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

This study has been completed.
Sponsor:
Information provided by:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00392925
First received: October 24, 2006
Last updated: June 6, 2014
Last verified: January 2014
  Purpose

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


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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2A, Randomized, Controlled, Double-Blind, Multicenter Study to Evaluate the Safety, Tolerability, and Effect on Body Weight of Recombinant-Methionyl Human Leptin Administered in Conjunction With Pramlintide in Overweight and Obese Subjects

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Mean Absolute Change From Baseline to Week 16 in Body Weight - Evaluable Population [ Time Frame: Baseline to Week 16 ] [ Designated as safety issue: No ]
    Absolute change in body weight as measured in kilograms (kg) from baseline to Week 16. Baseline defined as Day 1 of randomized treatment.


Secondary Outcome Measures:
  • LS Mean Percent Change in Body Weight From Baseline to Weeks 4, 8, 12, 16, and 20 - Evaluable Population [ Time Frame: Baseline up to Week 20 ] [ Designated as safety issue: No ]
    Least Squares (LS) mean percent change in body weight from baseline to Weeks 4 through 20. Baseline defined as Day 1 of randomized treatment.

  • LS Mean Absolute Change From Baseline to Weeks 4, 8, 12, 20 in Body Weight - Evaluable Population [ Time Frame: Baseline to Week 20 ] [ Designated as safety issue: No ]
    Least Squares (LS) mean absolute change in body weight as measured in kilograms (kg) from baseline to Weeks 4, 8, 12, 20. Baseline defined as Day 1 of randomized treatment

  • LS Mean Absolute Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population [ Time Frame: Enrollment to Week 20 ] [ Designated as safety issue: No ]
    Least Squares (LS) mean change in body weight as measured in kilograms (kg) from enrollment to each study visit. Enrollment was Visit 2 (Week -4) which was the start of the Lead-In Period. After the 4 week Lead-In Period, at Day 1, the participant was randomized to one of the 3 study arms and the participant was treated as per that arm up to Week 20.

  • LS Mean Percent Change in Body Weight From Enrollment to Weeks 4, 8, 12, 16, and 20 - Evaluable Population [ Time Frame: Enrollment to Week 20 ] [ Designated as safety issue: No ]
    Least Squares (LS) mean percent change is percentage that body weight changed over time at each visit. Enrollment was Visit 2 (Week -4) which was the start of the Lead-In Period. After the 4 week Lead-In Period, at Day 1, the participant was randomized to one of the 3 study arms and treated up to Week 20.

  • Initial, Late, and Overall Rates of LS Mean Absolute Change in Body Weight From Day 1 to Week 20 - Evaluable Population [ Time Frame: Baseline to Week 20 ] [ Designated as safety issue: No ]
    Initial (Day 1 through Week 12), late (Week 12 through Week 20), and overall (Day 1 through Week 20) rates of Least squares (LS) mean absolute change in body weight were defined by the slopes of the regression lines fitted to the observed body weights during the periods from Baseline (Day 1) through each visit to Week 20. Initial, late and overall absolute change was measured in kilograms of body weight per week (kg/week). Baseline refers to Visit 4 (Day 1 of randomization period).

  • Number of Participants Achieving at Least 5% and at Least 10% Body Weight Loss From Baseline to Weeks 16 and 20, and Number of Participants With Sustained Weight Loss in Each Category - Evaluable Population [ Time Frame: Baseline to Weeks 16 and Weeks 20 ] [ Designated as safety issue: No ]
    Baseline refers to Visit 4 (Day 1 of randomization period). Number of participants with 5% or more and 10% or more change in weight from baseline at each visit. Number of participants with 5% or more change in weight that was sustained through Week 16. Number of participants with 10% or more change in weight that was sustained through Week 20.

  • LS Mean Percent Change in Weight From Enrollment to Baseline and LS Mean Percent Change in Excess Weight From Enrollment to Baseline - Evaluable Population [ Time Frame: Enrollment to Baseline ] [ Designated as safety issue: No ]
    Excess body weight: the difference between a participant's actual body weight and the weight a participant of his/her height would have if his/her BMI were 24.9 kg/m2. Excess body weight at a given visit was calculated as body weight in kilograms (kg) at that visit minus 24.9 × height in meters (m)^2 or 0, whichever was greater. If a participant achieved a normal BMI (24.9 kg/m^2), that subject was considered to have no excess weight. Additional weight loss that occurred after a normal BMI was achieved was not included in the calculation of excess weight loss. Enrollment was Visit 2 (Week -4), the start of the Lead-In Period. Baseline was Day 1 of the randomization to a study arm.

