Type 1 Diabetes Mellitus
Conditions
Brief summary
The primary purpose of this study is to determine whether teplizumab (MGA031) infusions lead to greater reductions in insulin requirements in conjunction with near normal blood sugar control compared to placebo in patients recently diagnosed with type 1 diabetes.
Interventions
BIOLOGICALTeplizumab Herold Regimen
Full dose of teplizumab IV for 14 days, repeated at Week 26
DRUGPlacebo
IV dosing daily for 14 days repeated at Week 26
BIOLOGICALTeplizumab 33.3% Herold Regimen
One third full dose of teplizumab IV for 14 days, repeated at Week 26
BIOLOGICALTeplizumab Curtailed Herold Regimen
Full dose of teplizumab IV for 6 days followed by placebo for 8 days, repeated at Week 26
Sponsors
Eli Lilly and Company
MacroGenics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
8 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects 8-35 years old 2. Body weight \> 36 Kg 3. Diagnosis of diabetes mellitus according to the American Diabetes Association (ADA) criteria 4. Randomization on Study Day 0 within 12 weeks of first visit to any physician for symptoms or signs of diabetes 5. Requires insulin for T1DM or has required insulin at some time between diagnosis and administration of study drug 6. Detectable fasting or stimulated C-peptide level (above the lower limit of the reportable range of the assay) at screening 7. Diagnosis of T1DM as evidenced by one positive result on testing for any of the following antibodies at screening: * Islet-cell autoantibodies 512 (ICA512)/islet antigen-2 (IA-2), * Glutamic acid decarboxylase (GAD) autoantibodies, or * Insulin autoantibodies (in subjects on insulin for more than 2 weeks, ICA512/IA-2 or GAD must be positive).
Exclusion criteria
1. Prior administration of a monoclonal antibody-within the 1 year before randomization 2. Participation in any type of therapeutic drug or vaccine clinical trial within the last 12 weeks before randomization at Study Day 0 3. Any medical condition that, in the opinion of the investigator, would interfere with safe completion of the trial 4. Pregnant females or lactating females who intend to provide their own breast milk to the baby during the study 5. Current therapy with GLP-1 receptor agonists (e.g., exenatide or pramlintide), or any other agents that might stimulate pancreatic beta cell regeneration or insulin secretion 6. Current treatment with oral antidiabetic agents 7. Evidence of active or latent tuberculosis 8. Vaccination with a live virus or organism within the 8 weeks before randomization continuing through Week 52 of the study. * Influenza vaccination with a killed virus, including booster vaccinations, within 4 weeks before or after each dosing cycle. * Vaccination with other antigens or killed organisms within 8 weeks before or after each dosing cycle 9. Any infectious mononucleosis-like illness within the 6 months before randomization
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of Subjects 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%. | 52 weeks after randomization |
| Mean Change From Baseline in HbA1c Between Teplizumab and Placebo | 52 weeks after randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Daily Insulin Injections | 52 weeks after randomization | — |
| Number of Subjects 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%. | 104 weeks after randomization | — |
| The Proportion of Subjects Who Have Both a Total Daily Insulin Dose < 0.5 U/Kg/Day and Hemoglobin A1c (HbA1c) Level < 7.0% | 52 weeks after randomization | — |
| The Change in Beta-cell Function as Measured by C-peptide Secretory Response Following a Mixed Meal | 52 weeks after randomization | — |
| Number of Participants With Adverse Events | throughout the study, up to 104 weeks | — |
| Number of Participants With Serious Adverse Events | throughout the study, up to 104 weeks | — |
| The Mean HbA1c Change From Baseline | 104 weeks after randomization | — |
| Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Throughout the study up to 2 years | Number of hypoglycemic events by type per participant |
Countries
Belgium, Czechia, Finland, France, Germany, India, Israel, Italy, Mexico, Netherlands, Poland, Romania, Spain, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Herold Regimen 14-day cycle of teplizumab consisting of daily IV doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, and 413 µg/m2 on Study Days 1-4, respectively, and one dose of 826 µg/m2 on each of Study Days 5-14. Repeat at Week 26
Teplizumab Herold Regimen: Full dose of teplizumab IV for 14 days, repeated at Week 26 | 63 |
