Type 1 Diabetes Mellitus
Conditions
Keywords
T1D, type 1 diabetes, recent-onset T1D
Brief summary
The purpose of this study is to determine whether teplizumab slows the loss of β cells and preserves β cell function in children and adolescent 8-17 years old who have been diagnosed with T1D in the previous 6 weeks.. Subjects will receive two courses of either teplizumab or placebo treatment 6 months apart.
Detailed description
This is a Phase 3, randomized, double-blind, placebo-controlled, multinational, multi-center study to evaluate the efficacy and safety of teplizumab, a humanized, anti-CD3 monoclonal antibody, in children and adolescents ages 8 through 17 recently diagnosed with type 1 diabetes (within 6 weeks of diagnosis). Approximately 300 participants will be randomized at a ratio of 2:1 to either the teplizumab group or the placebo group. Teplizumab or matching placebo will be administered in two courses 6 months apart. Each course of treatment will include daily infusions for 12 days. The total study duration for each participant will be up to 86 weeks. The primary objective is to determine whether two courses of teplizumab administered 6 months apart slows the loss of β cells and preserves β cell function over 18 months (78 weeks) in children and adolescents 8-17 years old who have been diagnosed with T1D in the previous 6 weeks. The secondary objectives are to evaluate improvements in key clinical parameters of diabetes management, to determine the safety and tolerability of teplizumab, and to evaluate the pharmacokinetics (PK) and immunogenicity of teplizumab
Interventions
BIOLOGICALteplizumab
Treatment
BIOLOGICALPlacebo
Control
Sponsors
Provention Bio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Phase 3, randomized, double-blind, placebo-controlled, multinational, multicenter study
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Is 8 to 17 years of age, inclusive, at the time of randomization/initiation of study drug administration. 2. Has received a diagnosis of type 1 diabetes (T1D) according to the criteria from the American Diabetes Association. 3. Is able to be randomized and initiate study drug within 6 weeks (42 days) of the formal T1D diagnosis. 4. Has a peak stimulated C-peptide of ≥0.2 pmol/mL from a mixed meal tolerance test (MMTT) at screening. 5. Has a positive result on testing for T1D-related autoantibodies.
Exclusion criteria
1. Has any autoimmune disease other than T1D with the exception of stable thyroid or celiac disease. 2. Has an active infection and/or fever. 3. Has a history of or serologic evidence at screening of current or past infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). 4. An individual who has a medical, psychological or social condition that, in the opinion of the Principal Investigator, would interfere with safe and proper completion of the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in C-peptide ln(AUC+1) Standardized by Duration of the Mixed Meal Tolerance Test (MMTT) | Baseline to Week 78 | The area under the concentration-time curve (AUC) of C-peptide was measured after a 4-hour mixed meal tolerance test (MMTT) and is a measure of endogenous insulin production and β cell function. The AUC was computed using the trapezoidal rule and standardized by the duration of the MMTT test, i.e., AUC was divided by the last blood sample collection time (240 minutes or the last collection time for 4h MMTT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycated Hemoglobin (HbA1c) Levels (%) | Baseline to Week 78 | Change in percentage (%) glycated hemoglobin (HbA1c) |
| Time in Range for Glycemia Control | Week 78 | Time in range (%) for glycemia control was assessed using Continuous Glucose Monitoring (CGM). Time in range was defined as daily average percentage of time a participant's glucose is \>= 70 mg/dL and \<=180 mg/dL. Time in range was calculated based on participants who had at least 3 days of CGM data recorded for Week 78 visit with a range of at least 8 hours on a given day. |
