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

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

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Biological: teplizumab; Biological: Placebo

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
• Enrollment (Actual): 328
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Namur, Belgium, 5000
    • CHU UCL Namur, site Clinique Sainte-Elisabeth (Site 205)
  • Brussels Capital Region
    • Bruxelles, Brussels Capital Region, Belgium, 1090
      • UZ Brussel - Campus Jette (Site 202)
  • Oost-Vlaanderen
    • Gent, Oost-Vlaanderen, Belgium, 9000
      • UZ Gent (Site 206)
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2J3
      • Alberta Diabetes Institute Clinical Research Unit Li Ka Shing Centre for Health Research Innovation (Site 103)
  • British Columbia
    • Vancouver, British Columbia, Canada
      • BC Diabetes (Site 102)
  • Quebec
    • Montreal, Quebec, Canada
      • Montreal Children's Hospital-McGill (Site 101)
• Czechia
  • Praha 5, Czechia, 150 06
    • Fakultni nemocnice v Motole (Site 301)
• France
  • Pau cedex, France, 64046
    • Centre hospitalier de Pau (Site 501)
  • Alpes-Maritimes
    • Nice, Alpes-Maritimes, France, 6200
      • Hopitaux Pediatriques de Nice CHU-Lenval service de diabetologie et d'endocrinologia (Site 508)
  • Bouces-du-Rhone
    • Marseille, Bouces-du-Rhone, France, 13005
      • CHU Hopital de la Timone-Hopital d'Enfants (Site 512)
  • Ile-de-France
    • Paris, Ile-de-France, France, 75015
      • Groupe Hospitalier Necker Enfants Malades (site 502)
  • Loiret
    • Orleans, Loiret, France, 45100
      • Centre Hospitalier Regional (CHR) d'Orleans-Service de pediatrie (Site 513)
  • Rhone
    • Bron Cedex, Rhone, France, 69677
      • Groupe hospitalier Est-Hopital Femme, Mere, Enfant (Site 509)
  • cote-d'Or
    • Dijon Cedex, cote-d'Or, France, 21079
      • CHU DIJON hopital d'enfant (Site 504)
• Germany
  • Hannover, Germany, 30173
    • Kinderkrankenhaus Auf Der Bult (Site 604)
  • Baden-Wurttemberg
    • Freiburg im Breisgau, Baden-Wurttemberg, Germany, 79106
      • Universitätsklinikum Freiburg (Site 603)
  • Baden-Wurtternberg
    • Heidelberg, Baden-Wurtternberg, Germany, 69120
      • Universitätsklinikum Heidelberg (Site 608)
  • Bayem
    • Augsburg, Bayem, Germany, 86156
      • Universitätsklinikum Augsburg (Site 606)
  • Nordrhein-Westfalen
    • Bielefeld, Nordrhein-Westfalen, Germany, 33617
      • Evangelisches Klinikum Bethel Kinderklinik (Site 602)
  • Sachson
    • Dresden, Sachson, Germany, -1307
      • Universitatsklinikum Carl Gustav Carus (Site 601)
• Hungary
  • Gyula, Hungary
    • Békés Megyei Központi Kórház Pándy Kálmán Tagkórház ( Site 705)
• Poland
  • Warszawa, Poland, 04-730
    • Instytut "Pomnik - Centrum Zdrowia Dziecka" (Site 801)
  • Warszawa, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne (Site 803)
  • Warszawa, Poland, 02-117
    • Instytut Diabetologii Sp. z o.o. (Site 802)
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 01-184
      • Uniwersyteckie Centrum Kliniczne Warszawskiego Uniwersytetu (Site 804)
• United Kingdom
  • Cardiff, United Kingdom, CF14 4XN
    • Cardiff and Vale NHS Trust - University Hospital of Wales (Site 902)
  • Sheffield, United Kingdom, s10 2TH
    • Sheffield Children's NHS Foundation Trust Western Bank (Site 903)
  • City Of London
    • London, City Of London, United Kingdom, HA1 3UJ
      • Northwick Park Hospital - Paediatrics (site 904)
• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital-San Diego (Site 004)
    • San Francisco, California, United States, 94158
      • UCSF Medical Center (Site 001)
    • Walnut Creek, California, United States, 94598
      • Diablo Clinical Research, Inc. (Site 002)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado-Barbara Davis Center for Childhood Diabetes (Site 005)
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University of Medicine (Site 020)
  • Florida
    • Gainesville, Florida, United States, 32610
      • UF Clinical and Translation Research Building (Site 015)
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Specialty Care-Endocrinology (Site 047)
    • Miami, Florida, United States, 33136
      • University of Miami Health System (Site 028)
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital-Johns Hopkins Medicine (Site 048)
    • Tampa, Florida, United States, 33612
      • University of South Florida Diabetes and Endocrinology Center (Site 011)
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Atlanta Diabetes Associates (Site 009)
    • Columbus, Georgia, United States, 31904
      • Centricity Research (Site 006)
  • Idaho
    • Boise, Idaho, United States, 82712
      • St. Luke's Children's Endocrinology (Site 052)
    • Idaho Falls, Idaho, United States, 83404
      • Rocky Mountain Diabetes and Osteoporosis Center (Site 007)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center (Site 017)
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Hospital and Riley Hospital for Children (Site 014)
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • U. Iowa Children's Hospital (Site 023)
  • Maryland
    • Camp Springs, Maryland, United States, 20746
      • Capital Diabetes & Endocrine Associates (Site 029)
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Baystate Pediatric Endocrinology & Diabetes (Site 040)
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • U. Minnesota Health Clinical Research Unit (Site 031)
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals & Clinics (Site 026)
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine (Site 018)
  • New York
    • Buffalo, New York, United States, 14203
      • Women and Children's Hospital of Buffalo (Site 010)
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Hospitals Children's Specialty Clinic (Site 038)
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies & Children's Hospital (Site 049)
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic (Site 051)
  • Oregon
    • Bend, Oregon, United States, 97702
      • Endocrinology Service Northwest, LLC (Site 034)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Childrens Hospital of Philadelphia - Endocrinology (Site 021)
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Sanford Diabetes and Thyroiid Clinical (Site 013)
  • Tennessee
    • Bartlett, Tennessee, United States, 38133
      • AM Diabetes & Endocrinology Center (Site 008)
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center (Site 024)
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center Dallas (Site 033)
  • Washington
    • Seattle, Washington, United States, 98101
      • Benaroya Research Institute at Virginia Mason (Site 016)
    • Tacoma, Washington, United States, 98405
      • MultiCare Institute for Research & Innovation (Site 003)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Biological: teplizumab; Treatment
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.	Biological: Placebo; Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Baseline to Week 78

