Type 1 Diabetes
Conditions
Keywords
Type 1 Diabetes Mellitus
Brief summary
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.
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.
Interventions
DRUGLeptin
weight based sub-cutaneous injection twice daily of Leptin
Sponsors
Juvenile Diabetes Research Foundation
Amylin Pharmaceuticals, LLC.
University of Texas Southwestern Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c | Baseline and 12 weeks | Change in Hba1c after 12 weeks on Leptin Therapy compared to Baseline value |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weight | Baseline to 12 weeks | Change in Body Weight after 12 weeks on Leptin Therapy compared to Baseline value |
| Insulin Dose | Baseline to 12 weeks | Change in Insulin dose after 12 weeks on Leptin Therapy compared to Baseline value |
| Change in HbA1c From Baseline to Week 20 on Leptin Therapy | Baseline to Week 20 (On leptin) | 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. |
Countries
United States
Participant flow
Recruitment details
Patients with T1DM between the 18 and 50 years of age and with a BMI less than 27 kg/m2 and an HbA1c of 7.0-10.0% (53-86 mmol/mol) were eligible for the study.
Participants by arm
| Arm | Count |
|---|---|
| Week 0 (Baseline) After a 4-week lead-in period, baseline evaluation was conducted at week 0. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Week 0 (Baseline) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 33 years STANDARD_DEVIATION 10 |
| HbA1c | 7.6 % of Hemoglobin STANDARD_DEVIATION 0.4 |
| Insulin dose | 45.9 Units/day STANDARD_DEVIATION 11.5 |
| Leptin | 23 ng/mL |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 3 Participants |
| Weight | 70.7 kg STANDARD_DEVIATION 5.9 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 1 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
HbA1c
Change in Hba1c after 12 weeks on Leptin Therapy compared to Baseline value
Time frame: Baseline and 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Leptin Therapy Week 12 | HbA1c | -0.19 % of hemoglobin |
p-value: 0.14Mixed Models Analysis
Secondary
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.
Time frame: Baseline to Week 20 (On leptin)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Leptin Therapy Week 12 | Change in HbA1c From Baseline to Week 20 on Leptin Therapy | -0.04 % of Hemoglobin |
p-value: 0.75Mixed Models Analysis
Secondary
Insulin Dose
Change in Insulin dose after 12 weeks on Leptin Therapy compared to Baseline value
Time frame: Baseline to 12 weeks
Population: One subject withdrew after 12 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Leptin Therapy Week 12 | Insulin Dose | -5.84 units/day |
p-value: 0.009Mixed Models Analysis
Secondary
Weight
Change in Body Weight after 12 weeks on Leptin Therapy compared to Baseline value
Time frame: Baseline to 12 weeks
Population: One subject withdrew after 12 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Leptin Therapy Week 12 | Weight | -2.60 kg |
p-value: 0.01Mixed Models Analysis