Inducing Remission in Type 1 Diabetes With Alefacept

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to test whether a drug called alefacept will slow or halt destruction of the beta cells in the pancreas. If the destruction of the beta cells is stopped, the patients might be able to produce insulin on their own longer, which could stop or slow the progression of their type 1 diabetes. This is a multi-center prospective, placebo-controlled, double-blind and randomized trial to investigate the ability of alefacept to protect residual beta cells from ongoing autoimmune destruction in adolescents and young adults with newly diagnosed Type 1 Diabetes Mellitus (T1DM).

Detailed Description
-----------------
T1DM is an autoimmune disease that can emerge suddenly, causing dependence on insulin for life. This means that the immune system (the part of your body that helps fight infections) mistakenly attacks the cells in the pancreas that produce insulin (beta cells). As beta cells are destroyed, one's ability to produce insulin is decreased. Insulin helps keep blood glucose (sugar) levels normal. For a period right after diagnosis, the pancreas is still able to make small amounts of insulin. Individuals with diabetes who have the ability to produce some of their own insulin may be able to achieve better blood sugar control than people who produce no insulin at all. Based on previous research, doctors think that giving medicines to affect the immune system soon after diagnosis may stop, delay, or decrease the destruction of beta cells, resulting in better glucose control. This can help prevent secondary complications of diabetes down the road. Research has improved the outlook for T1DM over the last decade. Doctors are investigating, for example, how to save insulin-producing cells and extend the honeymoon period as long as possible. Despite progress towards understanding the science behind T1DM, there remains a significant need to investigate alternative approaches to this disease in order to bring about long-term remission. For this reason, scientists are working hard to develop new treatments that can be given soon after diagnosis to preserve the remaining beta cells. Currently there is no cure for T1DM; however, with new investigational medications and innovative clinical research studies, such as T1DAL, a new approach towards managing T1DM may be on the horizon. Enrollees will receive weekly intramuscular injections of alefacept or placebo for two 12 week periods, with a 12-week pause between treatment intervals. This schedule or drug dosing may be altered due to the needs of the subject or at the discretion of the physician investigator.

Official Title
-----------------
Inducing Remission in New Onset Type 1 Diabetes Mellitus With Alefacept (Amevive®)

Conditions
-----------------
New-onset Type 1 Diabetes Mellitus

Intervention / Treatment
-----------------
* Biological: Alefacept
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Recent diagnosis (within 100 days of enrollment) of T1DM Positive for at least one diabetes autoantibody (Glutamate decarboxylase [GAD-65GAD65], IA2, ZnT8, ICA and Insulin, if obtained within 10 days of the onset of exogenous insulin therapy) Peak stimulated C-peptide level > 0.2 pmol/mL following a mixed-meal tolerance test (MMTT) Willingness to provide written informed consent (either the subject or the subject's legally authorized representative). Exclusion Criteria: Severe reaction or anaphylaxis to human monoclonal antibodies History of malignancy or significant cardiovascular disease (including history of myocardial infarction, angina, use of anti-anginal medicines (e.g., nitroglycerin), or abnormal stress test) History of recent or ongoing uncontrolled bacterial, viral, fungal, or other opportunistic infections Evidence of infection with hepatitis B virus (HBV) as defined by hepatitis B surface antigen, HBsAg; hepatitis C virus (HCV) defined by anti-HCV antibodies; human immunodeficiency virus (HIV); or toxoplasmosis Positive tuberculin skin test (PPD) Clinically active infection with Epstein-Barr virus (EBV)-EBV viral load ≥ 10,000 copies per 10^6 PBMCs; cytomegalovirus (CMV) -CMV viral load ≥10,000 copies per mL whole blood; or tuberculosis (TB) Diagnosis of liver disease or hepatic enzymes, as defined by ALT and/or AST ≥ 2 times the upper limit of normal Prior or current treatment that is known to cause a significant, ongoing change in the course of T1DM or immunologic status, including high-dose inhaled, extensive topical or systemic glucocorticoids Current or prior (within the last 30 days) use of metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or amylin Current use of any medication known to influence glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, thiazide, or other potassium-depleting diuretics, β-adrenergic blockers, niacin) Any of the following hematologic abnormalities, confirmed by repeat tests at least 1 week apart: White blood count <4000/μL or >14,000/μL; CD4+ count below the lower limit of normal; Platelet count <150,000 /μL; or Hemoglobin <10 g/dL. Females who are pregnant, lactating, or planning on pregnancy during the 2-year study period History of bone marrow transplantation, or autoimmune disease associated with lymphopenia Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial Prior participation in a clinical trial that could potentially affect T1DM or immunologic status Receipt of a live vaccine (e.g., varicella, measles, mumps, rubella, cold-attenuated intranasal influenza vaccine, bacillus Calmette-Guérin, and smallpox) in the 6 weeks before enrollment Participation in an investigational clinical trial within the last six weeks.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alefacept<br>Subjects in this group receive weekly intramuscular injections of alefacept (15 mg) for 2 cycles of 12 weeks each, separated by a 12 week pause in treatment. | Biological: Alefacept<br>* Weekly intramuscular injections of alefacept (15 mg) for 2 cycles of 12 weeks each, separated by a 12 week pause in treatment.<br>* Other names: Amevive®;|
| Placebo Comparator: Placebo<br>Subjects in this group received weekly intramuscular injections of a placebo saline solution of equal volume to the alefacept group for 2 cycles of 12 weeks each, separated by a 12 week pause in treatment. | Drug: Placebo<br>* Weekly intramuscular injections of a placebo saline solution of equal volume to the alefacept group for 2 cycles of 12 weeks each, separated by a 12 week pause in treatment.<br>* Other names: Inactive drug (pharmacologically);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) | C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy primary endpoint. | Baseline (pre-treatment initiation), Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) | C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy primary endpoint. | Baseline (Pre-treatment initiation), Week 52, and Week 104 | 
| 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) | C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy primary endpoint. | Baseline (Pre-treatment initiation), Week 52, and Week 104 | 
| Insulin Use in Units Per Kilogram Body Weight Per Day | The need to use insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity. | Baseline (Pre-treatment initiation), Week 52, and Week 104 | 
| Major Hypoglycemic Events Occurring From Randomization | Major hypoglycemic events are defined as a glucose concentration <55 mg/dL (grades 2-5, NCI-CTCAE version 3.0), or clinically: involving seizure(s) or involving loss of consciousness (coma), or requiring assistance from another individual in order to recover. | Baseline to Week 52 and Week 52 to Week 104 | 
| Hemoglobin A1c | Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c level of 5.6% or less is considered normal. HbA1c levels of 6.5% or higher is typical for individuals with Type 1 Diabetes Mellitus (T1DM). The closer HbA1c levels are to normal, the better controlled the disease is. | Baseline (Pre-treatment initiation), Week 52, and Week 104 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
New-onset Type 1 Diabetes Mellitus, New-onset T1DM, New-onset T1D, Alefacept, Amevive®