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

Study Overview
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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.

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.

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

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Biological: Anti-CD3 mAb
* Other: Diabetes Standard of Care Treatment
* Dietary Supplement: Iron supplementation


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-CD3 mAb Plus Diabetes Standard of Care Treatment<br>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. | Biological: Anti-CD3 mAb<br>* Daily 14-day dose escalation course at study entry, with possible second course after 12-month interval<br>* Other names: MGA031;Other: Diabetes Standard of Care Treatment<br>* 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.<br>Dietary Supplement: Iron supplementation<br>* Immediately following randomization, all participants regardless of arm allocation begin iron supplementation with either ferrous sulfate or multivitamin with iron.<br>* Other names: Irospan;|
| Active Comparator: Diabetes Standard of Care Treatment<br>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. | Other: Diabetes Standard of Care Treatment<br>* 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.<br>Dietary Supplement: Iron supplementation<br>* Immediately following randomization, all participants regardless of arm allocation begin iron supplementation with either ferrous sulfate or multivitamin with iron.<br>* Other names: Irospan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean C-peptide Area Under the Curve (AUC) Response to a Mixed Meal Tolerance Test (MMTT) | C-peptide AUC is computed using the trapezoidal rule and dividing by the interval of time from the 4 hour Mixed Meal Tolerance Test (MMTT) where assessments are taken every 30 minutes after initial assessments 15 minutes apart. A higher C-peptide AUC is desirable as detectable C-peptide is a marker for the ability of the pancreas to produce insulin in response to a MMTT. The baseline data was used to adjust for the C-peptide AUC primary endpoint at 24 months. Missing month 24 C-peptide results are imputed using a conservative scenario. | Baseline (Pre-treatment), Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Glycosylated hemoglobin (HbA1c) is a measure of the average plasma glucose concentration over prolonged periods of time and measures the level of optimal management of underlying disease. (Normal :< 5.7%; pre-diabetes: 5.7% -6.4%; diabetes: 6.5% or higher).A decline in HbA1c from baseline to month 24 signifies an improvement in diabetic control. The goal of treatment: to maintain the HgA1c level as close to normal as possible without frequent occurrence of hypoglycemia. | Baseline (Pre-treatment), Month 24 | 
| Change in Average Total Insulin Dose Per Body Weight | This measure is computed using the average amount of exogenous insulin taken per day for the 3 days prior to the visit. The average insulin use is divided by the subject's weight in kilograms (kg). The need for lower dose(s) of prescribed exogenous insulin while maintaining optimal control of a subject's diabetes reflects improved management of the underlying disease. | Baseline (Pre-treatment), Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T1D, type 1 diabetes, type 1 diabetes mellitus, juvenile diabetes, autoimmune diabetes, autoimmune, anti-CD3 mAb, mAb hOKT3g1(Ala-Ala), teplizumab