injection of study medication.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered twice a day (BID) for 28 weeks, subcutaneous (SC) placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 54 41 49 47 44 47 39
    PR Interval
    1.1
    (12.73)
    -0.1
    (12.23)
    0.3
    (10.37)
    0.1
    (13.74)
    16.8
    (97.51)
    4.4
    (17.89)
    0.4
    (11.86)
    -1.6
    (14.27)
    QRS Interval
    -0.3
    (5.20)
    -1.4
    (8.76)
    1.0
    (4.66)
    -0.5
    (6.26)
    -1.8
    (5.62)
    -0.2
    (4.12)
    0.3
    (4.78)
    -0.4
    (5.33)
    QT Interval
    0.4
    (28.72)
    9.9
    (21.80)
    16.2
    (28.64)
    7.0
    (19.33)
    8.9
    (20.53)
    4.4
    (24.97)
    15.0
    (21.56)
    6.3
    (28.03)
    QTcF
    -0.3
    (21.75)
    4.0
    (15.58)
    8.2
    (21.39)
    -1.2
    (16.02)
    -0.8
    (15.13)
    0.3
    (15.40)
    1.3
    (12.34)
    -2.3
    (22.00)
    27. Secondary Outcome
    Title Mean Change From Screening to Week 28 in the Electrocardiogram Parameter of Heart Rate - Intent to Treat Population
    Description A 12-Lead electrocardiogram (ECG) was obtained at Screening (visit 2), Day 1, Weeks 1, 12, 28 (study termination). Heart Rate was measured in beats per min (bpm).
    Time Frame Screening to Week 28 (or early termination)

    Outcome Measure Data

    Analysis Population Description
    Intent to treat population included all randomized participants who received at least one injection of study medication.
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered twice a day (BID) for 28 weeks, subcutaneous (SC) placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    Measure Participants 46 54 41 49 47 44 47 39
    Mean (Standard Deviation) [bpm]
    0.3
    (13.96)
    -2.8
    (8.45)
    -4.1
    (8.18)
    -4.7
    (10.12)
    -4.9
    (9.42)
    -1.9
    (9.73)
    -6.6
    (8.41)
    -3.4
    (9.69)