  • LS Mean Absolute Change in Waist Circumference From Enrollment to Weeks 4, 8, 12, 16, 20 - Evaluable Population [ Time Frame: Enrollment to Week 20 ] [ Designated as safety issue: No ]
    Waist circumference was measured in centimeters (cm). Least Squares mean = LS mean. Enrollment was Visit 2 (Week -4) which was the start of the 4 week Lead-In Period. At Day 1, the participant was randomized to one of the 3 study arms and the participant was treated up to Week 20.

  • LS Mean Absolute Change in Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20 - Evaluable Population [ Time Frame: Baseline to Week 20 ] [ Designated as safety issue: No ]
    Baseline was Visit 4 (Day 1 of randomization period). Waist circumference was measured in centimeters (cm).

  • LS Mean Absolute Change in Hip Circumference From Screening up to Week 20 - Evaluable Population [ Time Frame: Screening up to Week 20 ] [ Designated as safety issue: No ]
    Screening (Week -5 or -6) was the first visit for a participant. This first visit determined participant eligibility and occurred prior to enrollment (Week -4). Hip circumference was measured in centimeters (cm).

  • Number of Participants With BMI Change From Enrollment to Week 16 - Evaluable Population [ Time Frame: Enrollment up to Week 16 ] [ Designated as safety issue: No ]
    BMI was measured as kilogram per meter of height squared (kg/m^2). Enrollment was Visit 2 (Week -4). Participants who were obese (BMI of 30 kg/m^2 to <35 kg/m^2) at enrollment were evaluated at Week 16 to see if the same number who were obese at enrollment were still obese at Week 16 or if they had changed to an BMI of overweight (BMI of 25 kg/m^2 to <30 kg/m^2) or a BMI of normal (BMI of <25 kg/m^2) or a greater obesity (BMI >35 kg/m^2). Participants who were overweight (BMI of 25 kg/m^2 to <30 kg/m^2) at enrollment were evaluated at Week 16 to see if the same number who were overweight at enrollment were still overweight at Week 16 or if they had changed to normal (or obese).

  • Number of Participants With BMI Change From Enrollment to Week 20 - Evaluable Population [ Time Frame: Enrollment up to Week 20 ] [ Designated as safety issue: No ]
    BMI was measured as kilogram per meter of height squared (kg/m^2). Enrollment was Visit 2 (Week -4). Participants who were obese (BMI of 30 kg/m^2 to <35 kg/m^2) at enrollment were evaluated at Week 20 to see if the same number who were obese at enrollment were still obese at Week 20 or if they had changed to an BMI of overweight (BMI of 25 kg/m^2 to <30 kg/m^2) or a BMI of normal (BMI of <25 kg/m^2) or a greater obesity (BMI >35 kg/m^2). Participants who were overweight (BMI of 25 kg/m^2 to <30 kg/m^2) at enrollment were evaluated at Week 20 to see if the same number who were overweight at enrollment were still overweight at Week 20 or if they had changed to normal (or obese).

  • Mean Absolute Change From Enrollment to Week 16 in Fasting Glucose and Lipids - Evaluable Population [ Time Frame: Enrollment to Week 16 ] [ Designated as safety issue: No ]
    Enrollment was Visit 2 (Week -4). Baseline refers to Visit 4 (Day 1 of randomization period). Fasting Lipids included: total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and Triglycerides. Fasting Glucose and Lipids were measured in milligrams per deciliter (mg/dL).

  • Mean Absolute Change From Enrollment to Baseline, Weeks 4 and 16 in Fasting Total Leptin Concentration - Evaluable Population [ Time Frame: Enrollment to Week 16 ] [ Designated as safety issue: No ]
    Enrollment was Visit 2 (Week -4). Baseline refers to Visit 4 (Day 1 of randomization period). Leptin was measured in nanograms per milliliter (ng/mL). Plasma total leptin (including endogenous leptin and exogenous metreleptin) concentrations were measured using a validated sandwich-type immunoenzymetric assay utilizing polyclonal capture antibody, monoclonal detection antibody, and colorimetric readout by Amylin Pharmaceuticals, Inc. This assay is not specific for metreleptin and detects both endogenous leptin and exogenous recombinant-methionyl human leptin [metreleptin]).

  • Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Amylin -Evaluable Population [ Time Frame: Enrollment to Week 16 ] [ Designated as safety issue: No ]
    Enrollment was Visit 2 (Week -4). Baseline refers to Visit 4 (Day 1 of randomization period). Fasting total plasma amylin (peptide produced by beta cells in the pancreas) concentration was measured in picomolar (pM) and samples were obtained at screening, enrollment, baseline, Week 4 and Week 16.