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Week 78
Change in Glycated Hemoglobin (HbA1c) Levels (%)	Change in percentage (%) glycated hemoglobin (HbA1c)	Baseline to Week 78
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.	Week 78
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).	During the entire study (from the first dose to the last study contact, up to 78 Weeks)
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.	During the entire study (from the first dose to the last study contact, up to 78 Weeks)
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.	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.
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.	Baseline through 78 Week
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.	From baseline through Week 78

Collaborators and Investigators

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

Publications and helpful links

General 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.

Helpful Links

• New England Journal of Medicine publication of the study results

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2019
• Primary Completion (Actual): May 1, 2023
• Study Completion (Actual): May 1, 2023

Study Registration Dates

• First Submitted: March 13, 2019
• First Submitted That Met QC Criteria: March 13, 2019
• First Posted (Actual): March 15, 2019

Study Record Updates

• Last Update Posted (Estimated): April 24, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: T1D, type 1 diabetes, recent-onset T1D
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: PRV-031-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: After drug approval
• IPD Sharing Access Criteria: Qualified researchers
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Study Data/Documents

1. Individual Participant Data Set
   Information comments: Qualified researchers can submit a research proposal that includes specific information about the purpose of the research, the objectives, the analysis plan, the publication plan, etc. Qualified researchers may request access to patient level data and related study documents. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No