Diabetes Mellitus, Type 1
Conditions
Keywords
Recent-onset type 1 diabetes, Teplizumab, T1D, Stage 3, Type 1 diabetes, New onset type 1 diabetes
Brief summary
This study was an extension of the NIH-sponsored At-Risk (TN-10) type 1 diabetes study (NCT 01030861). Teplizumab-treated and placebo-treated participants in the NIH trial who developed clinical type 1 diabetes after the conclusion of that trial, were eligible to enroll and receive teplizumab treatment within one year of diagnosis of clinical type 1 diabetes.
Detailed description
The study was a single-arm, multicenter, open-label clinical trial. All participants received a 12-day course of teplizumab given through daily IV infusion and were followed for 78 weeks. The purpose of this study was to evaluate the safety and tolerability of teplizumab treatment, administered intravenously (IV) to participants in the NIH-sponsored trial who have developed type 1 diabetes and were able to start teplizumab treatment within 1 year of diagnosis of type 1 diabetes. Whether teplizumab treatment reduced the loss of insulin-producing pancreatic beta cells were evaluated.
Interventions
DRUGteplizumab 1 mg/mL
Solution for infusion administered as IV infusion (anti-CD3 humanized monoclonal antibody). Cumulative dose: 9 mg/m2. Day 1: 106 μg/m2, Day 2: 425 μg/m2, Days 3-12: 850 μg/m2 daily
Sponsors
Provention Bio, a Sanofi Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single-arm, multicenter, open-label clinical trial
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Previous participant in the TN-10 study 2. Participant had received a diagnosis of type 1 diabetes after the conclusion of the TN-10 study, according to the criteria from the American Diabetes Association (ADA). 3. Participant was able to initiate teplizumab treatment required in this study within 1 year of type 1 diabetes diagnosis. 4. Participant was willing to forego other forms of experimental treatment during the entire study. 5. Participant and/or guardian had given informed consent and assent as applicable.
Exclusion criteria
1. Had an active infection and/or fever. 2. Had 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). 3. An individual who had 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 |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Adverse Events of Special Interest (TEAESIs) and Treatment-emergent Serious Adverse Events (TESAEs) | From the first dose of study drug administration (Day 1) up to approximately 78 weeks | An AE was any untoward medical occurrence in a participant or clinical study participant,temporally associated with use of study dose,whether or not considered related to study dose.AESI was any AE that met any of following:All \>=Grade 3 infections (including all opportunistic infections);acute mononucleosis-like illness;lymphomas or other malignancies;severe hypoglycemic episode;\>=Grade 3 liver function abnormalities, thrombocytopenia, neutropenia or rash;\>= Grade 4 allergic/hypersensitivity reaction (anaphylaxis) or cytokine-release syndrome; lymphocyte count \<500/cubic millimeter for 7 days or longer. An SAE was as any untoward medical occurrence that,at any dose:resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization,resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or any other medically important event.A TEAE was any AE which started during or after the first dose of teplizumab. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Anti-drug Antibodies (ADA) Against Teplizumab | Up to Day 364 | Blood samples were collected for the evaluation of ADA against teplizumab. |
| Area Under the Time-Versus-Concentration Curve (AUC) of C-peptide After a 4-hour (4h) Mixed Meal Tolerance Test (MMTT) at Week 78 | Week 78 | The AUC of C-peptide was measured after a 4-hour MMTT as a measure of assessing endogenous insulin production and beta cell function. The AUC was computed using the trapezoidal rule and standardized by the duration of the MMTT test for the analysis. |
| Glycated Hemoglobin (HbA1c) Levels at Week 78 | Week 78 | Blood samples were collected for evaluation of HbA1c. |
| Serum Concentration Immediately Prior to Administration of the Next Dose (Ctrough) of Teplizumab at Day 364 | Pre-dose on Day 364 | Blood samples were collected for evaluation of pharmacokinetic (PK) data. |