| Rate of Clinically Important Hypoglycemic Events | During the entire study (from the first dose to the last study contact, up to 78 Weeks) | Rate = clinically important hypoglycemic events/patient-year. A clinically important episode was defined as a blood glucose value of \<54 mg/dL (3.0 mmol/L) (i.e., Level 2 Hypoglycemia, International Hypoglycemia Study Group, 2017) or a hypoglycemia event of severe cognitive impairment requiring external assistance (such as seizure, syncope, severe confusion with or without a confirmatory low blood glucose reading) (i.e., Level 3 Hypoglycemia, International Hypoglycemia Study Group 2017). Event rate was calculated for each participant as number of events / total study follow-up time. Total study follow-up time was calculated as (the date of last study contact - the first dose date + 1)/365.25. The summary is based on the data reported post-baseline in the Hypoglycemic Events Electronic Diary (eDiary). |
| Average Daily Exogenous Insulin Use | Week 78 | The average daily insulin use was calculated based on participants who have at least 3 days of insulin use recorded in the dairy for the Week 78 visit. |
| Teplizumab Serum Concentrations | Pre-dose samples collected on Days 1, 4, 9, 12 and 28 for each of the two treatment courses, and one post-dose sample collected on Day 9 during the first treatment course. | PK samples were collected prior to dosing except for Day 9 in Course 1. An additional PK sample was collected 45 minutes after infusion on Day 9 in Course 1. Concentration values below Lower Limit of Quantification (2.50 ng/mL) were set to zero for summary statistics. Course 2 day numbers were set relative to the first day of dosing, regardless of normal or modified dosing schedule. |
| Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Baseline through 78 Week | Baseline was defined as the most recent value collected prior to the first dose of study drug. Week 26 Day 187 and Weeks 27 and 34 are planned for subjects under the normal dosing schedule. Week 52 Day 369 and Weeks 53, 56, and 60 are planned for subjects under the modified dosing schedule. |
| Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | From baseline through Week 78 | Baseline is defined as the most recent value collected prior to the first dose of study drug. Week 26 Day 187 and Weeks 27 and 34 are planned for subjects under the normal dosing schedule. Week 52 Day 369 and Weeks 53, 56, and 60 are planned for subjects under the modified dosing schedule. |
| Number of Participants With Adverse Events of Special Interest (AESIs) | During the entire study (from the first dose to the last study contact, up to 78 Weeks) | AESIs are defined in the protocol and categories in the statistical analysis plan. Participants with multiple events are counted only once for each preferred term and category. |
Countries
Belgium, Canada, Czechia, France, Germany, Hungary, Poland, United Kingdom, United States
Participant flow
Recruitment details
The first participant was enrolled on April 5, 2019, and the last participant was enrolled on November 4, 2021.
Pre-assignment details
Of 422 assessed for eligibility, 328 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: Control | 111 |
| Teplizumab Teplizumab: Treatment | 217 |
| Total | 328 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 5 |
| Overall Study | Lost to Follow-up | 0 | 5 |
| Overall Study | Personal reasons | 2 | 0 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 11 |
Baseline characteristics
| Characteristic | Placebo | Teplizumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 111 Participants | 217 Participants | 328 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 12.3 years STANDARD_DEVIATION 2.55 | 12.0 years STANDARD_DEVIATION 2.53 | 12.1 years STANDARD_DEVIATION 2.54 |
| Age group at randomization >12 - 17 years | 49 Participants | 97 Participants | 146 Participants |
| Age group at randomization 8 - 12 years | 62 Participants | 120 Participants | 182 Participants |
