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

Type 1 Diabetes Mellitus Clinical Trial

— PROTECT  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03875729
• Other study ID #: PRV-031-001
• Status: Completed
• Phase: Phase 3
• Start date: April 5, 2019
• Est. completion date: May 1, 2023

Study information

• Verified date: August 2023
• Source: Provention Bio, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 328
• Est. completion date: May 1, 2023
• Est. primary completion date: May 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes Mellitus

Intervention

Biological:
• teplizumab
Treatment
• Placebo
Control

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Provention Bio, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Czechia,  France,  Germany,  Hungary,  Poland,  United Kingdom, 

References & Publications (1)

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 — View Citation

Outcome

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

External Links

•   New England Journal of Medicine publication of the study results