| 33.3% Herold Regimen Subjects received a 14-day cycle of teplizumab consisting of daily IV doses of 17 µg/m2, 34 µg/m2, 68 µg/m2, and 136 µg/m2 on Study Days 1-4, respectively, and one dose of 273 µg/m2 on each of Study Days 5-14. Repeat at Week 26
Teplizumab 33.3% Herold Regimen: One third full dose of teplizumab IV for 14 days, repeated at Week 26 | 66 |
| Curtailed Herold Regimen Subjects received a 6 day cycle of teplizumab consisting of daily IV doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, and 413 µg/m2 on Study Days 1-4, respectively, and one dose of 826 µg/m2 on each of Study Days 5-6, followed by 8 days of IV placebo (Study Days 7-14). Repeat at Week 26
Teplizumab Curtailed Herold Regimen: Full dose of teplizumab IV for 6 days followed by placebo for 8 days, repeated at Week 26 | 63 |
| Placebo 14-day cycle of placebo consisting of daily IV doses. Repeat at Week 26
Placebo: IV dosing daily for 14 days repeated at Week 26 | 62 |
| Total | 254 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 1 | 2 | 0 |
| Overall Study | Other | 2 | 1 | 3 | 2 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 4 | 6 | 3 |
Baseline characteristics
| Characteristic | Herold Regimen | 33.3% Herold Regimen | Curtailed Herold Regimen | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 16.0 years | 16.0 years | 15.0 years | 16.0 years | 16.0 years |
| Age, Customized 12-17 years | 24 Participants | 29 Participants | 24 Participants | 25 Participants | 102 Participants |
| Age, Customized 18-35 years | 26 Participants | 25 Participants | 26 Participants | 26 Participants | 103 Participants |
| Age, Customized 8-11 years | 13 Participants | 12 Participants | 13 Participants | 11 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 65 Participants | 62 Participants | 58 Participants | 248 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 26 Participants | 25 Participants | 23 Participants | 99 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 36 Participants | 39 Participants | 35 Participants | 37 Participants | 147 Participants |
| Region of Enrollment Belgium | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Czechia | 4 participants | 5 participants | 6 participants | 5 participants | 20 participants |
| Region of Enrollment Finland | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Germany | 1 participants | 2 participants | 1 participants | 1 participants | 5 participants |
| Region of Enrollment India | 25 participants | 26 participants | 25 participants | 23 participants | 99 participants |
| Region of Enrollment Israel | 3 participants | 3 participants | 4 participants | 2 participants | 12 participants |
| Region of Enrollment Mexico | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Poland | 3 participants | 2 participants | 2 participants | 2 participants | 9 participants |
| Region of Enrollment Romania | 3 participants | 3 participants | 1 participants | 3 participants | 10 participants |
| Region of Enrollment Spain | 1 participants | 2 participants | 2 participants | 2 participants | 7 participants |
| Region of Enrollment Ukraine | 5 participants | 5 participants | 4 participants | 6 participants | 20 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 17 participants | 17 participants | 17 participants | 17 participants | 68 participants |
| Sex: Female, Male Female | 25 Participants | 20 Participants | 17 Participants | 21 Participants | 83 Participants |
| Sex: Female, Male Male | 38 Participants | 46 Participants | 46 Participants | 41 Participants | 171 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 0 / 66 | 0 / 63 | 0 / 62 |
| other Total, other adverse events | 63 / 63 | 66 / 66 | 63 / 63 | 62 / 62 |
| serious Total, serious adverse events | 7 / 63 | 6 / 66 | 8 / 63 | 3 / 62 |
Outcome results
Primary
Mean Change From Baseline in HbA1c Between Teplizumab and Placebo
Time frame: 52 weeks after randomization
Population: Analysis population includes all participants with available data at 52 weeks after randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herold Regimen | Mean Change From Baseline in HbA1c Between Teplizumab and Placebo | 0.01 percent HbA1c | Standard Deviation 1.803 |
| 33.3% Herold Regimen | Mean Change From Baseline in HbA1c Between Teplizumab and Placebo | -0.02 percent HbA1c | Standard Deviation 2.169 |
| Curtailed Herold Regimen | Mean Change From Baseline in HbA1c Between Teplizumab and Placebo | 0.35 percent HbA1c | Standard Deviation 25.12 |
| Placebo | Mean Change From Baseline in HbA1c Between Teplizumab and Placebo | 0.03 percent HbA1c | Standard Deviation 2.566 |
Primary
Proportion of Subjects 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%.
