The primary objective of this trial is to determine whether alefacept will slow the progression of the autoimmune destruction of β cells and lead to the preservation of C-peptide secretion in T1DM. This trial will be conducted as a multi-center, prospective, double-blind, placebo-controlled, 66-patient, 2:1 randomized, phase II clinical trial for individuals with recent-onset T1DM aged 12-35 years. Participants will receive weekly intramuscular injections of alefacept (15 mg) or placebo for 12 weeks, followed by a 12-week pause before resuming another 12 weeks of dosing, for a total course of 24 weeks of alefacept or placebo. Prior to initiating the study in the pediatric age group (12-15 years of age), the study drug will be given to an initial safety cohort of adult participants, defined as age 16-35 years old. When the 10th participant in the adult cohort has completed visit 11, or 6 months after the first participant is enrolled, the safety data will be reviewed by the study team and Data Safety and Monitoring Board (DSMB). Enrollment will continue in the adult cohort during this first safety review. Children (ages 12-15) may only be enrolled after completion of a satisfactory safety review of the first cohort of 10 adult participants (16-35) who have completed 12 weeks of treatment. This will require an additional safety review (review 1b) if the initial safety review does not achieve this milestone.

Plan to Share IPD: Yes Plan Description: Participant level data access and additional relevant materials are available to the public in: 1.) the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts that also provides data analysis tools available to researchers; and 2.) TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal that makes data from the consortium's clinical trials publicly available.

instance of dataset

available with registration

T1DAL

National Institute of Allergy and Infectious Diseases (NIAID)

Biological: Alefacept Weekly intramuscular injections of alefacept (15 mg) for 2 cycles of 12 weeks each, separated by a 12 week pause in treatment. Other Name: Amevive® Drug: Placebo 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. Other Name: Inactive drug (pharmacologically)

registration required

New-onset Type 1 Diabetes Mellitus

Mark R Rigby, MD, PhD

Indiana University

Principal Investigator

Inducing Remission in Type 1 Diabetes With Alefacept

49

2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) [ Time Frame: Baseline (pre-treatment initiation), Week 52 ] 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.

4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) [ Time Frame: Baseline (Pre-treatment initiation), Week 52, and Week 104 ] 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. 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) [ Time Frame: Baseline (Pre-treatment initiation), Week 52, and Week 104 ] 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. Insulin Use in Units Per Kilogram Body Weight Per Day [ Time Frame: Baseline (Pre-treatment initiation), Week 52, and Week 104 ] 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. Major Hypoglycemic Events Occurring From Randomization [ Time Frame: Baseline to Week 52 and Week 52 to Week 104 ] 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. Hemoglobin A1c [ Time Frame: Baseline (Pre-treatment initiation), Week 52, and Week 104 ] 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.

NC

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.

2013-03-01

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

Experimental: Alefacept 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. Intervention: Biological: Alefacept Placebo Comparator: Placebo 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. Intervention: Drug: Placebo

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).

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.

Allocation: Randomized Intervention Model: Parallel Assignment Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Treatment

United States

2011-03-01

ITN TrialShare