Clinical trial NCT00965458: Inducing Remission in Type 1 Diabetes With Alefacept
Official title: Inducing Remission in New Onset Type 1 Diabetes Mellitus With Alefacept (Amevive®)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: New-onset Type 1 Diabetes Mellitus
Keywords: New-onset Type 1 Diabetes Mellitus
New-onset T1DM
New-onset T1D
Alefacept
Amevive®
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
name: Juvenile Diabetes Research Foundation
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2009-08-25
Enrollment: 49
Sex: ALL
Minimum age (years): 12
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

  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.

Primary outcomes:
measure: 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)
timeFrame: Baseline (pre-treatment initiation), Week 52
Secondary outcomes:
measure: 4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)
timeFrame: Baseline (Pre-treatment initiation), Week 52, and Week 104
measure: 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)
timeFrame: Baseline (Pre-treatment initiation), Week 52, and Week 104
measure: Insulin Use in Units Per Kilogram Body Weight Per Day
timeFrame: Baseline (Pre-treatment initiation), Week 52, and Week 104
measure: Major Hypoglycemic Events Occurring From Randomization
timeFrame: Baseline to Week 52 and Week 52 to Week 104
measure: Hemoglobin A1c
timeFrame: Baseline (Pre-treatment initiation), Week 52, and Week 104
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Aurora
country: United States
facility: Barbara Davis Center for Childhood Diabetes - University of Colorado
state: Colorado
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospital & Clinics
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Omaha
country: United States
facility: Creighton University
state: Nebraska
city: Durham
country: United States
facility: University of North Carolina
state: North Carolina
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute at Virginia Mason
state: Washington
Study officials:
affiliation: Indiana University
name: Mark R Rigby, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Herold KC. Restoring immune balance in type 1 diabetes. Lancet Diabetes Endocrinol. 2013 Dec;1(4):261-3. doi: 10.1016/S2213-8587(13)70123-2. Epub 2013 Sep 23. No abstract available.
citation: Rigby MR, DiMeglio LA, Rendell MS, Felner EI, Dostou JM, Gitelman SE, Patel CM, Griffin KJ, Tsalikian E, Gottlieb PA, Greenbaum CJ, Sherry NA, Moore WV, Monzavi R, Willi SM, Raskin P, Moran A, Russell WE, Pinckney A, Keyes-Elstein L, Howell M, Aggarwal S, Lim N, Phippard D, Nepom GT, McNamara J, Ehlers MR; T1DAL Study Team. Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol. 2013 Dec;1(4):284-94. doi: 10.1016/S2213-8587(13)70111-6. Epub 2013 Sep 23.
citation: Rigby MR, Harris KM, Pinckney A, DiMeglio LA, Rendell MS, Felner EI, Dostou JM, Gitelman SE, Griffin KJ, Tsalikian E, Gottlieb PA, Greenbaum CJ, Sherry NA, Moore WV, Monzavi R, Willi SM, Raskin P, Keyes-Elstein L, Long SA, Kanaparthi S, Lim N, Phippard D, Soppe CL, Fitzgibbon ML, McNamara J, Nepom GT, Ehlers MR. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest. 2015 Aug 3;125(8):3285-96. doi: 10.1172/JCI81722. Epub 2015 Jul 20.
citation: Boyle KD, Keyes-Elstein L, Ehlers MR, McNamara J, Rigby MR, Gitelman SE, Weiner LJ, Much KL, Herold KC. Two- and Four-Hour Tests Differ in Capture of C-Peptide Responses to a Mixed Meal in Type 1 Diabetes. Diabetes Care. 2016 Jun;39(6):e76-8. doi: 10.2337/dc15-2077. Epub 2016 Apr 13. No abstract available.