Time frame: 52 weeks after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Herold Regimen | Proportion of Subjects 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%. | 8 Participants |
| 33.3% Herold Regimen | Proportion of Subjects 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%. | 8 Participants |
| Curtailed Herold Regimen | Proportion of Subjects 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%. | 9 Participants |
| Placebo | Proportion of Subjects 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%. | 6 Participants |
p-value: 0.60995% CI: [0.431, 4.219]Mantel Haenszel
p-value: 0.60195% CI: [0.453, 4.23]Mantel Haenszel
p-value: 0.495% CI: [0.521, 5.066]Mantel Haenszel
Secondary
Mean Number of Daily Insulin Injections
Time frame: 52 weeks after randomization
Population: The number of daily insulin injections was not collected. Insulin use was analyzed as units/kg/day, not by number of injections.
Secondary
Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events
Number of hypoglycemic events by type per participant
Time frame: Throughout the study up to 2 years
Population: Analysis of hypoglycemic events at 52 weeks and 104 weeks was combined in the statistical analysis plan. The presentation reflects the total hypoglycemic events throughout the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Total (any) | 13.7 events | Standard Deviation 22.35 |
| Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Minor hypoglycemia | 4.1 events | Standard Deviation 6.97 |
| Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Major hypoglycemia | 10.0 events | Standard Deviation 0.13 |
| Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Nocturnal hypoglycemia | 2.0 events | Standard Deviation 3.17 |
| 33.3% Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Minor hypoglycemia | 4.4 events | Standard Deviation 6.38 |
| 33.3% Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Major hypoglycemia | 0.1 events | Standard Deviation 0.42 |
| 33.3% Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Nocturnal hypoglycemia | 2.1 events | Standard Deviation 5.54 |
| 33.3% Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Total (any) | 15.9 events | Standard Deviation 22.9 |
| Curtailed Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Major hypoglycemia | 0.0 events | Standard Deviation 0.18 |
| Curtailed Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Minor hypoglycemia | 5.4 events | Standard Deviation 12.11 |
| Curtailed Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Nocturnal hypoglycemia | 1.4 events | Standard Deviation 2.46 |
| Curtailed Herold Regimen | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Total (any) | 18.9 events | Standard Deviation 41.42 |
| Placebo | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Nocturnal hypoglycemia | 1.6 events | Standard Deviation 3.33 |
| Placebo | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Minor hypoglycemia | 4.7 events | Standard Deviation 10.45 |
| Placebo | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Total (any) | 15.5 events | Standard Deviation 22.7 |
| Placebo | Mean Number of Total, Major, Minor and Nocturnal Hypoglycemia Events | Major hypoglycemia | 0.0 events | Standard Deviation 0.13 |
Secondary
Number of Participants With Adverse Events
Time frame: throughout the study, up to 104 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Herold Regimen | Number of Participants With Adverse Events | 63 Participants |
| 33.3% Herold Regimen | Number of Participants With Adverse Events | 66 Participants |
| Curtailed Herold Regimen | Number of Participants With Adverse Events | 63 Participants |
| Placebo | Number of Participants With Adverse Events | 62 Participants |
Secondary
Number of Participants With Serious Adverse Events
Time frame: throughout the study, up to 104 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Herold Regimen | Number of Participants With Serious Adverse Events | 7 Participants |
| 33.3% Herold Regimen | Number of Participants With Serious Adverse Events | 6 Participants |
| Curtailed Herold Regimen | Number of Participants With Serious Adverse Events | 8 Participants |
| Placebo | Number of Participants With Serious Adverse Events | 3 Participants |
Secondary
Number of Subjects 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%.