| Anti-glutamic acid decarboxylase 65 (GAD65) autoantibody Negative | 15 Participants | 34 Participants | 49 Participants |
| Anti-glutamic acid decarboxylase 65 (GAD65) autoantibody Positive | 96 Participants | 183 Participants | 279 Participants |
| Anti-insulin autoantibody Negative | 26 Participants | 73 Participants | 99 Participants |
| Anti-insulin autoantibody Positive | 85 Participants | 144 Participants | 229 Participants |
| Anti-islet antigen 2 (IA-2) autoantibody Negative | 24 Participants | 52 Participants | 76 Participants |
| Anti-islet antigen 2 (IA-2) autoantibody Positive | 87 Participants | 165 Participants | 252 Participants |
| Anti-islet cell cytoplasmic antibody (ICA) Negative | 57 Participants | 105 Participants | 162 Participants |
| Anti-islet cell cytoplasmic antibody (ICA) Positive | 54 Participants | 112 Participants | 166 Participants |
| Anti-zinc transporter 8 (ZnT8) autoantibody Negative | 28 Participants | 55 Participants | 83 Participants |
| Anti-zinc transporter 8 (ZnT8) autoantibody Positive | 83 Participants | 162 Participants | 245 Participants |
| Body mass index (BMI) | 19.063 kg/m^2 STANDARD_DEVIATION 3.6415 | 18.868 kg/m^2 STANDARD_DEVIATION 3.4517 | 18.934 kg/m^2 STANDARD_DEVIATION 3.5127 |
| Body mass index (BMI) z-score | 0.0557 z-score STANDARD_DEVIATION 1.0957 | 0.0627 z-score STANDARD_DEVIATION 1.0723 | 0.0603 z-score STANDARD_DEVIATION 1.0786 |
| C-peptide area under concentration-time curve standardized by mixed meal tolerance test duration | 0.7237 pmol/mL STANDARD_DEVIATION 0.319 | 0.7445 pmol/mL STANDARD_DEVIATION 0.3653 | 0.7375 pmol/mL STANDARD_DEVIATION 0.3499 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 14 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 101 Participants | 193 Participants | 294 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 10 Participants | 16 Participants |
| Glycated hemoglobin (HbA1c) | 9.18 Percentage of glycated hemoglobin STANDARD_DEVIATION 1.918 | 8.90 Percentage of glycated hemoglobin STANDARD_DEVIATION 1.729 | 9.00 Percentage of glycated hemoglobin STANDARD_DEVIATION 1.797 |
| Height | 158.48 cm STANDARD_DEVIATION 14.977 | 155.35 cm STANDARD_DEVIATION 15.358 | 156.41 cm STANDARD_DEVIATION 15.279 |
| History of diabetic ketoacidosis (DKA) No | 107 Participants | 217 Participants | 324 Participants |
| History of diabetic ketoacidosis (DKA) Yes | 4 Participants | 0 Participants | 4 Participants |
| Human leukocyte antigen (HLA) genotyping - DR3 Negative | 53 Participants | 119 Participants | 172 Participants |
| Human leukocyte antigen (HLA) genotyping - DR3 Positive | 56 Participants | 96 Participants | 152 Participants |
| Human leukocyte antigen (HLA) genotyping - DR4 Negative | 34 Participants | 78 Participants | 112 Participants |
| Human leukocyte antigen (HLA) genotyping - DR4 Positive | 75 Participants | 137 Participants | 212 Participants |
| Insulin use | 0.383 U/kg/day STANDARD_DEVIATION 0.2535 | 0.447 U/kg/day STANDARD_DEVIATION 0.3093 | 0.426 U/kg/day STANDARD_DEVIATION 0.2928 |
| Number of positive type 1 diabetes (T1D) autoantibodies Five | 26 Participants | 55 Participants | 81 Participants |
| Number of positive type 1 diabetes (T1D) autoantibodies Four | 39 Participants | 66 Participants | 105 Participants |
| Number of positive type 1 diabetes (T1D) autoantibodies None | 0 Participants | 1 Participants | 1 Participants |
| Number of positive type 1 diabetes (T1D) autoantibodies One | 3 Participants | 10 Participants | 13 Participants |
| Number of positive type 1 diabetes (T1D) autoantibodies Three | 30 Participants | 47 Participants | 77 Participants |
| Number of positive type 1 diabetes (T1D) autoantibodies Two | 13 Participants | 38 Participants | 51 Participants |
| Peak C-peptide at screening 0.2 - 0.7 pmol/mL | 47 Participants | 91 Participants | 138 Participants |
| Peak C-peptide at screening >0.7 pmol/mL | 64 Participants | 126 Participants | 190 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 6 Participants | 6 Participants |
