The Protégé Study - Clinical Trial of MGA031 in Children and Adults With Recent-Onset Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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The primary purpose of this protocol is to assess the efficacy, tolerability, and safety of MGA031 when administered according to 3 different MGA031 dosing regimens in children and adults with recent-onset (diagnosis within past 12 weeks) type 1 diabetes mellitus. All regimens will be administered as an addition to insulin and other standard of care treatments. Efficacy will be defined primarily by the capacity of MGA031 to markedly reduce typical insulin requirements while maintaining relatively normal blood sugar levels. Other studies involving the study drug use the name hOKT3γ1 (Ala-Ala). MGA031, a humanized monoclonal antibody, is the name used for hOKT3γ1 (Ala-Ala) that is produced by MacroGenics, Inc. The United States Adopted Name (USAN) for MGA031 is teplizumab.

Detailed Description
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The Protégé Study - A Multinational Clinical Trial of MGA031 for Preserving the Capability to Produce Insulin, Reducing Insulin Usage and Improving Blood Sugar Levels in Children and Adults With Recent-Onset Type 1 Diabetes Mellitus

Official Title
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A Phase 2/3, Randomized, Double-Blind, Multicenter, Multinational, 4-Arm, Controlled, Dose-Ranging Study to Evaluate Efficacy and Safety of MGA031, a Humanized, FcR Non-Binding, Anti-CD3 Monoclonal Antibody, in Children and Adults With Recent-Onset Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Biological: Teplizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following criteria: Enrollment (Segment #1) or randomization (Segment #2) on Study Day 0 within 12 weeks of first visit to any physician for symptoms or signs of diabetes. Study Day 0 is the first day of study drug dosing. Diagnosis of type 1 diabetes mellitus, according to the American Diabetes Association (ADA) criteria Requirement for injected insulin therapy Have a detectable fasting or stimulated C-peptide level (above the lower limit of detection of the assay) One positive result on testing for any of the following antibodies: islet-cell autoantibodies (ICA512/IA-2), glutamic acid decarboxylase autoantibodies, or insulin autoantibodies (if present during first 2 weeks, but not beyond 2 weeks, of insulin treatment) Male or female Subject must be in one of the following age groups: Age 18-35 years Age 12-17 years pending approval by Data Monitoring Committee Age 8-11 years pending approval by Data Monitoring Committee Body weight ≥ 36 kg Exclusion Criteria: Subjects must have none of the following: Prior administration of a monoclonal antibody -- within the 1 year before enrollment or randomization at Study Day 0 -- that could potentially prevent or confound a therapeutic response to MGA031 Participation in any type of therapeutic drug or vaccine clinical trial within the 12 weeks before enrollment or randomization Any medical condition that, in the opinion of the investigator, would interfere with safe completion of the trial Pregnant or lactating females Prior murine OKT®3 treatment at any time before enrollment or randomization Current or planned therapy with exenatide or any other agents that stimulate pancreatic beta cell regeneration or insulin secretion Current or planned therapy with inhaled insulin Uncompensated heart failure, fluid overload, myocardial infarction or evidence of ischemic heart disease, or other serious cardiac disease within the 12 weeks before enrollment or randomization History of epilepsy, cancer, cystic fibrosis, sickle cell anemia, neuropathy, peripheral vascular disease or cerebrovascular disease Newly diagnosed hypothyroidism (not currently being treated but which, in the opinion of the investigator, should be treated) or active Graves' disease Eczema, asthma or severe atopic disease requiring treatment within the 12 weeks before enrollment or randomization Evidence of active infection, such as fever ≥ 38.0 degrees Celsius (100.5 degrees Fahrenheit) Known or suspected infection with human immunodeficiency virus (HIV) Evidence of active hepatitis B (HBV) or hepatitis C virus (HCV) Evidence of active or latent tuberculosis Vaccination with a live virus within the 8 weeks before enrollment or randomization or planned live virus vaccination continuing through week 52 of the study. Vaccination with an antigen or killed organism must not be given within 8 weeks before or planned within 8 weeks after each dosing cycle. Any infectious mononucleosis-like illness within the 6 months before enrollment or randomization Serologic and clinical evidence of acute infection with Epstein-Barr virus (EBV) Serologic evidence of acute infection with cytomegalovirus (CMV)