    Adverse Events

    Time Frame From enrollment to Study Termination (Week 28). Clinically significant events that continued beyond termination were followed until diagnosis/resolution occurred. Serious adverse events were followed 30 days post last dose of study medication.
    Adverse Event Reporting Description All participants enrolled were treated with Placebo for 1 week and then randomized into a treatment group. Enrolled = 636 (commenced placebo for 1 week); Enrolled but not randomized = 28; Randomized = 608; Intent to treat = Randomized and received at least 1 dose. Events presented below from Randomized population, treatment-emergent (ITT).
    Arm/Group Title Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Arm/Group Description Self administered BID for 28 weeks, SC placebo matched to pramlintide (Placebo-P) plus SC placebo matched to metreleptin (Placebo-M). Self administered BID for 28 weeks, SC 360 mcg pramlintide acetate plus SC Placebo matched to Metreleptin (Placebo-M). The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC metreleptin 5.0 mg plus SC Placebo matched to pramlintide (Placebo-P). Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 2.5 mg. Self administered BID for 28 weeks, SC Pramlintide 180 mcg plus SC Metreleptin 5.0 mg. Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 1.25 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 2.5 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant). Self administered BID for 28 weeks, SC Pramlintide 360 mcg plus SC Metreleptin 5.0 mg. The first week of the 28 weeks started with a lower pramlintide dose (180 mcg) in a blinded fashion (using 2 different concentrations of pramlintide so the dose change was not apparent to the participant).
    All Cause Mortality
    Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/75 (4%) 1/77 (1.3%) 0/72 (0%) 2/75 (2.7%) 0/78 (0%) 0/78 (0%) 0/78 (0%) 2/75 (2.7%)
    Blood and lymphatic system disorders
    lymphadenopathy 0/75 (0%) 0 0/77 (0%) 0 0/72 (0%) 0 0/75 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 1/75 (1.3%) 1
    Cardiac disorders
    Cardiac arrest 0/75 (0%) 0 0/77 (0%) 0 0/72 (0%) 0 1/75 (1.3%) 3 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Endocrine disorders
    Goiter 0/75 (0%) 0 0/77 (0%) 0 0/72 (0%) 0 1/75 (1.3%) 1 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    General disorders
    Non-cardiac chest pain 1/75 (1.3%) 1 0/77 (0%) 0 0/72 (0%) 0 0/75 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Immune system disorders
    Food Allergy 1/75 (1.3%) 1 0/77 (0%) 0 0/72 (0%) 0 0/75 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Parathyroid Tumor benign 0/75 (0%) 0 0/77 (0%) 0 0/72 (0%) 0 1/75 (1.3%) 1 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Papillary thyroid cancer 0/75 (0%) 0 0/77 (0%) 0 0/72 (0%) 0 0/75 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 1/75 (1.3%) 1
    Nervous system disorders
    Cervicobrachial syndrome 1/75 (1.3%) 1 0/77 (0%) 0 0/72 (0%) 0 0/75 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Convulsion 0/75 (0%) 0 0/77 (0%) 0 0/72 (0%) 0 1/75 (1.3%) 3 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Syncope vasovagal 0/75 (0%) 0 0/77 (0%) 0 0/72 (0%) 0 1/75 (1.3%) 3 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Vascular disorders
    Hypertension 1/75 (1.3%) 1 0/77 (0%) 0 0/72 (0%) 0 0/75 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Deep Vein Thrombosis 0/75 (0%) 0 1/77 (1.3%) 1 0/72 (0%) 0 0/75 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/78 (0%) 0 0/75 (0%) 0
    Other (Not Including Serious) Adverse Events
    Placebo Pramlintide 360 mcg Metreleptin 5.0 mg Pramlintide 180 mcg + Metreleptin 2.5 mg Pramlintide 180 mcg + Metreleptin 5.0 mg Pramlintide 360 mcg + Metreleptin 1.25 mg Pramlintide 360 mcg + Metreleptin 2.5 mg Pramlintide 360 mcg + Metreleptin 5.0 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 60/75 (80%) 66/77 (85.7%) 63/72 (87.5%) 67/75 (89.3%) 71/78 (91%) 68/78 (87.2%) 72/78 (92.3%) 68/75 (90.7%)
    Gastrointestinal disorders
    nausea 4/75 (5.3%) 4 31/77 (40.3%) 37 4/72 (5.6%) 4 27/75 (36%) 30 21/78 (26.9%) 22 26/78 (33.3%) 27 29/78 (37.2%) 32 19/75 (25.3%) 20
    diarrhea 5/75 (6.7%) 5 5/77 (6.5%) 5 3/72 (4.2%) 3 5/75 (6.7%) 5 4/78 (5.1%) 4 4/78 (5.1%) 5 7/78 (9%) 7 3/75 (4%) 3
