PRV-031-001

Provention Bio, Inc

55 Broad Street, Second Floor, Red Bank, NJ, United States, 07701

Kristin Neff, Provention Bio, Inc., 1 703-345-1819, kristin.neff@sanofi.com

Linda Arterburn, Provention Bio, Inc., 1 301-648-4284, linda.arterburn@sanofi.com

No

No

No

Final

18 Oct 2023

Yes

01 May 2023

Yes

01 May 2023

No

To determine whether two courses of teplizumab slow the loss of β cells and preserve 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.

An external, independent Data Monitoring Committee (DMC) consisting of individuals with medical, scientific, and biostatistical expertise, provided oversight on safety and efficacy data and the conduct of the study. The DMC was responsible for making recommendations regarding the continuation, termination, or modification of the study. Before initiating this study, the Investigator was required to have written and dated approval from the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the study protocol, informed consent form, Investigator’s Brochure (IB), sponsor-approved recruiting materials, and other written information to be provided to participants and their guardians. The study was conducted in full compliance with the principles of the "Declaration of Helsinki", International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and all of the applicable US Code of Federal Regulations (CFR), 21 CFR Parts 50 & 312. Written informed consent and assent were obtained from each individual and guardian(s). The Investigator was to comply with applicable regulatory requirement(s) and adhere to Good Clinical Practice (GCP) and the ethical principles that have their origin in the Declaration of Helsinki when obtaining and documenting informed consent.

27 Mar 2019

Yes

Yes

United States: 182

Canada: 20

Poland: 48

United Kingdom: 12

Belgium: 5

Czechia: 27

France: 14

Germany: 20

328

114

0

0

0

0

136

192

0

0

0

Post-randomization period (overall period)

Randomised - controlled

Blinding was maintained for all study participants, Investigators, and study coordinators throughout the study. In addition, the study team remained blinded to the treatment assignment through the completion of the study. Teplizumab and placebo were supplied to the sites in vials and kits that appeared identical. Each kit had a unique number printed on all labels, including the outer carton label and the label of each vial inside the kit.

Yes

Placebo

Solution for injection/infusion

Intravenous use, Infusion

Placebo was administered via intravenous infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course approximately 6 months later at Day 182 (Week 26). Participants who were unable to receive the second 12-day course due to COVID-19 pandemic restrictions were given the second course at approximately 12 months (Week 52 visit). Each course of treatment included daily infusions for 12 days. The placebo solution consisted of the same formulation as the study drug but without teplizumab. Placebo was administered in the same dose volume and by the same treatment schedule as the active drug.

Teplizumab

Solution for infusion

Infusion , Intravenous use

Teplizumab was administered via intravenous infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course approximately 6 months later at Day 182 (Week 26). Participants who were unable to receive the second 12-day course due to COVID-19 pandemic restrictions were given the second course at approximately 12 months (Week 52 visit). Each course of treatment included daily infusions for 12 days. Each course included: • Day 1: 106 μg/m2 • Day 2: 425 μg/m2 • Days 3-12: 850 μg/m2 Total per course: 9.0 mg/m2 The doses of study drug were calculated based on the participant’s body surface area (BSA) measured on the first day of each treatment course.

Placebo

Teplizumab

ITT

All randomized participants.

PP

Per protocol population. 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).

Placebo

Teplizumab

ITT

All randomized participants.

PP

Per protocol population. 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).

The area under the concentration-time curve (AUC) of C-peptide was measured after a 4-hour mixed meal tolerance test (MMTT), a measure of endogenous insulin production and β cell function. Intent-to-treat population

Primary

Baseline to Week 78

LSmean difference = Teplizumab – Placebo. Estimates and the p-value were obtained from an ANCOVA model that includes treatment, age group at randomization, and baseline C-peptide ln(AUC+1) as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.

Placebo v Teplizumab

328

Pre-specified

0.1253

2-sided

The area under the concentration-time curve (AUC) of C-peptide was measured after a 4-hour mixed meal tolerance test (MMTT), a measure of endogenous insulin production and β cell function. Per protocol population

Primary

Baseline to Week 78

LSmean difference = teplizumab - placebo Estimates and the p-value were obtained from an ANCOVA model that includes treatment, age group at randomization, and baseline C-peptide ln(AUC+1) as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.

Placebo v Teplizumab

275

Pre-specified

0.1385

2-sided

Insulin use is reported in Units/kg/day 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. Intent-to-treat population

Secondary

Week 78

LSmean difference = teplizumab - placebo. Estimates and the p-value were obtained from an ANOVA model that included treatment, age group at randomization, and screening peak c-peptide category as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.

Placebo v Teplizumab

328

Pre-specified

-0.131

2-sided

Insulin use is reported in Units/kg/day Average daily insulin use was calculated based on participants who have at least 3 days of insulin use recorded in the diary for each visit. Per protocol population

Secondary

Week 78

LSmean difference = teplizumab - placebo. Estimates and p-values were obtained from an ANCOVA model that included treatment, age group at randomization, and screening peak c-peptide category as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.

Placebo v Teplizumab

275

Pre-specified

-0.167

2-sided

Hemoglobin A1c (%) Intent-to-treat population

Secondary

Baseline to Week 78

LSmean difference = teplizumab - placebo Estimates and the p-value were obtained from an ANCOVA model that included treatment, age group at randomization, screening peak C-peptide category, and baseline HbA1c (%) as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.

Placebo v Teplizumab

328

Pre-specified

-0.09

2-sided

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. Intent-to-treat population

Secondary

Week 78

LSmean difference = teplizumab - placebo. Estimates and p-value were obtained from an ANCOVA model that included treatment, age group at randomization, and screening peak C-peptide category as independent variables. Missing data were multiply imputed using a pattern-mixture model under the missing not at random assumption.

Placebo v Teplizumab

328

Pre-specified

4.71

2-sided

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. Per protocol population

Secondary

Week 78

LSmean difference = teplizumab - placebo. Estimates and p-value were obtained from an ANCOVA model that included treatment, age group at randomization, and screening peak C-peptide category as independent variables. Missing data were multiply imputed using a pattern-mixture model under the missing not at random assumption.

Placebo v Teplizumab

275

Pre-specified

6.17

2-sided

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. Intent-to-treat population

Secondary

Across the entire study

Rate ratio = teplizumab / placebo. Estimates and p-values were obtained from a negative binomial regression model using rate of hypoglycemic episodes as dependent variable and treatment, age group at randomization, and screening peak C-peptide category as independent variables.

Placebo v Teplizumab

328

Pre-specified

1.1

2-sided

Hemoglobin A1c (%) Per protocol population

Secondary

Baseline to Week 78

LSmean difference = teplizumab - placebo. Estimates and the p-value were obtained from an ANOVA model that included treatment, age group at randomization, screening peak C-peptide category, and baseline HbA1c (%) as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.

Placebo v Teplizumab

275

Pre-specified

-0.13

2-sided

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. Per protocol population

Secondary

Across the entire study

Rate ratio = teplizumab / placebo. Estimates and p-values were obtained from a negative binomial regression model using rate of hypoglycemic episodes as dependent variable and treatment age group at randomization, and screening peak C-peptide category as independent variables.

Placebo v Teplizumab

275

Pre-specified

1.09

2-sided

Treatment-emergent adverse events = from the first dose of study drug administration through the end of the study

26.0

Placebo

Teplizumab