Trial of Otelixizumab for Adolescents and Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-2

Study Overview
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Brief Summary
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DEFEND-2 is a Phase 3 confirmatory study for the Phase 3 DEFEND-1 study. The study objective is to find out if an 8-day series of otelixizumab infusions leads to greater improvement in insulin secretion as compared with placebo. Insulin secretion will be assessed using mixed meal-stimulated C-peptide. Subjects will be assigned to receive either otelixizumab or placebo at a ratio of 2:1 (2/3 otelixizumab, 1/3 placebo). These study agents will be administered as an addition to insulin, diet, and other standard of care treatments.

Detailed Description
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The following visits are required: Screening Visits: 2 to 3 appointments will be conducted to determine eligibility. At 2 of these visits participants will drink a liquid meal and have blood tests done over the post-meal period. Participants will also be required to wear a continuous glucose monitor for a short period of time. Dosing Visits: 8 outpatient visits on consecutive days, each lasting about 2-4 hours. Follow-up Visits: weekly for the first month, then every 2 weeks for 3 months, followed by monthly visits through 1 year. There will be 3 visits in the second year. The total duration of the study is 2 years. Glucose test strips and glucose monitors will be provided to participants for the duration of the study. Frequent glycemic monitoring will occur through lab testing and blood glucose self-monitoring to help facilitate tight glycemic control in all subjects. Subjects will be asked to intermittently record their insulin doses using a telephone or web based system and continuous glucose monitoring will be performed every 6 months.

Official Title
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Durable-Response Therapy Evaluation For Early- or New-Onset Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Biological: Otelixizumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 12-17 Diagnosis of diabetes mellitus, consistent with ADA criteria No more than 90 days between diagnosis and administration of study compounds Requires insulin for type 1 diabetes mellitus, or has required insulin at some time between diagnosis and administration of study compounds. In Canada, has to be using insulin at the time of dosing. Stimulated C-peptide level greater than 0.20 nmol/L and less than or equal to 3.50 nmol/L Positive for one or more of the autoantibodies typically associated with T1DM: antibody to glutamic acid decarboxylase (anti-GAD); antibody to protein tyrosine phosphatase-like protein (anti-IA-2); zinc transporter autoantibodies (ZNT8); insulin autoantibodies (IAA). A subject who is positive for insulin autoantibodies (IAA) and negative for the other autoantibodies will only be eligible if the subject has used insulin for less than 7 days total. Exclusion Criteria: •Other, significant medical conditions based on the study doctor's evaluation

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: otelixizumab<br>otelixizumab | Biological: Otelixizumab<br>* infusion<br>* Other names: anti-CD3;|
| Placebo Comparator: placebo<br>placebo | Biological: Placebo<br>* Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide Area Under Curve (AUC) (Normalized for 120-minute Time Interval) at Month 12 | C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg per deciliter (mg/dL) and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the value at Month 12 from the Baseline value. | Baseline (Day 1) and Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months | C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg/dL and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value. | Baseline (Day 1) and Week 12, Month 6 | 
| Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg/dL and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value. | Baseline (Day 1) and Week 12, Month 6, 12, 18 | 
| Number of Participants With Responder Status | A participant was considered a responder when, at the given time point, the participant had: glycosylated hemoglobin (HbA1c) less than or equal to 6.5 percent and mean daily insulin use less than 0.5 international unit per kilogram per day (IU/kg/day) over 7 consecutive days during the 2 weeks preceding the visit. | Month 3, 6 and 12 | 
| Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Mean daily insulin use over 7 consecutive days during the 2 weeks preceding each key visit was calculated as the mean of the values of amount of insulin used per day on each of the 7 consecutive days. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value. | Baseline (Day 1) and Month 3, 6, 12 | 
| Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | HbA1c level was recorded at Baseline, Month 3, 6 and 12. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value. | Baseline (Day 1) and Month 3, 6, 12 | 
| Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 | Severe hypoglycemia was considered as an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was considered as an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration less than or equal to 70 mg/dL and it was collected in (1) eCRF using two forms - for single event and for mutiple events, and (2) the IVRS system. The numbers of participant-reported hypoglycemic events per participant of severe hypoglycemia and documented symptomatic hypoglycemia have been reported. | Baseline (Day 1) and Month 12 | 
| Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 | Severe hypoglycemia was considered as an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was considered as an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration less than or equal to 70 mg/dL and it was collected in (1) eCRF using two forms - for single event and for mutiple events, and (2) the IVRS system. The percentage of participant with incidence of severe hypoglycemia and documented symptomatic hypoglycemia have been reported. | Baseline (Day 1) and Month 12 | 
| Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months | O'Brien mean rank analyses was performed on a two-part composite of the Baseline-adjusted HbA1c level and the Baseline-adjusted mean total daily insulin use per kg body weight in the otelixizumab group compared with the placebo group at Months 6 and 12. Baseline adjustment was used to reduce the potential impact of imbalances in Baseline levels between treatment groups on the treatment comparisons at later time points. For the O'Brien mean rank analysis at a particular time point, adjusted HbA1c values (for both treatment groups together) and adjusted mean daily insulin use values was ranked from smallest to largest. For each participant, the HbA1c and insulin use ranks were added together, producing a composite rank. A treatment comparison test was then performed on the composite ranks. If otelixizumab treatment was effective on this composite endpoint, then the mean of the ranks sum in the otelixizumab group was smaller than the mean of the ranks sum in the placebo group. | Month 6 and 12 | 
| Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months | O'Brien analyses was performed on a three-part composite of HbA1c level, C-peptide AUC, and mean daily insulin use in the otelixizumab group compared with the placebo group at Months 6 and 12. The three variables was adjusted for Baseline values. Baseline adjustment was used to reduce the potential impact of imbalances in Baseline levels between treatment groups on the treatment comparisons at later time points. HbA1c and insulin use was ranked from smallest to largest, and C-peptide AUC was ranked from largest to smallest. If otelixizumab treatment was effective on the composite endpoint, then the mean of the ranks sum in the otelixizumab group was smaller than the mean of the ranks sum in the placebo group. | Month 6 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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new onset type 1 diabetes, juvenile diabetes, T1DM, Type 1 diabetes