Clinical trial NCT00129259: Autoimmunity-blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes
Official title: Phase II Multiple-Dose Treatment of New Onset Type 1 Diabetes Mellitus With Anti-CD3 mAb
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: T1D
type 1 diabetes
type 1 diabetes mellitus
juvenile diabetes
autoimmune diabetes
autoimmune
anti-CD3 mAb
mAb hOKT3g1(Ala-Ala)
teplizumab
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2005-08-11
Enrollment: 83
Sex: ALL
Minimum age (years): 8
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Anti-CD3 monoclonal antibody (a.k.a. hOKT3gamma1 \[Ala-Ala\],teplizumab, MGA031) is a humanized antibody that is commonly used to prevent organ rejection. The purpose of this study is determine whether anti-CD3 mAb treatment can halt the progression of newly diagnosed type 1 diabetes.

Detailed description: Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks insulin-producing beta cells in the pancreas. Without these cells, the body cannot maintain proper blood glucose levels in response to daily activities, such as eating or exercise. Generally, at the time of type 1 diabetes diagnosis, 60% to 85% of the diabetic person's beta cells have already been destroyed. However, between 15% and 40% of these cells remain and are able to produce insulin. Treatment that slows the destruction of additional beta cells may be able to decrease a patient's reliance on insulin and improve their quality of life.

Anti-CD3 mAb is genetically engineered and directed against the CD3 antigen on T cells; this antibody selectively attacks the immune cells responsible for beta cell destruction. In a small exploratory clinical trial, patients with newly diagnosed type 1 diabetes who received a single, 2-week treatment with anti-CD3 mAb had preserved beta cell function and significantly lower insulin requirements than untreated patients for up to two years after therapy. This study will investigate whether a second course of anti-CD3 mAb administered one year after the first administration is able to prolong or improve the effects of the biologic in people who have recently diagnosed type 1 diabetes mellitus.

Participants will be randomly assigned to one of two groups. The Experimental Group will receive anti-CD3 mAb treatment plus Diabetes Standard of Care Treatment; the Active Comparator Group will receive Diabetes Standard of Care Treatment. The Experimental Group will be treated with the antibody for the first 14 days of the study and again one year later. These participants will be admitted to the hospital for the first 5 days of a treatment cycle. Participants who live within 1 hour of the hospital may receive the remainder of a treatment cycle as an outpatient, but those who live farther away will be hospitalized for 14 days. For the first treatment cycle, there will be study visits on the 3 consecutive days after the treatment cycle and at Months 1, 2, 3, 6, 9, and 12. For the second treatment cycle, there will be study visits on the 3 consecutive days after the treatment cycle and at Months 13, 16, 19, 21, and 24.The Active Comparator Group will have 12 study visits over two years.

At study entry, all participants will receive daily iron supplementation, either as ferrous sulfate or a multivitamin with iron. Participants will be followed for up to 2 years to assess their overall diabetes health and to capture laboratory measures of beta cell and immune system function. Medication history and adverse event assessment will occur at all visits. A physical exam, vital signs measurement, and blood collection will occur at most visits. Medical history and urine collection will occur at selected visits.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of type 1 diabetes (according to American Diabetes Association \[ADA\] criteria) within the 8 weeks prior to study entry
* Weigh at least 25 kg (55 lbs)
* Insulin autoantibodies assessed within 10 days of any insulin use OR anti-glutamic acid decarboxylase (GAD) autoantibodies OR anti-ICA512/IA-2 autoantibodies
* Subjects or guardian(s) willing to provide informed consent

Exclusion Criteria:

* Prior participation in a clinical trial that could potentially affect diabetes condition or immunologic status
* Participation in another investigational clinical trial within the 6 weeks prior to study entry
* Pregnancy or breastfeeding

Primary outcomes:
measure: Change in Mean C-peptide Area Under the Curve (AUC) Response to a Mixed Meal Tolerance Test (MMTT)
timeFrame: Baseline (Pre-treatment), Month 24
Secondary outcomes:
measure: Change in HbA1c
timeFrame: Baseline (Pre-treatment), Month 24
measure: Change in Average Total Insulin Dose Per Body Weight
timeFrame: Baseline (Pre-treatment), Month 24
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: The Diabetes Center at UCSF
state: California
city: Denver
country: United States
facility: Barbara Davis Center for Childhood Diabetes
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: New York
country: United States
facility: Dept. of Medicine, Division of Endocrinology and the Naomi Berrie Diabetes Center/Columbia University
state: New York
city: Seattle
country: United States
facility: Benaroya Research Institute
state: Washington
city: Seattle
country: United States
facility: Pacific Northwest Research Institute/University of Washington
state: Washington
Study officials:
affiliation: Yale University
name: Kevan Herold, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005 Jun;54(6):1763-9. doi: 10.2337/diabetes.54.6.1763.
citation: Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002 May 30;346(22):1692-8. doi: 10.1056/NEJMoa012864.
citation: Herold KC, Gitelman SE, Ehlers MR, Gottlieb PA, Greenbaum CJ, Hagopian W, Boyle KD, Keyes-Elstein L, Aggarwal S, Phippard D, Sayre PH, McNamara J, Bluestone JA; AbATE Study Team. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes. 2013 Nov;62(11):3766-74. doi: 10.2337/db13-0345. Epub 2013 Jul 8.
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.
citation: Sherr JL, Ghazi T, Wurtz A, Rink L, Herold KC. Characterization of residual beta cell function in long-standing type 1 diabetes. Diabetes Metab Res Rev. 2014 Feb;30(2):154-62. doi: 10.1002/dmrr.2478.