| Number of Participants With Severe Hypoglycemic Episodes | From the first dose of study drug administration (Day 1) up to approximately 78 weeks | The severity of a hypoglycemia event was identified by the Investigator and classified according to National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0 as follows: * Grade 3 hypoglycemia: 30-39 milligram/deciliter (mg/dL) (1.7-2.1 millimole \[mmol\]/L). This is considered severe or medically significant but not immediately life-threatening. Hospitalization or prolongation of hospitalization is likely indicated. It is considered disabling and limits self-care. * Grade 4 hypoglycemia: \<=29 mg/dL (1.6 mmol/L). This is considered life threatening (seizures) with urgent intervention indicated. * Grade 5 hypoglycemia: Hypoglycemia resulting in death. Hypoglycemia \>=Grade 3 was considered as severe hypoglycemia. |
| Number of Participants With Change in Cluster of Differentiation (CD)8+ TIGIT+ KLRG1+ T Cells | From the first dose of study drug administration (Day 1) up to approximately 78 weeks | CD8+ TIGIT+ KLRG1+ T cells were measured using flow cytometry. |
| Average Daily Use of Exogenous Insulin at Week 78 | Week 78 | The average daily insulin use was calculated based on participants who had at least 3 days of insulin use recorded in the diary for the Week 78 visit. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in the United States from 26-Feb-2020 to 22-Jan-2024.
Pre-assignment details
A total of 6 participants from the TN-10 study (NCT01030861) who developed clinical (stage 3) type 1 diabetes (T1D) after the completion of that study were enrolled in this study. All participants received teplizumab in this study within 1 year of diagnosis of clinical T1D.
Participants by arm
| Arm | Count |
|---|---|
| Teplizumab Participants received teplizumab 9 mg/m\^2 via IV infusion as a 12-day course (once daily) split as: Day 1: 106 mcg/m\^2, Day 2: 425 mcg/m\^2 and Days 3 to 12: 850 mcg/m\^2. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Teplizumab |
|---|---|
| Age, Continuous | 21.3 years STANDARD_DEVIATION 11.59 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Adverse Events of Special Interest (TEAESIs) and Treatment-emergent Serious Adverse Events (TESAEs)
An AE was any untoward medical occurrence in a participant or clinical study participant,temporally associated with use of study dose,whether or not considered related to study dose.AESI was any AE that met any of following:All \>=Grade 3 infections (including all opportunistic infections);acute mononucleosis-like illness;lymphomas or other malignancies;severe hypoglycemic episode;\>=Grade 3 liver function abnormalities, thrombocytopenia, neutropenia or rash;\>= Grade 4 allergic/hypersensitivity reaction (anaphylaxis) or cytokine-release syndrome; lymphocyte count \<500/cubic millimeter for 7 days or longer. An SAE was as any untoward medical occurrence that,at any dose:resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization,resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or any other medically important event.A TEAE was any AE which started during or after the first dose of teplizumab.
Time frame: From the first dose of study drug administration (Day 1) up to approximately 78 weeks
Population: The safety analysis set included all participants who received at least 1 dose of teplizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Teplizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Adverse Events of Special Interest (TEAESIs) and Treatment-emergent Serious Adverse Events (TESAEs) | Any TEAE | 6 Participants |
| Teplizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Adverse Events of Special Interest (TEAESIs) and Treatment-emergent Serious Adverse Events (TESAEs) | Any TEAESI | 0 Participants |
| Teplizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Adverse Events of Special Interest (TEAESIs) and Treatment-emergent Serious Adverse Events (TESAEs) | Any TESAE | 1 Participants |
Secondary
Area Under the Time-Versus-Concentration Curve (AUC) of C-peptide After a 4-hour (4h) Mixed Meal Tolerance Test (MMTT) at Week 78
The AUC of C-peptide was measured after a 4-hour MMTT as a measure of assessing endogenous insulin production and beta cell function. The AUC was computed using the trapezoidal rule and standardized by the duration of the MMTT test for the analysis.
