Diabetes Mellitus, Type 1
Conditions
Keywords
new onset type 1 diabetes, juvenile diabetes, T1DM, Type 1 diabetes
Brief summary
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
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.
Interventions
BIOLOGICALOtelixizumab
infusion
BIOLOGICALPlacebo
Infusion
Sponsors
Juvenile Diabetes Research Foundation
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide Area Under Curve (AUC) (Normalized for 120-minute Time Interval) at Month 12 | Baseline (Day 1) and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Baseline (Day 1) and Week 12, Month 6, 12, 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. |
| Number of Participants With Responder Status | Month 3, 6 and 12 | 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. |
| Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Baseline (Day 1) and Month 3, 6, 12 | 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. |
| Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Baseline (Day 1) and Month 3, 6, 12 | 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. |
| Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months | Baseline (Day 1) and Week 12, Month 6 | 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. |
| Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 | Baseline (Day 1) and 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. |
| Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 6 and 12 | 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. |
| Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 6 and 12 | 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. |
| Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 | Baseline (Day 1) and 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. |
Countries
Italy
Participant flow
Recruitment details
This study was conducted across 73 centers in 10 countries (Belgium, Canada, Germany, Denmark, Spain, Finland, United Kingdom, Italy, Sweden, and United States of America) from 17 May 2010 to 09 March 2012.
Pre-assignment details
A total of 179 participants (125 adults and 54 adolescents) were randomized in this study and included in safety and intent-to-treat (ITT) population.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days. | 61 |
| Otelixizumab Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days. | 118 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative reasons | 0 | 4 |
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Investigator recommendation | 1 | 1 |
| Overall Study | Lost to Follow-up | 2 | 6 |
| Overall Study | Participant/legal representative request | 7 | 3 |
| Overall Study | Withdrew for another reason not covered | 0 | 1 |
Baseline characteristics
| Characteristic | Otelixizumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 23.6 Years STANDARD_DEVIATION 8.34 | 23.2 Years STANDARD_DEVIATION 8.29 | 22.5 Years STANDARD_DEVIATION 8.22 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 111 Participants | 165 Participants | 54 Participants |
| Sex: Female, Male Female | 50 Participants | 74 Participants | 24 Participants |
| Sex: Female, Male Male | 68 Participants | 105 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 118 |
| other Total, other adverse events | 50 / 61 | 108 / 118 |
| serious Total, serious adverse events | 4 / 61 | 11 / 118 |
Outcome results
Primary
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.
Time frame: Baseline (Day 1) and Month 12
Population: ITT population consisted of all participants who were randomized and received any part of at least 1 infusion of study drug. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide Area Under Curve (AUC) (Normalized for 120-minute Time Interval) at Month 12 | -0.14 nanomoles per liter | Standard Error 0.036 |
| Otelixizumab | Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide Area Under Curve (AUC) (Normalized for 120-minute Time Interval) at Month 12 | -0.23 nanomoles per liter | Standard Error 0.026 |
p-value: 0.05195% CI: [-0.17, 0]Repeated Measures Mixed Effects Model
Secondary
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.
Time frame: Baseline (Day 1) and Month 12
Population: ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 | Severe hypoglycemia | 33 Events |
| Placebo | Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 | Documented symptomatic hypoglycemia from IVRS | 429 Events |
| Placebo | Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 | Documented symptomatic hypoglycemia from eCRF | 822 Events |
| Otelixizumab | Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 | Severe hypoglycemia | 11 Events |
| Otelixizumab | Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 | Documented symptomatic hypoglycemia from IVRS | 690 Events |
| Otelixizumab | Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 | Documented symptomatic hypoglycemia from eCRF | 1300 Events |
Secondary
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.
Time frame: Baseline (Day 1) and Week 12, Month 6
Population: ITT population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months | Week 12 | 0.05 nanomoles per liter | Standard Error 0.031 |
| Placebo | Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months | Month 6 | -0.04 nanomoles per liter | Standard Error 0.037 |
| Otelixizumab | Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months | Week 12 | -0.05 nanomoles per liter | Standard Error 0.023 |
| Otelixizumab | Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months | Month 6 | -0.10 nanomoles per liter | Standard Error 0.027 |
Comparison: Week 12p-value: 0.02295% CI: [-0.18, -0.02]Repeated Measures Mixed Effects Model
Comparison: Month 6p-value: 0.19195% CI: [-0.15, 0.03]Repeated Measures Mixed Effects Model
Secondary
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.
Time frame: Baseline (Day 1) and Month 3, 6, 12
Population: ITT population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Week 12 | -0.82 Percentage of HbA1c | Standard Error 0.14 |
| Placebo | Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Month 6 | -0.65 Percentage of HbA1c | Standard Error 0.185 |
| Placebo | Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Month 12 | -0.61 Percentage of HbA1c | Standard Error 0.188 |
| Otelixizumab | Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Week 12 | -1.01 Percentage of HbA1c | Standard Error 0.101 |
| Otelixizumab | Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Month 6 | -0.65 Percentage of HbA1c | Standard Error 0.134 |
| Otelixizumab | Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Month 12 | -0.47 Percentage of HbA1c | Standard Error 0.133 |
Comparison: Week 12p-value: 0.58295% CI: [-0.52, 0.16]Repeated Measures Mixed Effects Model
Comparison: Month 6p-value: 0.98795% CI: [-0.46, 0.45]Repeated Measures Mixed Effects Model
Comparison: Month 12p-value: 0.57295% CI: [-0.33, 0.59]Repeated Measures Mixed Effects Model
Secondary
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.