Time frame: 104 weeks after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Herold Regimen | Number of Subjects 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%. | 1 Participants |
| 33.3% Herold Regimen | Number of Subjects 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%. | 2 Participants |
| Curtailed Herold Regimen | Number of Subjects 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%. | 1 Participants |
| Placebo | Number of Subjects 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%. | 1 Participants |
Secondary
The Change in Beta-cell Function as Measured by C-peptide Secretory Response Following a Mixed Meal
Time frame: 104 weeks after randomization
Population: The study was terminated early and no data for C-peptide secretory response following a mixed meal was collected at Week 104. Measurement of C-peptide response after a mixed meal at selected timepoints up to Week 104 was replaced with measurement of fasting C-peptide levels at Day 365 by protocol amendment. Data were collected only at Days 141 and 365, due to the early termination of the study.
Secondary
The Change in Beta-cell Function as Measured by C-peptide Secretory Response Following a Mixed Meal
Time frame: 52 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herold Regimen | The Change in Beta-cell Function as Measured by C-peptide Secretory Response Following a Mixed Meal | 0.04 nmol/L | Standard Deviation 0.276 |
| 33.3% Herold Regimen | The Change in Beta-cell Function as Measured by C-peptide Secretory Response Following a Mixed Meal | -0.05 nmol/L | Standard Deviation 0.456 |
| Curtailed Herold Regimen | The Change in Beta-cell Function as Measured by C-peptide Secretory Response Following a Mixed Meal | 0.04 nmol/L | Standard Deviation 0.287 |
| Placebo | The Change in Beta-cell Function as Measured by C-peptide Secretory Response Following a Mixed Meal | -0.04 nmol/L | Standard Deviation 0.419 |
p-value: 0.36595% CI: [-0.086, 0.031]ANCOVA
p-value: 0.84295% CI: [-0.078, 0.064]ANCOVA
p-value: 0.56595% CI: [-0.089, 0.171]ANCOVA
Secondary
The Mean HbA1c Change From Baseline
Time frame: 104 weeks after randomization
Population: No statistical analysis was performed on the limited data collected at 104 weeks after randomization. Only descriptive statistics are provided.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Herold Regimen | The Mean HbA1c Change From Baseline | 1.05 percent glycosylated hemoglobin | Standard Deviation 2.344 |
| 33.3% Herold Regimen | The Mean HbA1c Change From Baseline | 1.11 percent glycosylated hemoglobin | Standard Deviation 2.494 |
| Curtailed Herold Regimen | The Mean HbA1c Change From Baseline | 0.71 percent glycosylated hemoglobin | Standard Deviation 3.74 |
| Placebo | The Mean HbA1c Change From Baseline | 1.21 percent glycosylated hemoglobin | Standard Deviation 2.857 |
Secondary
The Proportion of Subjects Who Have Both a Total Daily Insulin Dose < 0.5 U/Kg/Day and Hemoglobin A1c (HbA1c) Level < 7.0%
Time frame: 52 weeks after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Herold Regimen | The Proportion of Subjects Who Have Both a Total Daily Insulin Dose < 0.5 U/Kg/Day and Hemoglobin A1c (HbA1c) Level < 7.0% | 13 Participants |
| 33.3% Herold Regimen | The Proportion of Subjects Who Have Both a Total Daily Insulin Dose < 0.5 U/Kg/Day and Hemoglobin A1c (HbA1c) Level < 7.0% | 10 Participants |
| Curtailed Herold Regimen | The Proportion of Subjects Who Have Both a Total Daily Insulin Dose < 0.5 U/Kg/Day and Hemoglobin A1c (HbA1c) Level < 7.0% | 12 Participants |
| Placebo | The Proportion of Subjects Who Have Both a Total Daily Insulin Dose < 0.5 U/Kg/Day and Hemoglobin A1c (HbA1c) Level < 7.0% | 7 Participants |
p-value: 0.14295% CI: [0.764, 6.312]Mantel Haenszel
p-value: 0.4695% CI: [0.517, 4.278]Mantel Haenszel
p-value: 0.19995% CI: [0.69, 5.532]Mantel Haenszel