| Race/Ethnicity, Customized Native Hawiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not reported | 6 Participants | 8 Participants | 14 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 94 Participants | 189 Participants | 283 Participants |
| Region of Enrollment Belgium | 4 participants | 1 participants | 5 participants |
| Region of Enrollment Canada | 7 participants | 13 participants | 20 participants |
| Region of Enrollment Czechia | 10 participants | 17 participants | 27 participants |
| Region of Enrollment France | 5 participants | 9 participants | 14 participants |
| Region of Enrollment Germany | 8 participants | 12 participants | 20 participants |
| Region of Enrollment Poland | 15 participants | 33 participants | 48 participants |
| Region of Enrollment United Kingdom | 6 participants | 6 participants | 12 participants |
| Region of Enrollment United States | 56 participants | 126 participants | 182 participants |
| Sex: Female, Male Female | 42 Participants | 98 Participants | 140 Participants |
| Sex: Female, Male Male | 69 Participants | 119 Participants | 188 Participants |
| Time from type 1 diabetes (T1D) diagnosis to randomization | 5.20 weeks STANDARD_DEVIATION 0.812 | 5.37 weeks STANDARD_DEVIATION 0.73 | 5.31 weeks STANDARD_DEVIATION 0.762 |
| Weight | 49.19 kg STANDARD_DEVIATION 15.889 | 46.68 kg STANDARD_DEVIATION 14.992 | 47.53 kg STANDARD_DEVIATION 15.323 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 111 | 0 / 217 |
| other Total, other adverse events | 88 / 111 | 212 / 217 |
| serious Total, serious adverse events | 6 / 111 | 12 / 217 |
Outcome results
Primary
Change in C-peptide ln(AUC+1) Standardized by Duration of the Mixed Meal Tolerance Test (MMTT)
The area under the concentration-time curve (AUC) of C-peptide was measured after a 4-hour mixed meal tolerance test (MMTT) and is a measure of endogenous insulin production and β cell function. The AUC was computed using the trapezoidal rule and standardized by the duration of the MMTT test, i.e., AUC was divided by the last blood sample collection time (240 minutes or the last collection time for 4h MMTT).
Time frame: Baseline to Week 78
Population: Intent-to-treat (ITT) and Per Protocol (PP). The main reason participants were excluded from the PP population was for treatment compliance \<80% (15 of 16 excluded participants in the placebo group and 32 of 37 in the teplizumab group). Other reasons included took prohibited medication (1 in placebo group, 3 in teplizumab group), received incorrect treatment (2 in teplizumab group), and pregnancy (1 in teplizumab group).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change in C-peptide ln(AUC+1) Standardized by Duration of the Mixed Meal Tolerance Test (MMTT) | Intent-to-treat | -0.2112 pmol/mL |
| Placebo | Change in C-peptide ln(AUC+1) Standardized by Duration of the Mixed Meal Tolerance Test (MMTT) | Per Protocol | -0.2185 pmol/mL |
| Teplizumab | Change in C-peptide ln(AUC+1) Standardized by Duration of the Mixed Meal Tolerance Test (MMTT) | Intent-to-treat | -0.0859 pmol/mL |
| Teplizumab | Change in C-peptide ln(AUC+1) Standardized by Duration of the Mixed Meal Tolerance Test (MMTT) | Per Protocol | -0.0800 pmol/mL |
Comparison: This study was designed to show a difference of at least a 40% in C-peptide response between teplizumab and placebo. In geometric means, this translates to a value of (1.4×0.28) = 0.392. Consequently, approximately 300 participants were planned for enrollment, assuming 2-sided α=0.05, 90% power, 2:1 randomization, and a 10% dropout rate.p-value: <0.00195% CI: [0.0852, 0.1653]ANCOVA
p-value: <0.00195% CI: [0.0994, 0.1776]ANCOVA
Secondary
Anti-teplizumab Antibody (ADA) Titers After Treatment Courses
Baseline was defined as the most recent value collected prior to the first dose of study drug. Week 26 Day 187 and Weeks 27 and 34 are planned for subjects under the normal dosing schedule. Week 52 Day 369 and Weeks 53, 56, and 60 are planned for subjects under the modified dosing schedule.
