Autoimmunity-blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes

Phase II Multiple-Dose Treatment of New Onset Type 1 Diabetes Mellitus With Anti-CD3 mAb

Sponsors

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator: Immune Tolerance Network (ITN)

Source National Institute of Allergy and Infectious Diseases (NIAID)
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.

Overall Status Completed
Start Date September 2005
Completion Date March 2011
Primary Completion Date March 2011
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Change in Mean C-peptide Area Under the Curve (AUC) Response to a Mixed Meal Tolerance Test (MMTT) Baseline (Pre-treatment), Month 24
Secondary Outcome
Measure Time Frame
Change in HbA1c Baseline (Pre-treatment), Month 24
Change in Average Total Insulin Dose Per Body Weight Baseline (Pre-treatment), Month 24
Enrollment 83
Condition
Intervention

Intervention Type: Biological

Intervention Name: Anti-CD3 mAb

Description: Daily 14-day dose escalation course at study entry, with possible second course after 12-month interval

Arm Group Label: Anti-CD3 mAb Plus Diabetes Standard of Care Treatment

Intervention Type: Other

Intervention Name: Diabetes Standard of Care Treatment

Description: Receipt of intensive diabetes standard of care treatment/management under the care of a physician: dietary counseling, insulin dosing and multiple consultations during the course of the trial with the clinical diabetes management team.

Intervention Type: Dietary Supplement

Intervention Name: Iron supplementation

Description: Immediately following randomization, all participants regardless of arm allocation begin iron supplementation with either ferrous sulfate or multivitamin with iron.

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

Gender: All

Minimum Age: 8 Years

Maximum Age: 30 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Kevan Herold, MD Principal Investigator Yale University
Location
Facility:
The Diabetes Center at UCSF | San Francisco, California, 94143, United States
Barbara Davis Center for Childhood Diabetes | Denver, Colorado, 80262, United States
Yale University | New Haven, Connecticut, 06520, United States
Medical College of Georgia | Augusta, Georgia, 30912, United States
Dept. of Medicine, Division of Endocrinology and the Naomi Berrie Diabetes Center/Columbia University | New York, New York, 10032, United States
Benaroya Research Institute | Seattle, Washington, 98108, United States
Pacific Northwest Research Institute/University of Washington | Seattle, Washington, 98122, United States
Location Countries

United States

Verification Date

April 2017

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Anti-CD3 mAb Plus Diabetes Standard of Care Treatment

Type: Experimental

Description: Subjects receive 1.) a 14-day course of anti-CD3 monoclonal antibody (mAb) intravenously (IV) comprised of daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 days of 826 µg/m2 [Cycle 1] and, when eligible per protocol, receipt of a second 14-day course after a 12-month interval (at month 13)[Cycle 2]. Note: Prior to May 2007, the course of IV daily doses of anti-CD3 mAb were: 57 µg/m2, 115 µg/m2, 230 µg/m2, 460 µg/m2, and 10 days of 919 µg/m2 and, when eligible per protocol, a second course after a 12-month interval (at month 13). 2.) and intensive diabetes standard of care treatment/management under the care of a physician: dietary counseling, insulin dosing and multiple consultations during the course of the trial with the clinical diabetes management team. Iron supplementation initiated status post treatment randomization.

Label: Diabetes Standard of Care Treatment

Type: Active Comparator

Description: Subjects receive intensive diabetes standard of care treatment/management under the care of a physician: dietary counseling, insulin dosing and multiple consultations during the course of the trial with the clinical diabetes management team. Iron supplementation initiated status post treatment randomization.

Acronym AbATE
Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Single (Outcomes Assessor)

Masking Description: The staff at Northwest Lipid Research Laboratory were masked to the treatment assignment since they performed the mixed-meal tolerance test (MMTT) and the HgA1C assays. All study staff including the PI were masked to the results of the MMTT. They were notified of a detectable or undetectable fasting C-peptide result to assess for continuation to the next treatment cycle.

Source: ClinicalTrials.gov