Tocilizumab (TCZ) in New-onset Type 1 Diabetes

NCT02293837 | Completed Phase 2 Results DMC

• 1 other identifier: DAIT ITN058AI
• Study Type: interventional
• Target: 136
• Locations: 2 countries
• Sites: 19

Brief Summary

Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Based on previous research, study doctors think that giving medicines to affect the immune system soon after diabetes is diagnosed may stop, delay or decrease the destruction of beta cells, resulting in better glucose control. Researchers believe that tocilizumab could have some effect on the cells in the immune system that are thought to be involved in the development of type 1 diabetes. This study will test whether tocilizumab can help preserve or delay destruction of remaining beta cells in people recently diagnosed type 1 diabetes.

Conditions

Type 1 Diabetes Mellitus; New-onset Type 1 Diabetes Mellitus; T1DM; T1D

Keywords

interleukin-6 (IL-6) receptor inhibitor

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) in Pediatric Participants

  C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes post-meal. C-peptide mAUC was calculated using the trapezoidal rule over the 2-hour time period. Larger numbers are preferable (better) in these mAUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., mAUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint.

  Baseline (Pre-treatment) to Week 52

Secondary Outcomes (10)

• Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC)

  Baseline (Pre-treatment) to Weeks 24, 52, and 104

• 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model

  Baseline (Pre-treatment), Weeks 12, 24, 39, 52, 78, and 104

• Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC)

  Baseline (Pre-treatment) to Weeks 52 and 104

• Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day

  Baseline (Pre-treatment) to Weeks 24, 52, and 104

• Change From Baseline in Average Insulin Use Per Kg, Mixed Model

  Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104

Study Arms (2)

Tocilizumab (TCZ) + SOC

EXPERIMENTAL

Subjects will receive intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥30 kg) or 10.0 mg/kg (body weight \<30kg) tocilizumab every 4 weeks for 24 weeks. Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines \[Standard of Care, SOC\])

Drug: Tocilizumab (TCZ); Other: Standard of Care

Tocilizumab Placebo Group + SOC

PLACEBO COMPARATOR

Subjects will receive IV infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight \<30kg) placebo every 4 weeks for 24 weeks. Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines \[Standard of Care, SOC\])

Drug: Placebo; Other: Standard of Care

Interventions

Tocilizumab (TCZ) DRUG

Subjects assigned to this group will receive tocilizumab intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight \<30kg) every 4 weeks for 24 weeks.

Also known as: Actemra®

Tocilizumab (TCZ) + SOC

Placebo DRUG

Subjects assigned to this group will receive placebo intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight \<30kg) every 4 weeks for 24 weeks.

Also known as: Placebo for Tocilizumab

Tocilizumab Placebo Group + SOC

Standard of Care OTHER

Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines \[Standard of Care, SOC\])

Also known as: SOC

Tocilizumab (TCZ) + SOC; Tocilizumab Placebo Group + SOC

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female aged 6-45 years\*
• \*Current Institutional Review Board (IRB)-approved age eligibility criteria is restricted to subjects 6 to 17 years of age at time of study enrollment
• Diagnosis of type 1 diabetes mellitus (T1DM), using the American Diabetes Association T1DM criteria, within 100 days of study enrollment
• Positive for at least one diabetes-related autoantibody, including but not limited to:
• Glutamate decarboxylase (GAD-65)
• Insulin, if obtained within 10 days of the onset of exogenous insulin therapy
• Insulinoma antigen-2 (IA-2)
• Zinc transporter-8 (ZnT8)
• Peak stimulated C-peptide level ≥ 0.2 pmol/mL following a mixed-meal tolerance test (MMTT) conducted at least 21 days from diagnosis and within 37 days of randomization (V0)
• Signed informed consent (and informed assent of minor, if applicable).

