Recent-Onset Type 1 Diabetes Trial Evaluating Efficacy and Safety of Teplizumab (PROTECT)

• ClinicalTrials.gov Identifier: NCT03875729
• Recruitment Status: Completed
• First Posted: March 15, 2019
• Results First Posted: April 24, 2024
• Last Update Posted: April 24, 2024
• Sponsor: Provention Bio, Inc.
• Information provided by (Responsible Party): Provention Bio, Inc.

Tracking Information

• First Submitted Date: March 13, 2019
• First Posted Date: March 15, 2019
• Results First Submitted Date: February 8, 2024
• Results First Posted Date: April 24, 2024
• Last Update Posted Date: April 24, 2024
• Actual Study Start Date: April 5, 2019
• Actual Primary Completion Date: May 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 27, 2024)

Change in C-peptide ln(AUC+1) Standardized by Duration of the Mixed Meal Tolerance Test (MMTT) [ Time Frame: 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).

Original Primary Outcome Measures (submitted: March 13, 2019)

The area under the time-concentration curve (AUC) of C-peptide after a mixed meal tolerance test (MMTT) at Week 78 [ Time Frame: Week 78 ]

Clinical Endpoint

Current Secondary Outcome Measures (submitted: March 27, 2024)

• Average Daily Exogenous Insulin Use [ Time Frame: 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.
• Change in Glycated Hemoglobin (HbA1c) Levels (%) [ Time Frame: Baseline to Week 78 ]
  Change in percentage (%) glycated hemoglobin (HbA1c)
• Time in Range for Glycemia Control [ Time Frame: 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 [ Time Frame: 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).
• Number of Participants With Adverse Events of Special Interest (AESIs) [ Time Frame: 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.
• Teplizumab Serum Concentrations [ 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. ]
  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 [ Time Frame: 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 [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: March 13, 2019)

• Exogenous insulin use [ Time Frame: Week 78 ]
  Clinical Endpoint
• HbA1c levels [ Time Frame: Week 78 ]
  Clinical Endpoint
• Time in glycemic target range [ Time Frame: Week 78 ]
  Clinical Endpoint
• Clinically important hypoglycemic episodes [ Time Frame: Week 78 ]
  Clinical Endpoint
• Incidence of treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) [ Time Frame: Up to Week 52 and Week 78 ]
  Safety Endpoint
• Teplizumab serum concentrations [ Time Frame: 78 Week ]
  PK Endpoint
• Incidence and titers of anti-teplizumab antibodies after treatment courses [ Time Frame: 78 Week ]
  Immunogenicity Endpoint

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Recent-Onset Type 1 Diabetes Trial Evaluating Efficacy and Safety of Teplizumab
• Official Title: Phase 3 Randomized Double-Blind Multinational Placebo-Controlled Study to Evaluate Efficacy and Safety of Teplizumab, a Humanized Fc Receptor (FcR) Non-Binding Anti-cluster of Differentiation 3 (CD3) Monoclonal Antibody, in Children and Adolescents With Newly Diagnosed Type 1 Diabetes

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

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Phase 3, randomized, double-blind, placebo-controlled, multinational, multicenter study

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Type 1 Diabetes Mellitus

Intervention

• Biological: teplizumab
  Treatment
• Biological: Placebo
  Control

Study Arms

• Experimental: Teplizumab

  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 COronaVIrus Disease of 2019 (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/m^2
  • Day 2: 425 μg/m^2
  • Days 3-12: 850 μg/m^2 Total per course: 9.0 mg/m^2 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.
  Intervention: Biological: teplizumab
• Placebo Comparator: Placebo

  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 COronaVIrus Disease of 2019 (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.

  Intervention: Biological: Placebo

• Publications *: Ramos EL, Dayan CM, Chatenoud L, Sumnik Z, Simmons KM, Szypowska A, Gitelman SE, Knecht LA, Niemoeller E, Tian W, Herold KC; PROTECT Study Investigators. Teplizumab and beta-Cell Function in Newly Diagnosed Type 1 Diabetes. N Engl J Med. 2023 Dec 7;389(23):2151-2161. doi: 10.1056/NEJMoa2308743. Epub 2023 Oct 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 13, 2023): 328
• Original Estimated Enrollment (submitted: March 13, 2019): 300
• Actual Study Completion Date: May 1, 2023
• Actual Primary Completion Date: May 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 8 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Czechia, France, Germany, Hungary, Poland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03875729
• Other Study ID Numbers: PRV-031-001
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient levels data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: After drug approval
• Access Criteria: Qualified researchers
• URL: http://Vivli.org

• Current Responsible Party: Provention Bio, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Provention Bio, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Chief Medical Officer, MD; Provention Bio, Inc.

• PRS Account: Provention Bio, Inc.
• Verification Date: August 2023