Atorvastatin in New Onset Type 1 Diabetes Mellitus (T1DM)

Study Overview
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Brief Summary
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The goal of this application is to evaluate the safety and efficacy of atorvastatin as a potential treatment to preserve beta cell function in children and young adults with newly diagnosed type 1 diabetes (T1DM).

Detailed Description
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Type 1 diabetes is an autoimmune disease that is characterized by destruction of the insulin-producing beta cells of the pancreas. T1DM therapy requires insulin administration, either by multiple daily injections or by insulin pump. However, in many patients, blood sugar control remains suboptimal and complications develop that shorten life expectancy and severely impact quality of life. At the time of diagnosis, most patients still have significant residual beta cell function. Previous research has shown that weakening the immune system's attack on the pancreatic beta cells may help to preserve or potentially increase insulin production. Preliminary studies have shown that members of the statin family of medications, including atorvastatin (Lipitor®), preserve beta cell function in a mouse model of type 1 diabetes. These finding suggest that use of atorvastatin in combination with insulin therapy may delay and potentially reverse the destruction of beta cells in patients who have recently developed type 1 diabetes. Atorvastatin (Lipitor®) is approved for use in adults and children (>10 years of age) who have elevated blood cholesterol levels. This study will examine whether atorvastatin (Lipitor®) may also help the body preserve insulin production in patients with newly diagnosed (within 8 weeks) type 1 diabetes. Patients will be randomly assigned to take either atorvastatin (Lipitor®) or placebo. Two out of every 3 patients will receive atorvastatin and 1 out of 3 will get placebo. As this is a double-blinded study, neither the care team nor the patient will know if they are actually taking atorvastatin (Lipitor®). Patients who have given consent to participate in the study and pass the required screening tests will take the assigned treatment every day for 12 months. All patients will begin taking 10 mg once daily, the recommended starting dose. After 4 weeks, the dose will be increased to 20 mg. In addition to a high standard of diabetes care and the medication, patients will have blood tests during 7 visits over an 18 month period.

Official Title
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Phase II, Double Blind, Randomized, Placebo-controlled Trial to Evaluate the Safety and Efficacy of Atorvastatin in Subjects With Newly Diagnosed Type 1 Diabetes Mellitus.

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Atorvastatin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals 10-19 years of age (Tanner Stage II or greater), The presence of one or more serum antibodies to islet cell proteins (anti- glutamic acid decarboxylase [GAD], islet antigen 2 or insulin autoantibodies) as assessed in standard practice, Diagnosis of T1DM within the 8 weeks prior to study entry Peak stimulated C-peptide level >0.2pmol/mL following mixed meal tolerance test (MMTT) performed at least 3 weeks after diagnosis, Females of reproductive potential must not plan on conceiving a child during the treatment program, and agree to use a medically accepted form of contraception Exclusion Criteria: Subjects currently receiving cyclosporine, fibric acid derivatives, niacin (nicotinic acid), erythromycin, clarythromycin, nefazodone, itraconazole, ketoconazole or protease inhibitors, Pregnancy or breast-feeding, Clinical AIDS, AIDS related syndrome (ARS) or known positive HIV serology, Subjects treated with immunosuppressive therapy in the past 12 months, Subjects receiving glucocorticoid therapy or therapy other than insulin that is likely to affect glucose homeostasis (such as sulfonylureas, thiazolidinediones, metformin or amylin), Subjects with other autoimmune diseases, except autoimmune thyroid disease, Subjects with any illness that might complicate diabetes management or preclude treatment with atorvastatin, Transplant recipients, Evidence of liver dysfunction or myopathy

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atorvastatin<br>Two out of every three patients will receive atorvastatin. | Drug: Atorvastatin<br>* Pill, initially at 10 mg, then after 4 weeks, 20 mg Once daily for a total of 12 months<br>* Other names: Lipitor;|
| Placebo Comparator: Placebo<br>One out of three subjects will receive a placebo. | Other: Placebo<br>* One out of three subjects will receive a placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of a Daily Dose of Atorvastatin to Maintain Islet Cell Function as Measured by a 4-hour C-peptide Area Under Curve (AUC) in Patients With Newly Diagnosed Type 1 Diabetes Mellitus | The change in C-peptide measurements collected over a 4 hour period (0, 30, 60, 90, 120, 150, 180, 210 and 240 minutes) after a Mixed Meal Tolerance Test at baseline vs 12 months post-treatment were calculated. The area under the curve for these combined measurements is calculated and the unit of measure is nanogram x minutes / mL. Efficacy (success) is defined by < 7.5% reduction in AUC for 4-hr MMTT. | Baseline vs 12-month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % Subjects Without Change in 2-hour C-peptide AUC in Response to the MMTT at Baseline vs. 12 Months | The C-peptide AUC measurements are collected over a 2 hour period (with 30 minute intervals) after a Mixed Meal Tolerance Test. The area under the curve from these combined measurements (from 0 to 120 or 0 to 240 minutes) is calculated and the unit of measure is nanogram*minutes/ml. The change in C-peptide AUC in response to a 2 hour MMTT at baseline vs 12 months were calculated, and efficacy (success) is defined as < 7.5% reduction. | Baseline vs 12 months | 
| Mean Daily Insulin Dose Per kg Body Weight for 7 Days | Mean daily insulin dose per kg body weight for the 1 week preceding each scheduled study visit. | Visit 1, 2, 3, 4, 5, 6, 7 | 
| Levels of HbA1c at Months 3, 6, 9, 12 and 18 |  | 3, 6, 9, 12, and 18 months | 
| Blood Glucose Control (Number of Participants With Hypoglycemia) | Blood glucose control as determined from home glucose meter downloads for the 1 week preceding the visit. The number of subjects with hypoglycemic episodes requiring treatment (BG < 70 mg/dl) | Baseline, Month 12, Month 18 | 
| Number of Episodes of Hypoglycemia Requiring Any Treatment | number of episodes of hypoglycemia requiring any treatment, defined by the need for treatment with glucagon or third party intervention. | Baseline, Month 12, Month 18 | 
| Study Drug Compliance Rate Overall | Compliance is defined as >=80% expected dosage consumed during the visit period. | 12 months treatment | 
| HDL and LDL Cholesterol Levels in Participants Stratified by the Preservation of Islet Cell Function | Relationship between atorvastatin's effect on HDL and LDL cholesterol and the preservation of islet cell function. Islet cell preservation defined as: <7.5% Reduction in C-Pep | Baseline, Week 1, Month 3, Month 6, Month 9, Month 12, | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type I Diabetes (T1DM), Atorvastatin (Lipitor), Insulin, Pancreas, Beta Cells