Time frame: Baseline (Day 1) and Month 3, 6, 12
Population: ITT population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Week 12 | -0.04 International unit per kilogram (IU/kg) | Standard Error 0.02 |
| Placebo | Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Month 6 | 0.01 International unit per kilogram (IU/kg) | Standard Error 0.027 |
| Placebo | Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Month 12 | 0.01 International unit per kilogram (IU/kg) | Standard Error 0.036 |
| Otelixizumab | Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Week 12 | -0.08 International unit per kilogram (IU/kg) | Standard Error 0.016 |
| Otelixizumab | Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Month 6 | -0.04 International unit per kilogram (IU/kg) | Standard Error 0.021 |
| Otelixizumab | Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment | Month 12 | 0.05 International unit per kilogram (IU/kg) | Standard Error 0.028 |
Comparison: Week 12p-value: 0.2195% CI: [-0.08, 0.02]Repeated Measures Mixed Effects Model
Comparison: Month 6p-value: 0.2195% CI: [-0.11, 0.02]Repeated Measures Mixed Effects Model
Comparison: Month 12p-value: 0.40295% CI: [-0.05, 0.13]Repeated Measures Mixed Effects Model
Secondary
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.
Time frame: Baseline (Day 1) and Week 12, Month 6, 12, 18
Population: ITT population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Week 12 | 0.0519 nanomoles per liter | Standard Deviation 0.2443 |
| Placebo | Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Month 6 | -0.0455 nanomoles per liter | Standard Deviation 0.23802 |
| Placebo | Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Month 12 | -0.1236 nanomoles per liter | Standard Deviation 0.24362 |
| Placebo | Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Month 18 | -0.4125 nanomoles per liter | Standard Deviation 0.17059 |
| Otelixizumab | Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Month 18 | 0.0502 nanomoles per liter | Standard Deviation 0.25597 |
| Otelixizumab | Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Week 12 | -0.0472 nanomoles per liter | Standard Deviation 0.23394 |
| Otelixizumab | Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Month 12 | -0.2331 nanomoles per liter | Standard Deviation 0.30537 |
| Otelixizumab | Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 | Month 6 | -0.0945 nanomoles per liter | Standard Deviation 0.29151 |
Secondary
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.
Time frame: Month 6 and 12
Population: ITT population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 6 | 206 Rank | Standard Deviation 48.6 |
| Placebo | Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 12 | 180 Rank | Standard Deviation 42.5 |
| Otelixizumab | Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 6 | 186 Rank | Standard Deviation 41.6 |
| Otelixizumab | Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 12 | 170 Rank | Standard Deviation 46 |
Comparison: Month 12p-value: 0.373Hochberg-adjusted p-value
Comparison: Month 6p-value: 0.123Hochberg-adjusted p-value
Secondary
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.
Time frame: Month 6 and 12
Population: ITT population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 6 | 119 Rank | Standard Deviation 48.4 |
| Placebo | Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 12 | 96 Rank | Standard Deviation 51.2 |
| Otelixizumab | Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 6 | 110 Rank | Standard Deviation 49.8 |
| Otelixizumab | Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months | Month 12 | 110 Rank | Standard Deviation 55.3 |
Comparison: Month 6p-value: 0.452Hochberg-adjusted p-value
Comparison: Month 12p-value: 0.452Hochberg-adjusted p-value
Secondary
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.
Time frame: Month 3, 6 and 12
Population: ITT population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Responder Status | Week 12 | 19 Participants |
| Placebo | Number of Participants With Responder Status | Month 6 | 11 Participants |
| Placebo | Number of Participants With Responder Status | Month 12 | 10 Participants |
| Otelixizumab | Number of Participants With Responder Status | Month 12 | 23 Participants |
| Otelixizumab | Number of Participants With Responder Status | Week 12 | 42 Participants |
| Otelixizumab | Number of Participants With Responder Status | Month 6 | 26 Participants |
Comparison: Week 12p-value: 0.91295% CI: [0.5, 3.37]GEE Model
Comparison: Month 6p-value: 0.91295% CI: [0.37, 2.42]GEE Model
Comparison: Month 12p-value: 0.41295% CI: [0.54, 4.52]GEE Model
Secondary
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.
Time frame: Baseline (Day 1) and Month 12
Population: ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 | Severe hypoglycemia | 11.5 Percentage of participants |
| Placebo | Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 | Documented symptomatic hypoglycemia from IVRS | 36.1 Percentage of participants |
| Placebo | Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 | Documented symptomatic hypoglycemia from eCRF | 45.9 Percentage of participants |
| Otelixizumab | Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 | Severe hypoglycemia | 5.9 Percentage of participants |
| Otelixizumab | Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 | Documented symptomatic hypoglycemia from IVRS | 28.8 Percentage of participants |
| Otelixizumab | Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 | Documented symptomatic hypoglycemia from eCRF | 43.2 Percentage of participants |