Time frame: Baseline through 78 Week
Population: The Immunogenicity population includes all randomized participants who received at least one dose of teplizumab with at least one valid serum Anti-teplizumab Antibody (ADA) sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Baseline | 65.81 Titer | Geometric Coefficient of Variation 182.3 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 2 | 177.22 Titer | Geometric Coefficient of Variation 278.2 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 4 | 817.08 Titer | Geometric Coefficient of Variation 275 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 8 | 1040.58 Titer | Geometric Coefficient of Variation 239.1 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 26 Day 182 | 834.86 Titer | Geometric Coefficient of Variation 226.1 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 26 Day 187 | 807.26 Titer | Geometric Coefficient of Variation 681.6 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 27 | 9257.15 Titer | Geometric Coefficient of Variation 222.3 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 30 | 9985.29 Titer | Geometric Coefficient of Variation 218.7 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 34 | 7326.91 Titer | Geometric Coefficient of Variation 237 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 39 | 3701.64 Titer | Geometric Coefficient of Variation 202.8 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 52 Day 364 | 1398.22 Titer | Geometric Coefficient of Variation 240.1 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 52 Day 369 | 308.80 Titer | Geometric Coefficient of Variation 207.5 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 53 | 8043.22 Titer | Geometric Coefficient of Variation 165.7 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 56 | 14221.44 Titer | Geometric Coefficient of Variation 241.8 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 60 | 9040.49 Titer | Geometric Coefficient of Variation 299.4 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 65 | 996.15 Titer | Geometric Coefficient of Variation 484.4 |
| Placebo | Anti-teplizumab Antibody (ADA) Titers After Treatment Courses | Week 78 | 672.13 Titer | Geometric Coefficient of Variation 332.4 |
Secondary
Average Daily Exogenous Insulin Use
The average daily insulin use was calculated based on participants who have at least 3 days of insulin use recorded in the dairy for the Week 78 visit.
Time frame: Week 78
Population: Intent-to-treat and Per Protocol
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Average Daily Exogenous Insulin Use | Intent-to-treat | 0.593 Units/kg/day |
| Placebo | Average Daily Exogenous Insulin Use | Per Protocol | 0.613 Units/kg/day |
| Teplizumab | Average Daily Exogenous Insulin Use | Intent-to-treat | 0.463 Units/kg/day |
| Teplizumab | Average Daily Exogenous Insulin Use | Per Protocol | 0.446 Units/kg/day |
p-value: 0.08595% CI: [-0.28, 0.018]ANCOVA
p-value: <0.00195% CI: [-0.256, -0.078]ANCOVA
Secondary
Change in Glycated Hemoglobin (HbA1c) Levels (%)
Change in percentage (%) glycated hemoglobin (HbA1c)
Time frame: Baseline to Week 78
Population: Intent-to-treat and Per Protocol
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change in Glycated Hemoglobin (HbA1c) Levels (%) | Intent-to-treat | -1.89 Percentage of glycated hemoglobin |
| Placebo | Change in Glycated Hemoglobin (HbA1c) Levels (%) | Per Protocol | -1.94 Percentage of glycated hemoglobin |
| Teplizumab | Change in Glycated Hemoglobin (HbA1c) Levels (%) | Intent-to-treat | -1.98 Percentage of glycated hemoglobin |
| Teplizumab | Change in Glycated Hemoglobin (HbA1c) Levels (%) | Per Protocol | -2.07 Percentage of glycated hemoglobin |
p-value: 0.60695% CI: [-0.42, 0.24]ANCOVA
p-value: 0.45495% CI: [-0.46, 0.2]ANCOVA
Secondary
Incidence of Anti-drug Antibodies (ADA) After Treatment Courses
Baseline is defined as the most recent value collected prior to the first dose of study drug. Week 26 Day 187 and Weeks 27 and 34 are planned for subjects under the normal dosing schedule. Week 52 Day 369 and Weeks 53, 56, and 60 are planned for subjects under the modified dosing schedule.