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 35 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: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-blind Herold Regimen<br>Full dose of teplizumab IV for 14 days, repeated at Week 26 | Biological: Teplizumab<br>* Daily IV dosing for 14 days, repeated at Week 26<br>* Other names: MGA031;|
| Experimental: Double-blind 33.3% Herold Regimen<br>One third full dose of teplizumab IV for 14 days, repeated at Week 26 | Biological: Teplizumab<br>* Daily IV dosing for 14 days, repeated at Week 26<br>* Other names: MGA031;|
| Experimental: Double-blind Curtailed Herold Regimen<br>Full dose of teplizumab IV for 6 days followed by placebo for 8 days, repeated at Week 26 | Biological: Teplizumab<br>* Daily IV dosing for 14 days, repeated at Week 26<br>* Other names: MGA031;|
| Placebo Comparator: Double-blind Placebo<br>Placebo IV dosing daily for 14 days repeated at Week 26 | Drug: Placebo<br>* Daily IV dosing for 14 days, repeated at Week 26<br>|
| Experimental: Open-label Herold Regimen<br>Full dose of teplizumab IV for 14 days, repeated at Week 26 | Biological: Teplizumab<br>* Daily IV dosing for 14 days, repeated at Week 26<br>* Other names: MGA031;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects in Segment 2 With Both a Total Daily Insulin Dose of Less Than 0.5 U/kg/Day and Hemoglobin A1c (HbA1c) Level of Less Than 6.5%. | This is a composite endpoint is based on the proportion of subjects who have both a total daily insulin dose <0.5 U/Kg/day and an HbAlc level 6.5% at 52 weeks after randomization. | 52 weeks after randomization | 
| Number of Subjects in Segment 1 With Both a Total Daily Insulin Dose of Less Than 0.5 U/kg/Day and Hemoglobin A1c (HbA1c) Level of Less Than 6.5%. | This is a composite endpoint based on the proportion of subjects who have both a total daily insulin dose <0.5 U/Kg/day and an HbAlc level 6.5% | 52 weeks after first dose | 
| Mean HbA1c Change From Baseline in Segment 2 | Comparison among study treatments of average change from baseline HbA1C. This endpoint will be assessed in a hierarchical manner only if the composite primary endpoint shows a statistically significant difference between arms | 52 weeks after randomization | 
| Mean HbA1c Change From Baseline in Segment 1 | The average change in HbA1c levels after dosing. | 52 weeks after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in C-peptide Area Under the Curve (AUC) in Segment 2 | Comparison among study treatments on the AUC of C-peptide secretory responses following a mixed meal eaten by the subject | 104 weeks after randomization | 
| Change From Baseline in C-peptide AUC in Segment 1 | AUC of C-peptide secretory responses following a mixed meal eaten by the subject | 104 weeks after first dose | 
| Number of Subjects in Segment 2 With Both a Total Daily Insulin Dose of Less Than 0.5 U/kg/Day and HbA1c Level of Less Than 6.5% | Comparison among study treatments of a composite endpoint based on the proportion of subjects who have both a total daily insulin dose <0.5 U/Kg/day and an HbAlc level 6.5%. | 104 weeks after randomization | 
| Number of Subjects in Segment 1 With Both a Total Daily Insulin Dose of Less Than 0.5 U/kg/Day and HbA1c Level of Less Than 6.5% | Comparison among study treatments of a composite endpoint based on the proportion of subjects who have both a total daily insulin dose <0.5 U/Kg/day and an HbAlc level 6.5%. | 104 weeks after first dose | 
| Number of Subjects in Segment 2 With Both a Total Daily Insulin Dose of Less Than 0.5 U/kg/Day and HbA1c Level of Less Than 7.0%. | Comparison among study treatments of a composite endpoint based on the proportion of subjects who have both a total daily insulin dose <0.5 U/Kg/day and an HbAlc level 7.0%. | at 52 weeks after randomization | 
| Number of Subjects in Segment 1 With Both a Total Daily Insulin Dose of Less Than 0.5 U/kg/Day and HbA1c Level of Less Than 7.0%. | Composite endpoint based on the proportion of subjects who have both a total daily insulin dose <0.5 U/Kg/day and an HbAlc level 7.0%. | 52 weeks after first dose | 
| Mean HbA1c Change From Baseline in Segment 2 | Comparison among study treatments of the average change from baseline in HbA1c. | at 104 weeks after randomization | 
| Mean HbA1c Change From Baseline in Segment 1 | Comparison among study treatments of the average change from baseline in HbA1c. | 104 weeks after first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, Double Blind, Parallel Group, Controlled Clinical Trial