Teplizumab for Prevention of Type 1 Diabetes In Relatives "At-Risk"

AntiCD3 Mab (Teplizumab) For Prevention of Diabetes In Relatives At-Risk for Type 1 Diabetes Mellitus

The study will determine whether the anti-CD3 monoclonal antibody, teplizumab, can help to prevent or delay the onset of type 1 diabetes (T1D) in relatives determined to be at very high risk for developing the disease. Teplizumab has been studied in new onset type 1 diabetes for testing of efficacy and safety in previous studies; other studies are currently in progress. The results of previous studies indicate that teplizumab reduces the loss of insulin production during the first year after diagnosis in individuals with type 1 diabetes. The purpose of this study is to determine if teplizumab can interdict the immune process that causes the destruction of insulin secreting beta cells in the pancreas during the "pre-diabetic" state and thereby prevent or delay the onset of type 1 diabetes.

Study Overview

• Status: Completed
• Conditions: Impaired Glucose Tolerance; High Risk; Autoantibody Positive; Non-diabetic Relatives at Risk for Type 1 Diabetes
• Intervention / Treatment: Drug: Teplizumab; Drug: Placebo infusion

Detailed Description

The study plans to enroll approximately 71 subjects between the ages of 8-45 years, over 2-3 years. The study is projected to last between 4-6 years, depending upon rate of enrollment and number of subjects who develop diabetes.

The main study objective is to determine whether intervention with teplizumab will prevent or delay the development of type 1 diabetes in high risk autoantibody positive non-diabetic relatives of individuals with T1D. Secondary outcomes are to include analyses of C-peptide and other measures from Oral Glucose Tolerance Testing (OGTT), safety, tolerability, and other mechanistic outcomes will be assessed during the study.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, MSG-1X8
      • The Hospital for Sick Children
• Germany
  • Munich, Germany
    • Forschergruppe Diabetes
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California-San Francisco
    • San Francisco, California, United States, 94143
      • University of California in San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Denver, Colorado, United States, 80045
      • Barbara Davis Center for Childhood Diabetes/ University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University School of Medicine
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Children's Mercy Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15201
      • University of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Texas
    • Dallas, Texas, United States, 75390-9072
      • University of Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Washington
    • Seattle, Washington, United States, 982101
      • Benaroya Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Between ages of 8-45 years
• Have a relative with type 1 diabetes
• If first degree relative must be 8-45 years old (brother, sister, parent, offspring)
• If second degree relative must be between 8-20 years old (niece, nephew, aunt, uncle, grandchild, cousin)
• Abnormal glucose tolerance by OGTT confirmed with 7 weeks of baseline visit [fasting blood glucose greater than 110mg/dL or and less than 126 mg/dL OR 2 hour glucose greater or equal to 140 mg/dL and less than 200 mg/dL OR 30, 60, or 90 minute value on OGTT greater than or equal to 200 mg/dL]
• Presence of at least two confirmed diabetes autoantibodies

Exclusion Criteria:

• type 1 diabetes previously diagnosed or detected at screening [fasting glucose greater or equal to 126 mg/dL or 2 hour glucose greater or equal to 200 mg/dL]
• abnormalities in blood counts, liver enzymes, international normalised ratio (INR),

• positive purified protein derivative (PPD) test

  • vaccination with live virus within 6 weeks of randomization
• evidence of acute infection based on laboratory testing or clinical evidence
• serological evidence of past current or past HIV , hepatitis B, or hepatitis C infection
• Be currently pregnant or lactating
• Prior treatment with study drug
• Prior treatment with other monoclonal antibody in past one year

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
Active Comparator: teplizumab; Intravenous infusions of teplizumab given for 14 consecutive days. Each infusion takes about 30 minutes and is followed by a 2 hour observation period.	Drug: Teplizumab; intravenous infusions
Placebo Comparator: Placebo infusion; Intravenous infusion of placebo (saline) will be given for 14 consecutive days. Infusions will take approximately 30 minutes and will be followed by a two hour observation period.	Drug: Placebo infusion; Placebo for Teplizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of New Diabetes Per Year	Rate at which criteria are met for diabetes onset as defined by the American Diabetes Association (ADA) based on glucose testing or the presence of unequivocal hyperglycemia with acute metabolic decompensation.	During follow-up, median 745 days, range 74 to 2683

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	Adverse events categorized and graded via CTCAE.	Baseline Visit to Diagnosis of Type 1 Diabetes median 745 days, range 74 to 2683

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Juvenile Diabetes Research Foundation; National Center for Research Resources (NCRR); American Diabetes Association

Publications and helpful links

General Publications

• Leung SS, Borg DJ, McCarthy DA, Boursalian TE, Cracraft J, Zhuang A, Fotheringham AK, Flemming N, Watkins T, Miles JJ, Groop PH, Scheijen JL, Schalkwijk CG, Steptoe RJ, Radford KJ, Knip M, Forbes JM. Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells. Diabetes. 2022 Sep 1;71(9):1994-2008. doi: 10.2337/db22-0177.
• Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, Gitelman SE, Gottlieb PA, Krischer JP, Linsley PS, Marks JB, Moore W, Moran A, Rodriguez H, Russell WE, Schatz D, Skyler JS, Tsalikian E, Wherrett DK, Ziegler AG, Greenbaum CJ; Type 1 Diabetes TrialNet Study Group. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613. doi: 10.1056/NEJMoa1902226. Epub 2019 Jun 9. Erratum In: N Engl J Med. 2020 Feb 6;382(6):586.

Helpful Links

• Type 1 Diabetes TrialNet

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2010
• Primary Completion (Actual): November 1, 2018
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: December 11, 2009
• First Submitted That Met QC Criteria: December 11, 2009
• First Posted (Estimate): December 14, 2009

Study Record Updates

• Last Update Posted (Actual): August 5, 2020
• Last Update Submitted That Met QC Criteria: July 21, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: type 1 diabetes; glucose intolerance; pre-diabetic; autoantibody positive; at risk for type 1 diabetes; relatives of people with type 1 diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Hyperglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Intolerance
• Other Study ID Numbers: TrialNet - tep (IND); UC4DK106993 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data are available at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository: https://repository.niddk.nih.gov/studies/tn10-anti-cd3-prevention/?query=trialnet%20Teplizumab