  • Mean Absolute Change From Enrollment to Baseline and Week 16 in Fasting Total Insulin - Evaluable Population [ Time Frame: Enrollment to Week 16 ] [ Designated as safety issue: No ]
    Enrollment was Visit 2 (Week -4). Baseline refers to Visit 4 (Day 1 of randomization period). Total insulin was measured in micro international units per milliliter (µIU/mL)

  • LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcome (PRO) Instruments Measuring Quality of Life and Mood - Evaluable Population [ Time Frame: Enrollment to Week 16 ] [ Designated as safety issue: No ]
    Enrollment was Visit 2 (Week -4). PRO: Total Score in Impact of Weight on Quality of Life Questionnaire-lite Version (IWQOL-Lite), 31-item instrument used to assess the effect of weight on physical function, self-esteem, sexual life, public distress, and work. Individual items range from 1 to 5 with 5=always true and 1= never true. Total score measured on scale from 0 (worst) to 100 (best). Higher scores indicate improvement; Profile of Mood States (POMS), 65 mood adjectives that assess participants' mood over the past seven days. The POMS-B is an authorized, 30-item brief version of the POMS consisting of five items for each: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. Scores range from 0= Not at All to 4=Extremely. Factor scores added for total score. Lower score indicates improvement. 0=best outcome; 120=worst outcome.

  • LS Mean Absolute Change From Enrollment to Week 16 in Patient Reported Outcomes (PRO) for Eating Behavior - Evaluable Population [ Time Frame: Enrollment to Week 16 ] [ Designated as safety issue: No ]
    Enrollment was Visit 2 (Week -4). PRO for eating behavior: Binge Eating Scale (BES) Total Score (16-item questionnaire assessed the behavioral and cognitive correlates of binge eating, including participants' perceived self-control over eating behavior using a range of 1 to 4 with 1=positive perceptions and 4= negative perceptions. Minimum and maximum scores were 0 and 55, respectively); Susceptibility to Eating Questionnaire (SEQ) Total Score (measure of appetite, satiety, and perceived control over portion size using 10 VAS items with each response measured on a 100 mm visual analogue scale [ranges vary from Never to Very Often; Not at All Difficult to Extremely Difficult; Not at all Strong to Very Strong]. Responses to these items rated over the past 7 days;

  • LS Mean Absolute Change From Enrollment to Week 16 in Hospital Anxiety and Depression Scale (HADS) - Evaluable Population [ Time Frame: Enrollment to Week 16 ] [ Designated as safety issue: No ]
    The HADS is a questionnaire that uses 14 items to assess both anxiety and depression over the past week. The odd numbered items constitute the anxiety subscale, and the even numbered items constitute the depression subscale. The individual response scores for each subscale component are added together to obtain the individual subscale scores. The minimum and maximum score for each subscale is 0 and 21, respectively. The lower the score the more improvement a participant shows.

  • Mean Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Systolic and Diastolic Blood Pressure - Enrolled Population [ Time Frame: Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group) ] [ Designated as safety issue: Yes ]
    Enrollment was Visit 2 (Week -4). Blood pressure (BP) was measured after 5 minutes of quiet rest with the participant in a sitting position and was measured in millimeters of mercury (mm Hg). Blood pressure was taken at each visit (screening, Week -4, Week -2, Day 1, Weeks 4, 8, 12, 16, 20 (or early termination). After the Lead-In Period, participants were either randomized to one of the 3 arms of the study or they were dropped from the study so the time frame for evaluation of all participants in the study was either: enrollment up to Week 20 for Randomized participants or enrollment up to, but not including Day 1 for Non-Randomized participants who participated only in the Lead-In Period.

  • Absolute Change From Enrollment to Week -2, Week 16 and Week 20 in Heart Rate - Enrolled Population [ Time Frame: Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group) ] [ Designated as safety issue: Yes ]
    Enrollment was Visit 2 (Week -4). Heart rate was measured after the participant rested for 5 minutes and was sitting. Heart Rate was measured in beats per minute (bpm). Vital signs were taken at each visit (screening, Week -4, Week -2, Day 1, Weeks 4, 8, 12, 16, 20 (or early termination). After the Lead-In Period, participants were either randomized to one of the 3 arms of the study or they were dropped from the study so the time frame for evaluation of all participants in the study was either: enrollment up to Week 20 for Randomized participants or enrollment up to, but not including Day 1 for Non-Randomized participants who participated only in the Lead-In Period.