Time frame: Week 78
Population: The safety analysis set included all participants who received at least 1 dose of teplizumab. Only those participants with data collected at Week 78 are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teplizumab | Area Under the Time-Versus-Concentration Curve (AUC) of C-peptide After a 4-hour (4h) Mixed Meal Tolerance Test (MMTT) at Week 78 | 0.549 ln(AUC+1) (picomole/mL) | Standard Deviation 0.4276 |
Secondary
Average Daily Use of Exogenous Insulin at Week 78
The average daily insulin use was calculated based on participants who had at least 3 days of insulin use recorded in the diary for the Week 78 visit.
Time frame: Week 78
Population: The safety analysis set included all participants who received at least 1 dose of teplizumab. Only those participants with data collected at Week 78 are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teplizumab | Average Daily Use of Exogenous Insulin at Week 78 | 0.54 unit/kilogram/day | Standard Deviation 0.357 |
Secondary
Glycated Hemoglobin (HbA1c) Levels at Week 78
Blood samples were collected for evaluation of HbA1c.
Time frame: Week 78
Population: The safety analysis set included all participants who received at least 1 dose of teplizumab. Only those participants with data collected at Week 78 are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Teplizumab | Glycated Hemoglobin (HbA1c) Levels at Week 78 | 8.50 percentage of HbA1c | Standard Deviation 3.785 |
Secondary
Number of Participants With Anti-drug Antibodies (ADA) Against Teplizumab
Blood samples were collected for the evaluation of ADA against teplizumab.
Time frame: Up to Day 364
Population: The immunogenicity analysis set included all participants in the safety analysis set who had at least 1 eligible immunogenicity sample for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Teplizumab | Number of Participants With Anti-drug Antibodies (ADA) Against Teplizumab | 6 Participants |
Secondary
Number of Participants With Change in Cluster of Differentiation (CD)8+ TIGIT+ KLRG1+ T Cells
CD8+ TIGIT+ KLRG1+ T cells were measured using flow cytometry.
Time frame: From the first dose of study drug administration (Day 1) up to approximately 78 weeks
Population: The safety analysis set included all participants who received at least 1 dose of teplizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Teplizumab | Number of Participants With Change in Cluster of Differentiation (CD)8+ TIGIT+ KLRG1+ T Cells | 4 Participants |
Secondary
Number of Participants With Severe Hypoglycemic Episodes
The severity of a hypoglycemia event was identified by the Investigator and classified according to National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0 as follows: * Grade 3 hypoglycemia: 30-39 milligram/deciliter (mg/dL) (1.7-2.1 millimole \[mmol\]/L). This is considered severe or medically significant but not immediately life-threatening. Hospitalization or prolongation of hospitalization is likely indicated. It is considered disabling and limits self-care. * Grade 4 hypoglycemia: \<=29 mg/dL (1.6 mmol/L). This is considered life threatening (seizures) with urgent intervention indicated. * Grade 5 hypoglycemia: Hypoglycemia resulting in death. Hypoglycemia \>=Grade 3 was considered as severe hypoglycemia.
Time frame: From the first dose of study drug administration (Day 1) up to approximately 78 weeks
Population: The safety analysis set included all participants who received at least 1 dose of teplizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Teplizumab | Number of Participants With Severe Hypoglycemic Episodes | 0 Participants |
Secondary
Serum Concentration Immediately Prior to Administration of the Next Dose (Ctrough) of Teplizumab at Day 364
Blood samples were collected for evaluation of pharmacokinetic (PK) data.
Time frame: Pre-dose on Day 364
Population: The PK analysis set included all participants in the safety analysis set who had at least 1 eligible PK sample for analysis. Only those participants with data collected on Day 364 are reported.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Teplizumab | Serum Concentration Immediately Prior to Administration of the Next Dose (Ctrough) of Teplizumab at Day 364 | NA nanogram/milliliter (ng/mL) |