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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

83 participants

Study Classification

INTERVENTIONAL

Study Start Date

2005-09-30

Study Completion Date

2011-03-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Diabetes Mellitus, Type 1

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

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.

Study Groups

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Anti-CD3 mAb Plus Diabetes Standard of Care Treatment

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.

Group Type EXPERIMENTAL

Anti-CD3 mAb

Intervention Type BIOLOGICAL

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

Diabetes Standard of Care Treatment

Intervention Type OTHER

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.

Iron supplementation

Intervention Type DIETARY_SUPPLEMENT

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

Diabetes Standard of Care Treatment

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.

Group Type ACTIVE_COMPARATOR

Diabetes Standard of Care Treatment

Intervention Type OTHER

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.

Iron supplementation

Intervention Type DIETARY_SUPPLEMENT

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

Interventions

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Anti-CD3 mAb

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

Intervention Type BIOLOGICAL

Diabetes Standard of Care Treatment

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 OTHER

Iron supplementation

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

Intervention Type DIETARY_SUPPLEMENT

Other Intervention Names

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mAb hOKT3gamma1(Ala-Ala) teplizumab MGA031 MVI Fer-In-Sol Feosol Fer-Iron Ferolix FeroSul Irospan

Eligibility Criteria

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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

Minimum Eligible Age

8 Years

Maximum Eligible Age

30 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Kevan Herold, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

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The Diabetes Center at UCSF

San Francisco, California, United States

Site Status

Barbara Davis Center for Childhood Diabetes

Denver, Colorado, United States

Site Status

Yale University

New Haven, Connecticut, United States

Site Status

Medical College of Georgia

Augusta, Georgia, United States

Site Status

Dept. of Medicine, Division of Endocrinology and the Naomi Berrie Diabetes Center/Columbia University

New York, New York, United States

Site Status

Benaroya Research Institute

Seattle, Washington, United States

Site Status

Pacific Northwest Research Institute/University of Washington

Seattle, Washington, United States

Site Status

Countries

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United States

References

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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.

Reference Type BACKGROUND

PMID: 15919798 (View on PubMed)

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.

Reference Type BACKGROUND

PMID: 12037148 (View on PubMed)

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.

Reference Type RESULT

PMID: 23835333 (View on PubMed)

Ajmal N, Bogart MC, Khan P, Max-Harry IM, Healy AM, Nunemaker CS. Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation. J Diabetes Res. 2024 Dec 20;2024:5151171. doi: 10.1155/jdr/5151171. eCollection 2024.

Reference Type DERIVED

PMID: 39735417 (View on PubMed)

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.

Reference Type DERIVED

PMID: 27208317 (View on PubMed)

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.

Reference Type DERIVED

PMID: 24115337 (View on PubMed)

Study Documents

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Document Type: Individual Participant Data Set

TrialShare is the Immune Tolerance Network (ITN) clinical trials research portal that makes data from their clinical trials publicly available without charge.

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Document Type: Study overview and synopsis, -data and reports, -schedule of assessments, -participant flow diagram, -abstracts and manuscripts

TrialShare is the Immune Tolerance Network (ITN) clinical trials research portal that makes data from their clinical trials publicly available without charge.

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