Time frame: From baseline through Week 78
Population: The Immunogenicity population includes all randomized participants who received at least one dose of teplizumab with at least one valid serum Anti-teplizumab Antibody (ADA) sample.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Baseline | Positive | 15 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Baseline | Negative | 200 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 2 | Positive | 182 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 2 | Negative | 25 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 4 | Positive | 178 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 4 | Negative | 26 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 8 | Positive | 175 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 8 | Negative | 31 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 26 Day 182 | Positive | 139 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 26 Day 182 | Negative | 53 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 26 Day 187 | Positive | 130 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 26 Day 187 | Negative | 40 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 27 | Positive | 167 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 27 | Negative | 8 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 30 | Positive | 169 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 30 | Negative | 7 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 34 | Positive | 163 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 34 | Negative | 13 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 39 | Positive | 170 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 39 | Negative | 22 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 52 Day 364 | Positive | 155 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 52 Day 364 | Negative | 37 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 52 Day 369 | Positive | 11 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 52 Day 369 | Negative | 4 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 53 | Positive | 15 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 53 | Negative | 1 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 56 | Positive | 18 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 56 | Negative | 1 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 60 | Positive | 17 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 60 | Negative | 1 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 65 | Positive | 153 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 65 | Negative | 38 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 78 | Positive | 146 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADA) After Treatment Courses | Week 78 | Negative | 45 Participants |
Secondary
Number of Participants With Adverse Events of Special Interest (AESIs)
AESIs are defined in the protocol and categories in the statistical analysis plan. Participants with multiple events are counted only once for each preferred term and category.
Time frame: During the entire study (from the first dose to the last study contact, up to 78 Weeks)
Population: Safety population = all randomized study participants receiving any exposure to study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >=grade 3 liver function abnormality | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 3 infection | 2 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 3 thrombocytopenia | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one lymphoma or other malignancy, including benign tumors | 1 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 3 neutropenia | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Treatment-emergent AESI | 24 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 4 allergic/hypersensitivity reaction | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one instance of severe hypoglycemic event | 18 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 3 rash | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one acute mononucleosis-like illness | 3 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 3 rash | 4 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 3 infection | 1 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one acute mononucleosis-like illness | 17 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one lymphoma or other malignancy, including benign tumors | 2 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one instance of severe hypoglycemic event | 29 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >=grade 3 liver function abnormality | 8 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 3 thrombocytopenia | 0 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 3 neutropenia | 7 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Participants with at least one >= grade 4 allergic/hypersensitivity reaction | 0 Participants |
| Teplizumab | Number of Participants With Adverse Events of Special Interest (AESIs) | Treatment-emergent AESI | 63 Participants |
Secondary
Rate of Clinically Important Hypoglycemic Events
Rate = clinically important hypoglycemic events/patient-year. A clinically important episode was defined as a blood glucose value of \<54 mg/dL (3.0 mmol/L) (i.e., Level 2 Hypoglycemia, International Hypoglycemia Study Group, 2017) or a hypoglycemia event of severe cognitive impairment requiring external assistance (such as seizure, syncope, severe confusion with or without a confirmatory low blood glucose reading) (i.e., Level 3 Hypoglycemia, International Hypoglycemia Study Group 2017). Event rate was calculated for each participant as number of events / total study follow-up time. Total study follow-up time was calculated as (the date of last study contact - the first dose date + 1)/365.25. The summary is based on the data reported post-baseline in the Hypoglycemic Events Electronic Diary (eDiary).
