Effects of Metreleptin in Type 1 Diabetes Mellitus

Open Label Single Center Pilot Study to Study Teh Effects of Metreleptin Administration in Patients With Type 1 Diabetes Mellitus ( T1DM ).

This study will add leptin therapy to the current insulin therapy of Type 1 Diabetics with the aim of lowering the total insulin requirements and suppressing the steep fluctuations typically associated with Type 1 Diabetes.

Study Overview

• Status: Terminated
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Leptin

Detailed Description

The adipocyte hormone, leptin, has been shown to restore the health and glucoregulation of near-death, insulin deficient diabetic rodents. This makes leptin the only hormone, since the discovery of insulin in 1922, with this capability. Leptin normalizes the hyperglucagonemia of diabetes and reduces lipogenesis and cholesterologenenesis. Treatment of diabetic rodents with a combination of leptin and insulin, leads to a stable pattern of glucose control with reduced insulin requirements, as opposed to the high glucose variability that characterizes the treatment of type 1 diabetes with supraphysiologic doses of insulin alone. As such, we will initiate a pilot clinical trial to test combination leptin and insulin therapy in type 1 diabetes. Fifteen leptin sensitive patients (body mass index <27 kg/m²) with uncontrolled diabetes (HbA1c 7.0 to 10.0 %) will be treated with slightly supraphysiologic doses of recombinant human leptin (Amylin Pharmaceuticals). Subjects will be compared to themselves before and after treatment with leptin. Endpoint variables include HbA1c, change in daily insulin dose, mean and standard deviation of blood glucose from inpatient glucose monitoring and glucose meter download. We will also assess effects of leptin therapy on energy intake as assessed by 3-day food record and body weight and fat by DEXA. Intramyocellular and intrahepatic lipid concentration by 1H-MRS will be assessed before and after 3 months of metreleptin therapy. A satiety analysis will be employed. In addition, plasma hormones and inflammatory biomarkers will be assayed during the course of this study.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All of the following criteria are to be fulfilled for inclusion of an individual in the study. An eligible individual:

1. Is male or female and is 18 to 50 years of age
2. Has been diagnosed with T1DM for at least 1 year. Diagnosis of T1DM will be based on clinical criteria including: insulin-dependence within 6 months of the onset, history of prior episode of ketoacidosis, previous documentation of positive serum islet cell autoantibodies or low or undetectable serum C-peptide levels.
3. Has an HbA1c 7.0 to 10.0 %, inclusive
4. Currently on insulin pump or on a combination of basal (long-acting insulin preparation) and pre-prandial (short-acting insulin preparation) insulin therapy
5. Is male, or if female of childbearing potential, is non-lactating, and has a negative pregnancy test (human chorionic gonadotropin, beta subunit [βhCG]) result at screening (Visit 1) and Visit 2 regardless of menopausal status (If female and of childbearing potential [including peri menopausal women who have had a menstrual period within one year], must practice and be willing to continue to practice appropriate birth control [defined as a method which results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as implants, injectables, oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, tubal ligation, or a vasectomized partner] during the entire duration of the study.)
6. Has a BMI < 27 kg/m2
7. Has clinical laboratory test values (clinical chemistry, hematology, and urinalysis) judged to be not clinically significant by the investigator at screening (Visit 1)
8. Has a physical examination and electrocardiogram (ECG) with no clinically significant abnormalities as judged by the investigator

Exclusion Criteria:

1. Has a fasting serum triglyceride concentration >400 mg/dL at screening
2. Has hypoglycemia unawareness (Loss of consciousness due to hypoglycemia without preceding symptoms or recent history of blood glucose <50 mg/dl without symptoms)
3. Currently abuses drugs or alcohol, or has a history of abuse that in the investigator's opinion could cause the individual to be noncompliant with study procedures, or has a positive urine screen for drugs of abuse at screening (Visit 1)
4. Has chronic renal insufficiency with serum creatinine > 2 mg/dL
5. Has a history of weight loss (>3%) in the last 3 months
6. Is currently enrolled or plans to enroll in a diet, weight loss, or exercise program
7. Has a sitting blood pressure >160/95 mmHg (either systolic or diastolic) at screening (Visit 1)

8. Has a clinically significant history or presence of any of the following conditions:

   • Active cardio- or cerebrovascular disease
   • Active pulmonary disease

   • Hepatic disease defined as follows:

     • At screening (Visit 1), alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase > three times the upper limit of normal (elevated Liver Function Test values suggestive of obesity related non-alcoholic fatty liver disease may not be exclusionary)
   • The presence of any other co morbid disorders that, in the opinion of the investigator, would interfere with the subject's compliance of study procedures
   • Clinically significant malignancies within 5 years of screening (Visit 1)
   • Chronic infections (e.g., HIV [human immunodeficiency virus] or tuberculosis)
9. Has received any investigational drug within 30 days or within a period corresponding to five half-lives of that drug, whichever is greater, before screening (Visit 1)
10. Has had major surgery or a blood transfusion within 2 months before screening (Visit 1) or has a hematocrit < 30%
11. Has a known hypersensitivity to any of the components of the study treatment (e.g. has a known hypersensitivity to E. Coli derived proteins
12. Is an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the investigative site, or is personally directly affiliated with the study at the investigative site
13. Is employed by Amylin Pharmaceuticals, Inc., (i.e., an employee, temporary contract worker, or designee responsible for the conduct of the study)
14. Has previously received treatment with recombinant leptin (metreleptin or Fc leptin)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: active open label Leptin; Active open label Leptin for type 1 Diabetes	Drug: Leptin; weight based sub-cutaneous injection twice daily of Leptin; Other Names: Metreleptin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HbA1c	Change in Hba1c after 12 weeks on Leptin Therapy compared to Baseline value	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight	Change in Body Weight after 12 weeks on Leptin Therapy compared to Baseline value	Baseline to 12 weeks
Insulin Dose	Change in Insulin dose after 12 weeks on Leptin Therapy compared to Baseline value	Baseline to 12 weeks
Change in HbA1c From Baseline to Week 20 on Leptin Therapy	Change in Hba1c after 20 weeks on Leptin Therapy compared to Baseline value. With ongoing metreleptin therapy, the concomitant basal insulin dose was actively reduced by 50% after week 12.	Baseline to Week 20 (On leptin)

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: Juvenile Diabetes Research Foundation; Amylin Pharmaceuticals, LLC.
• Investigators: Principal Investigator: Abhimanyu Garg, M.D., UT Southwestern Medical Center

Publications and helpful links

General Publications

• Vasandani C, Clark GO, Adams-Huet B, Quittner C, Garg A. Efficacy and Safety of Metreleptin Therapy in Patients With Type 1 Diabetes: A Pilot Study. Diabetes Care. 2017 May;40(5):694-697. doi: 10.2337/dc16-1553. Epub 2017 Feb 21.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: December 29, 2010
• First Submitted That Met QC Criteria: December 30, 2010
• First Posted (Estimate): December 31, 2010

Study Record Updates

• Last Update Posted (Actual): August 28, 2019
• Last Update Submitted That Met QC Criteria: July 17, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Type 1 Diabetes Mellitus
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: FBA937; CTRC # 953 (Other Grant/Funding Number: JDRF and Amylin)