    constipation 1/75 (1.3%) 1 3/77 (3.9%) 3 2/72 (2.8%) 2 5/75 (6.7%) 5 3/78 (3.8%) 3 2/78 (2.6%) 2 0/78 (0%) 0 2/75 (2.7%) 2
    vomiting 0/75 (0%) 0 6/77 (7.8%) 6 3/72 (4.2%) 3 0/75 (0%) 0 2/78 (2.6%) 2 5/78 (6.4%) 5 1/78 (1.3%) 1 1/75 (1.3%) 1
    General disorders
    injection site erythema 1/75 (1.3%) 1 7/77 (9.1%) 8 15/72 (20.8%) 25 15/75 (20%) 17 17/78 (21.8%) 21 8/78 (10.3%) 9 24/78 (30.8%) 25 21/75 (28%) 24
    injection site pruritus 1/75 (1.3%) 1 4/77 (5.2%) 4 13/72 (18.1%) 19 19/75 (25.3%) 20 21/78 (26.9%) 23 11/78 (14.1%) 11 18/78 (23.1%) 20 22/75 (29.3%) 23
    injection site bruising 11/75 (14.7%) 14 11/77 (14.3%) 13 9/72 (12.5%) 13 9/75 (12%) 16 9/78 (11.5%) 9 11/78 (14.1%) 13 8/78 (10.3%) 9 16/75 (21.3%) 23
    injection site hemorrhage 3/75 (4%) 3 10/77 (13%) 11 13/72 (18.1%) 17 14/75 (18.7%) 17 10/78 (12.8%) 10 7/78 (9%) 7 10/78 (12.8%) 11 11/75 (14.7%) 12
    injection site urticaria 0/75 (0%) 0 2/77 (2.6%) 2 12/72 (16.7%) 12 13/75 (17.3%) 13 12/78 (15.4%) 12 5/78 (6.4%) 5 11/78 (14.1%) 14 11/75 (14.7%) 11
    injection site rash 0/75 (0%) 0 2/77 (2.6%) 2 13/72 (18.1%) 15 3/75 (4%) 5 8/78 (10.3%) 9 9/78 (11.5%) 12 12/78 (15.4%) 12 7/75 (9.3%) 10
    injection site nodule 3/75 (4%) 3 2/77 (2.6%) 2 8/72 (11.1%) 11 3/75 (4%) 3 10/78 (12.8%) 10 2/78 (2.6%) 2 6/78 (7.7%) 6 8/75 (10.7%) 10
    injection site induration 3/75 (4%) 3 2/77 (2.6%) 2 2/72 (2.8%) 4 0/75 (0%) 0 6/78 (7.7%) 7 2/78 (2.6%) 2 1/78 (1.3%) 1 5/75 (6.7%) 5
    injection site inflammation 0/75 (0%) 0 0/77 (0%) 0 1/72 (1.4%) 4 3/75 (4%) 3 4/78 (5.1%) 4 3/78 (3.8%) 3 3/78 (3.8%) 4 4/75 (5.3%) 4
    fatigue 1/75 (1.3%) 1 3/77 (3.9%) 3 3/72 (4.2%) 3 5/75 (6.7%) 5 1/78 (1.3%) 1 1/78 (1.3%) 1 4/78 (5.1%) 4 1/75 (1.3%) 1
    Infections and infestations
    Upper respiratory tract infection 8/75 (10.7%) 9 8/77 (10.4%) 9 2/72 (2.8%) 2 7/75 (9.3%) 7 10/78 (12.8%) 10 11/78 (14.1%) 11 9/78 (11.5%) 13 5/75 (6.7%) 5
    nasopharyngitis 4/75 (5.3%) 5 8/77 (10.4%) 9 8/72 (11.1%) 11 3/75 (4%) 5 4/78 (5.1%) 5 6/78 (7.7%) 9 6/78 (7.7%) 7 4/75 (5.3%) 7
    urinary tract infection 5/75 (6.7%) 6 7/77 (9.1%) 13 3/72 (4.2%) 3 2/75 (2.7%) 2 2/78 (2.6%) 2 3/78 (3.8%) 5 3/78 (3.8%) 3 1/75 (1.3%) 1
    gastroenteritis viral 2/75 (2.7%) 2 4/77 (5.2%) 5 2/72 (2.8%) 2 3/75 (4%) 3 3/78 (3.8%) 3 1/78 (1.3%) 1 1/78 (1.3%) 1 2/75 (2.7%) 2
    bronchitis 1/75 (1.3%) 1 1/77 (1.3%) 1 1/72 (1.4%) 1 0/75 (0%) 0 4/78 (5.1%) 4 2/78 (2.6%) 2 3/78 (3.8%) 3 0/75 (0%) 0
    Investigations
    blood creatine phosphokinase increased 6/75 (8%) 6 2/77 (2.6%) 2 1/72 (1.4%) 1 4/75 (5.3%) 4 3/78 (3.8%) 3 1/78 (1.3%) 2 5/78 (6.4%) 5 1/75 (1.3%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 4/75 (5.3%) 4 1/77 (1.3%) 1 3/72 (4.2%) 3 2/75 (2.7%) 2 1/78 (1.3%) 1 2/78 (2.6%) 2 3/78 (3.8%) 3 3/75 (4%) 4
    Nervous system disorders
    headache 4/75 (5.3%) 4 5/77 (6.5%) 5 4/72 (5.6%) 5 3/75 (4%) 3 7/78 (9%) 13 3/78 (3.8%) 3 3/78 (3.8%) 3 4/75 (5.3%) 4
    dizziness 4/75 (5.3%) 4 3/77 (3.9%) 3 1/72 (1.4%) 1 4/75 (5.3%) 4 1/78 (1.3%) 1 2/78 (2.6%) 2 1/78 (1.3%) 1 1/75 (1.3%) 1
    Respiratory, thoracic and mediastinal disorders
    pharyngolaryngeal pain 0/75 (0%) 0 3/77 (3.9%) 3 1/72 (1.4%) 1 4/75 (5.3%) 4 3/78 (3.8%) 3 1/78 (1.3%) 1 0/78 (0%) 0 1/75 (1.3%) 1
    sinus congestion 4/75 (5.3%) 4 2/77 (2.6%) 2 0/72 (0%) 0 2/75 (2.7%) 2 1/78 (1.3%) 1 2/78 (2.6%) 2 0/78 (0%) 0 1/75 (1.3%) 1
    sinusitis 3/75 (4%) 5 1/77 (1.3%) 1 2/72 (2.8%) 3 2/75 (2.7%) 2 4/78 (5.1%) 4 5/78 (6.4%) 5 5/78 (6.4%) 5 2/75 (2.7%) 2

    Limitations/Caveats

    Drug Randomization stratified:sex,3 categories baseline BMI (12 arms); 3 treatment arms combined for summaries as single placebo treatment group; 3 combined for summaries as single pramlintide monotherapy treatment group (total:8 treatment groups).

    More Information

    Certain Agreements

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

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

    Results Point of Contact

    Name/Title Peter Ohman, Medical Science Director
    Organization AstraZeneca
    Phone
    Email ClinicalTrialTransparency@astrazeneca.com
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT00673387
    Other Study ID Numbers:
    • DFA102
    First Posted:
    May 7, 2008
    Last Update Posted:
    Apr 15, 2015
    Last Verified:
    Mar 1, 2015