  • Number of Chemistry Values of Potential Clinical Importance - Enrolled Population [ Time Frame: Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group) ] [ Designated as safety issue: Yes ]
    Number of values (not participants). Greater than (>), Less than (<), high (H), low (L). Criteria for laboratory values of potential clinical importance for obese and overweight (BMI>=25 kg/m^2) participants: Total bilirubin H > 2 mg/dL; glucose fasting or non-fasting H >200 mg/dL, L <60 mg/dL; Albumin L <2.5 g/dL; Creatine Phosphokinase (CPK) H >3*Upper limit of Normal (ULN); Sodium L<130 milliequivalents per liter (mEq/L), H >150 mEq/L; potassium L<3.0 mEq/L, H>5.5 mEq/L;bicarbonate L<18 mEq/L, H>35 mEq/L;calcium L <8 mg/dL, H>11 mg/dL; triglycerides H>500 mg/dL; Cholesterol L < 100 mg/dL, H > 350 mg/dL; Alkaline phosphatase H >3*ULN; Gamma-glutamyltransferase (GGT) H>3*ULN; creatinine males >1.6 mg/dL, females >1.4 mg/dL; alanine aminotransferase (ALT) H >3*ULN; aspartate aminotransferase (AST) H >3*ULN; urea nitrogen H >45 mg/dL; uric acid males >10.0 mg/dL, females > 8.0 mg/dL; Phosphorus L <1.0 mg/dL H >6.0 mg/dL. Time frame differs depending on randomization status.

  • Number of Hematology and Urinalysis Values of Potential Clinical Importance - Enrolled Population [ Time Frame: Enrollment up to Week 20(Randomized Group) or Enrollment up to, not including Day 1(Non-Randomized Group) ] [ Designated as safety issue: Yes ]
    Number of laboratory values of potential clinical importance (not participants) observed. Criteria for laboratory values of potential clinical importance for obese and overweight (BMI >= 25 kg/m^2) participants: Platelets high (H) >500,000/µL; low (L) <75,000/µL. Hematocrit males <36%, females <30%. Hemoglobin males <12 g/dL, females <10 g/dL. White blood cell count (WBC) H >18,000/µL; L <1,500/µL. Urine protein H >= 3+ or >= 500 mg/dL. Urine glucose H >= 3+ or >= 500 mg/dL. Urine ketones >= 3+ or Large. Time frame of evaluation differs depending on randomization status.

  • Number of Participants With Clinically Significant Abnormal ECG at Weeks 16, 20, or Early Termination - Randomized Population [ Time Frame: Weeks 16, 20, early termination ] [ Designated as safety issue: Yes ]
    A 12-Lead electrocardiogram (ECG) was obtained at Week -4, Day 1, Week 16, Week 20 or early termination and the overall interpretation of the ECG was made by the investigator as normal, abnormal (not clinically significant) and abnormal (clinically significant). The ECG consisted of the PR interval = time from beginning of the P wave to the beginning of the QRS complex; (Note: QRS complex is a name for the combination of 3 of the graphical deflections seen in an ECG); QRS (time from the beginning to the end of the QRS complex) interval; QT interval (measure between Q wave and T wave in the heart's electrical cycle); and QT interval corrected for heart rate using Fridericia's formula (QTcF) were measured in milliseconds (msec). .

  • Number of Participants With Treatment-emergent Anti-Leptin Antibodies by Week 4, Week 8, Week 12, Week 16 - Intent to Treat Population [ Time Frame: Baseline up to Week 16 ] [ Designated as safety issue: Yes ]
    Serum titer determinations for antibodies to leptin were made using a validated electrochemical luminescence (ECLA) bridging assay. Antibody titers were assessed according to the following dilutions: 0, 5, 25, 125, 625, 3125, 15625, and 78125. Participants were considered to have a positive titer to treatment-emergent antibodies to leptin at a given visit if they had a titer >=5 following a negative or missing titer at baseline or if they had a titer that had increased by at least 2 dilutions from a detectable level at baseline. All participants were evaluated (including those who did not receive metreleptin as their randomized study drug). Baseline was Day 1 (randomization).


