Inducing Remission in Type 1 Diabetes With Alefacept (T1DAL)

• MMTT-stimulated peak and 4-hour C-peptide AUC [ Time Frame: weeks 52 and 104 ] [ Designated as safety issue: No ]
• MMTT-stimulated 2-hour C-peptide AUC assessed [ Time Frame: weeks 24, 52 and 104 ] [ Designated as safety issue: No ]
• Insulin use in units per kilogram body weight per day [ Time Frame: weeks 52 and 104 ] [ Designated as safety issue: No ]
• Major hypoglycemic events occurring from randomization [ Time Frame: weeks 52 and 104 ] [ Designated as safety issue: No ]
• HbA1C levels [ Time Frame: weeks 52 and 104 ] [ Designated as safety issue: No ]
• Rate of injection reactions; defined as fever, chills, headache, nausea, vomiting, and injection-site pain in participants receiving alefacept or placebo. [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]
• Rate of hypersensitivity reactions; defined as signs and symptoms of anaphylaxis, wheezing, dyspnea, urticaria, and hypotension in participants receiving alefacept or placebo. [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]
• Rate of evidence of infection with Epstein-Barr virus (EBV), Cytomegalovirus (CMV), or Tuberculosis (TB) in participants receiving alefacept or placebo. [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]
• Frequency and severity of all AEs in participants receiving alefacept or placebo [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]

• •Compared to baseline, change in C-peptide AUC from enrollment to AUC at 3, 6, 18 and 24 months. This change will be compared between subjects receiving alefacept and those receiving placebo. [ Time Frame: 3, 6, 18, 24mos ] [ Designated as safety issue: No ]
• Absolute C-peptide AUC at enrollment, compared between alefacept and placebo groups. [ Time Frame: 3, 6, 12, 18 and 24 months ] [ Designated as safety issue: No ]
• • Absolute peak C-peptide levels with MMTT at enrollment and 3, 6, 12, 18 and 24 months, comparing between alefacept and placebo groups. [ Time Frame: enrollment and 3, 6, 12, 18 and 24 months ] [ Designated as safety issue: No ]
• • Change from baseline and absolute insulin use from enrollment to 3, 6, 12, 18 and 24 months, compared between alefacept and placebo groups. [ Time Frame: enrollment, 3, 6, 12, 18 and 24 months ] [ Designated as safety issue: No ]
• • Change from baseline and absolute glycemic control (reflected by HgbA1C) from enrollment to 3, 6, 12, 18 and 24 months, compared between alefacept and placebo groups. [ Time Frame: enrollment, 3, 6, 12, 18 and 24 months ] [ Designated as safety issue: No ]
• • Change from baseline and absolute numbers of positive diabetes auto-antibodies from enrollment to 3, 6, 12, 18 and 24 months, compared between alefacept and placebo groups. [ Time Frame: enrollment, 3, 6, 12, 18 and 24 months ] [ Designated as safety issue: No ]

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 proposal is for a multi-center prospective, placebo-controlled, double-blind and randomized, controlled trial to investigate the ability of alefacept to protect residual beta cells in adolescents and young adults with newly diagnosed Type 1 diabetes mellitus from ongoing autoimmune destruction.

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease that can emerge suddenly causing dependence on insulin for life. This means that your 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, your ability to produce insulin is decreased. Insulin helps keep blood glucose (sugar) levels normal.

For a period right after diagnosis, your pancreas is still able to make small amounts of insulin. People 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.

Doctors are investigating how to save the insulin producing cells and extend the honeymoon period as long as possible. But research has dramatically improved the outlook for type 1 diabetes over the last decade.

Despite progress towards understanding the science behind T1DM, there still remains a significant need to investigate alternative approaches to type 1 diabetes in order to bring about long-term remission in this condition. For this reason, scientists are working hard to develop new treatments that can be given soon after diagnosis to preserve the remaining beta cells.

At the moment there is no cure. But with new investigational mediations and innovative clinical research studies, such as T1DAL, a new approach towards managing type 1 diabetes 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. This schedule or drug dosing may be altered due to the needs of the subject or at the discretion of the physician investigator.

• Drug: alefacept
  alefacept Intramuscular injection, 15mg weekly for 2 12-week courses (separated by a 12-week pause between)
  Other Name: Amevive
• Drug: placebo (saline)
  normal saline intramuscular injection, 15mg weekly for 2 12-week courses (separated by a 12-week pause between)

• Experimental: Treatment (alefacept)
  The dose of 15mg via the intramuscular route is the FDA-approved adult dose for psoriasis. In addition 15mg has been used in case series and case reports in children and adolescents successfully without obvious side effects. Dosing and/or schedule may be altered due to the needs of the subject or at the discretion of the physician investigator.
  Intervention: Drug: alefacept
• Placebo Comparator: Control
  IM injection of equal volume and appearance to treatment on the same schedule formulated and prepared by the Emory University Research Pharmacy.
  Intervention: Drug: placebo (saline)

Inclusion Criteria:

• Recent diagnosis of T1DM within 100 days of enrollment.
• 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 HBV (as defined by hepatitis B surface antigen, HBsAg), HCV (anti-HCV antibodies), HIV or toxoplasmosis.
• Positive tuberculin skin test (PPD).
• Clinically active infection with EBV, CMV, or tuberculosis; or EBV viral load ≥ 10,000 copies per 106 PBMCs or CMV viral load ≥10,000 copies per mL whole blood.
• 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:

  1. White blood count <4000/μL or >14,000/μL;
  2. CD4+ count below the lower limit of normal;
  3. Platelet count <150,000 /μL; or
  4. 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.