You may not qualify if:

• Severe reaction or anaphylaxis to human, humanized or murine monoclonal antibodies
• History of malignancy or serious uncontrolled cardiovascular, nervous system, pulmonary, renal, or gastrointestinal disease, or significant dyslipidemia
• Any history of recent serious bacterial, viral, fungal, or other opportunistic infections
• Have serologic evidence of current or past HIV (Human immunodeficiency virus), Hepatitis B, or Hepatitis C
• Positive QuantiFERON Tuberculosis (TB) test, history of TB, or active TB infection
• Active infection with Epstein-Barr virus (EBV) as defined by EBV viral load ≥10,000 copies per mL of whole blood
• Active infection with Cytomegalovirus (CMV) as defined by CMV viral load ≥10,000 copies per mL of whole blood
• Diagnosis of liver disease or elevated hepatic enzymes, as defined by Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), or both \> 1.5 x the upper limit of age-determined normal (ULN) or total bilirubin \> ULN
• Current or prior treatment that is known to cause a significant, ongoing change in the course of T1D or immunologic status
• Current or prior (within last 30 days) use of drugs other than insulin to treat hyperglycemia (e.g. metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, Dipeptidyl peptidase-4 Intravenous (DPP-IV) inhibitors, or amylin)
• Current use of any medication known to significantly influence glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, niacin)
• Any of the following hematologic abnormalities, confirmed by repeat tests:
• White blood count \<3,000/microL or \>14,000/microL
• Lymphocyte count \<500/microL
• Platelet count \<150,000 /microL

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator
• PPD Development, LP: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (19)

University of California San Francisco

San Francisco, California, 94143, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

Yale University School of Medicine: Diabetes Endocrinology Research Center

New Haven, Connecticut, 06519, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

University of Miami: Diabetes Research Institute

Miami, Florida, 33136, United States

Location

University of South Florida: Diabetes Center

Tampa, Florida, 33612, United States

Location

Indiana University Health - Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Harvard University, Joslin Diabetes Center

Boston, Massachusetts, 002215, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64111, United States

Location

Columbia University, Naomi Berrie Diabetes Center

New York, New York, 10032, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Sanford Research

Sioux Falls, South Dakota, 57104, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Benaroya Research Institute

Seattle, Washington, 98101, United States

Location

The Children's Hospital at Westmead: Kids Research Institute

Westmead, New South Wales, Westmead 2145, Australia

Location

Lady Cilento Children's Hospital: Department of Endocrinology

South Brisbane, Queensland, 4101, Australia

Location

Related Publications (2)

• Greenbaum CJ, Serti E, Lambert K, Weiner LJ, Kanaparthi S, Lord S, Gitelman SE, Wilson DM, Gaglia JL, Griffin KJ, Russell WE, Raskin P, Moran A, Willi SM, Tsalikian E, DiMeglio LA, Herold KC, Moore WV, Goland R, Harris M, Craig ME, Schatz DA, Baidal DA, Rodriguez H, Utzschneider KM, Nel HJ, Soppe CL, Boyle KD, Cerosaletti K, Keyes-Elstein L, Long SA, Thomas R, McNamara JG, Buckner JH, Sanda S; ITN058AI EXTEND Study Team. IL-6 receptor blockade does not slow beta cell loss in new-onset type 1 diabetes. JCI Insight. 2021 Nov 8;6(21):e150074. doi: 10.1172/jci.insight.150074.

  PMID: 34747368 DERIVED

• Hundhausen C, Roth A, Whalen E, Chen J, Schneider A, Long SA, Wei S, Rawlings R, Kinsman M, Evanko SP, Wight TN, Greenbaum CJ, Cerosaletti K, Buckner JH. Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression. Sci Transl Med. 2016 Sep 14;8(356):356ra119. doi: 10.1126/scitranslmed.aad9943.

  PMID: 27629486 DERIVED

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Division of Allergy, Immunology, and Transplantation (DAIT) website
• Immune Tolerance Network (ITN) website
• EXTEND's study-specific ITN website

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

tocilizumab; Standard of Care

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Carla Greenbaum

  Benaroya Research Institute at Virginia Mason: Diabetes Research Program

  STUDY CHAIR

• Jane Buckner, M.D.

  Benaroya Research Institute at Virginia Mason: Diabetes Research Program

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2014
• First Posted: November 18, 2014
• Study Start: March 12, 2015
• Primary Completion: July 10, 2019
• Study Completion: August 31, 2020
• Last Updated: September 8, 2021
• Results First Posted: August 17, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will share
• Time Frame: On average, within 24 months after database lock for the trial.
• Access Criteria: Open access.

Locations

AU (2); US (17)