Time frame: During the entire study (from the first dose to the last study contact, up to 78 Weeks)
Population: Intent-to-treat and Per Protocol
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Rate of Clinically Important Hypoglycemic Events | Intent-to-treat | 4.24 Events/patient-year |
| Placebo | Rate of Clinically Important Hypoglycemic Events | Per protocol | 4.63 Events/patient-year |
| Teplizumab | Rate of Clinically Important Hypoglycemic Events | Intent-to-treat | 4.68 Events/patient-year |
| Teplizumab | Rate of Clinically Important Hypoglycemic Events | Per protocol | 5.04 Events/patient-year |
p-value: 0.63495% CI: [0.74, 1.64]Negative binomial regression model
p-value: 0.6995% CI: [0.72, 1.65]Rate ratio
Secondary
Teplizumab Serum Concentrations
PK samples were collected prior to dosing except for Day 9 in Course 1. An additional PK sample was collected 45 minutes after infusion on Day 9 in Course 1. Concentration values below Lower Limit of Quantification (2.50 ng/mL) were set to zero for summary statistics. Course 2 day numbers were set relative to the first day of dosing, regardless of normal or modified dosing schedule.
Time frame: Pre-dose samples collected on Days 1, 4, 9, 12 and 28 for each of the two treatment courses, and one post-dose sample collected on Day 9 during the first treatment course.
Population: The Pharmacokinetic (PK) population includes all randomized participants who received at least one dose of teplizumab with at least one valid pharmacokinetic sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Teplizumab Serum Concentrations | Course 1, Day 1 | 7.4271 ng/mL | Geometric Coefficient of Variation 628.114 |
| Placebo | Teplizumab Serum Concentrations | Course 1, Day 4 | 70.4769 ng/mL | Geometric Coefficient of Variation 50.767 |
| Placebo | Teplizumab Serum Concentrations | Course 1, Day 9 | 250.3928 ng/mL | Geometric Coefficient of Variation 44.677 |
| Placebo | Teplizumab Serum Concentrations | Course 1, Day 9 post-dose | 636.4390 ng/mL | Geometric Coefficient of Variation 33.171 |
| Placebo | Teplizumab Serum Concentrations | Course 1, Day 12 | 305.6569 ng/mL | Geometric Coefficient of Variation 47.048 |
| Placebo | Teplizumab Serum Concentrations | Course 1, Day 28 | 25.0317 ng/mL | Geometric Coefficient of Variation 79.953 |
| Placebo | Teplizumab Serum Concentrations | Course 2, Day 1 | 5.5433 ng/mL | Geometric Coefficient of Variation 522.457 |
| Placebo | Teplizumab Serum Concentrations | Course 2, Day 4 | 82.0166 ng/mL | Geometric Coefficient of Variation 50.333 |
| Placebo | Teplizumab Serum Concentrations | Course 2, Day 9 | 145.9498 ng/mL | Geometric Coefficient of Variation 75.737 |
| Placebo | Teplizumab Serum Concentrations | Course 2, Day 12 | 108.2988 ng/mL | Geometric Coefficient of Variation 107.776 |
| Placebo | Teplizumab Serum Concentrations | Course 2, Day 28 | 13.2159 ng/mL | Geometric Coefficient of Variation 181.421 |
Secondary
Time in Range for Glycemia Control
Time in range (%) for glycemia control was assessed using Continuous Glucose Monitoring (CGM). Time in range was defined as daily average percentage of time a participant's glucose is \>= 70 mg/dL and \<=180 mg/dL. Time in range was calculated based on participants who had at least 3 days of CGM data recorded for Week 78 visit with a range of at least 8 hours on a given day.
Time frame: Week 78
Population: Intent-to-treat and Per Protocol
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Time in Range for Glycemia Control | Intent-to-treat | 62.65 Percentage of time in range |
| Placebo | Time in Range for Glycemia Control | Per Protocol | 61.44 Percentage of time in range |
| Teplizumab | Time in Range for Glycemia Control | Intent-to-treat | 67.36 Percentage of time in range |
| Teplizumab | Time in Range for Glycemia Control | Per Protocol | 67.61 Percentage of time in range |
p-value: 0.15195% CI: [-1.72, 11.15]ANCOVA
p-value: 0.04595% CI: [0.13, 12.22]ANCOVA