Enrollment: 177
Study Start Date: October 2006
Study Completion Date: September 2007
Primary Completion Date: September 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Placebo and Metreleptin
Placebo-pramlintide 600 microliters (µL) twice a day (BID) and metreleptin (recombinant-methionyl human leptin) 5 milligram (mg) BID, 20 weeks
Drug: metreleptin
subcutaneous injection, twice a day, 5mg
Other Name: recombinant-methionyl human leptin
Drug: placebo-pramlintide 600 uL
twice a day
Experimental: Pramlintide Acetate and Placebo
Lead-in period: 2 weeks pramlintide acetate 180 mcg BID, then 2 weeks pramlintide acetate 360 mcg BID Study period: Pramlintide acetate 360 mcg BID and placebo-metreleptin 1 mL BID, 20 weeks
Drug: pramlintide acetate 360 mcg
subcutaneous injection, twice a day, 360mcg
Other Name: SYMLIN®
Drug: placebo-metreleptin 1 mL
twice a day
Experimental: Pramlintide Acetate and Metreleptin
Lead-in period: 2 weeks pramlintide acetate 180 mcg BID, then 2 weeks pramlintide acetate 360 mcg BID Study period: Pramlintide acetate 360 mcg BID and metreleptin (recombinant-methionyl human leptin) 5 mg BID, 20 weeks
Drug: pramlintide acetate 360 mcg
subcutaneous injection, twice a day, 360mcg
Other Name: SYMLIN®
Drug: metreleptin
subcutaneous injection, twice a day, 5mg
Other Name: recombinant-methionyl human leptin
Lead-In Period
During the Lead-In Period before a participant was randomized to a study arm, the participant received 180 mcg pramlintide acetate twice a day (BID) for 2 weeks, followed by 360 mcg pramlintide acetate BID for 2 weeks (total of 4 weeks in the Lead-In Period).
Drug: pramlintide acetate 360 mcg
subcutaneous injection, twice a day, 360mcg
Other Name: SYMLIN®
Drug: Pramlintide acetate 180 mcg
subcutaneous injection twice a day, 180 mcg
Other Name: SYMLIN®

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Is obese (Body Mass Index [BMI]>=30kg/m^2 and <=35kg/m^2); or overweight (BMI>=27kg/m^2 and <30kg/m^2) with abdominal obesity, based on the following: *waist circumference >102 cm if male, *waist circumference >88 cm if female
  • Is a nonsmoker (has not smoked for at least 6 months prior to the study)
  • Consumes a morning and evening meal each day

Exclusion Criteria:

  • Is diagnosed with type 2 diabetes
  • Is currently enrolled or plans to enroll in a diet, weight loss, or exercise program with the specific intent of losing weight (subjects who have been following an exercise regimen resulting in stable weight maintenance for at least 2 months prior to enrollment are eligible for study inclusion)
  • Has been treated over the past 2 months, is currently treated, or is expected to require or undergo treatment with any of the following medications: *antiobesity agents (prescription or over-the-counter), *antipsychotic agents, *antiepileptic agents, *antidepressant agents, *drugs that directly affect gastrointestinal motility
  • Has received any investigational drug within 30 days or within a period corresponding to 5 half-lives of that drug, whichever is greater, prior to this study starting
  • Has previously received treatment with recombinant leptin or pramlintide
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00392925

Locations
United States, Florida
Research Site
Deland, Florida, United States
United States, Illinois
Research Site
Chicago, Illinois, United States
United States, Indiana
Research Site
Indianapolis, Indiana, United States
United States, Kansas
Research Site
Overland Park, Kansas, United States
United States, Louisiana
Research Site
Baton Rouge, Louisiana, United States
United States, Michigan
Research Site
Detroit, Michigan, United States
United States, Minnesota
Research Site
Edina, Minnesota, United States
United States, Montana
Research Site
Butte, Montana, United States
United States, Ohio
Research Site
Cincinnati, Ohio, United States
United States, Oregon
Research Site
Portland, Oregon, United States
United States, Utah
Research Site
Salt Lake City, Utah, United States
United States, Washington
Research Site
Olympia, Washington, United States
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Lisa Porter, MD Amylin Pharmaceuticals, LLC.
  More Information

No publications provided

Responsible Party: Lisa Porter, MD, Study Director, Amylin Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00392925     History of Changes
Other Study ID Numbers: DFA101
Study First Received: October 24, 2006
Results First Received: August 12, 2013
Last Updated: June 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by AstraZeneca:
overweight
obesity
pramlintide
leptin
Amylin

Additional relevant MeSH terms:
Body Weight
Obesity
Overweight
Nutrition Disorders
Overnutrition
Signs and Symptoms
Islet Amyloid Polypeptide
Pramlintide
Anti-Obesity Agents
Appetite Depressants
Central Nervous System Agents
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014