Tocilizumab (TCZ) in New-onset Type 1 Diabetes (EXTEND)

• ClinicalTrials.gov Identifier: NCT02293837
• Recruitment Status: Completed
• First Posted: November 18, 2014
• Results First Posted: August 17, 2021
• Last Update Posted: September 8, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Immune Tolerance Network (ITN); PPD; Rho Federal Systems Division, Inc.
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus; New-onset Type 1 Diabetes Mellitus; T1DM; T1D	Drug: Tocilizumab (TCZ); Drug: Placebo; Other: Standard of Care	Phase 2

Detailed Description:

Staggered enrollment is planned for this trial.

Prior to initiating the study in the pediatric age group (6-17 years old), 30-99 eligible adults (ages 18-45 years) will be randomized 2:1 to tocilizumab or placebo, respectively. Once the first thirty adult participants have completed 12 weeks of treatment, the FDA and Data and Safety Monitoring Board (DSMB) will review available data (e.g., interim analysis) to weigh potential risks and benefits before opening the trial to pediatric participants.

As of ≥ May 15, 2017: Study enrollment limited to participants ages 6 to 17 years inclusive.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Preserving Beta-Cell Function With Tocilizumab in New-onset Type 1 Diabetes (ITN058AI)
• Actual Study Start Date: March 12, 2015
• Actual Primary Completion Date: July 10, 2019
• Actual Study Completion Date: August 31, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tocilizumab (TCZ) + SOC; 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); 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.; Other Name: Actemra®; Other: Standard of Care; Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC]); Other Name: SOC
Placebo Comparator: Tocilizumab Placebo Group + SOC; 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; 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.; Other Name: Placebo for Tocilizumab; Other: Standard of Care; Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC]); Other Name: SOC

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) in Pediatric Participants [ Time Frame: Baseline (Pre-treatment) to Week 52 ]
   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.

Secondary Outcome Measures :

1. Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) [ Time Frame: Baseline (Pre-treatment) to Weeks 24, 52, and 104 ]
   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.
2. 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model [ Time Frame: Baseline (Pre-treatment), Weeks 12, 24, 39, 52, 78, and 104 ]
   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.
3. Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) [ Time Frame: Baseline (Pre-treatment) to Weeks 52 and 104 ]
   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 4-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.
4. Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day [ Time Frame: Baseline (Pre-treatment) to Weeks 24, 52, and 104 ]
   The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity. Insulin use was collected each day for 5 days prior to the visit. Average insulin use per kg is the average insulin use over the 5 days prior to the visit divided by the participant's weight in kg.
5. Change From Baseline in Average Insulin Use Per Kg, Mixed Model [ Time Frame: Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104 ]
   The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity. Insulin use was collected each day for 5 days prior to the visit. Average insulin use per kg is the average insulin use over the 5 days prior to the visit divided by the participant's weight in kg.
6. Change From Baseline in Hemoglobin A1c [ Time Frame: Baseline (Pre-treatment) to Weeks 24, 52, and 104 ]
   Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c of 5.6% or less is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes mellitus (T1DM). The closer HbA1c levels are to normal, the better controlled the disease is.
7. Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model [ Time Frame: Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104 ]
   Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c of 5.6% or less is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes mellitus (T1DM). The closer HbA1c levels are to normal, the better controlled the disease is.
8. Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation [ Time Frame: Day 0 (Treatment Initiation) to Weeks 52 and 104 ]

   Major hypoglycemic adverse events are defined as: Blood glucose concentration < 40 mg/dL (Grades 3-5, NCI-CTCAE version 4.03*), or hypoglycemic events involving seizure or loss of consciousness (coma) or requiring assistance from another individual in order to recover.

   *NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events

9. Number of Participants Who Experienced Infusion-Related Adverse Events [ Time Frame: Day 0 (Treatment Initiation) to Week 52 ]
   An infusion/dose reaction is defined as an adverse event occurring during and within 24 hours after the infusion or subcutaneous injection of tocilizumab. This may include hypersensitivity reactions or anaphylactic reactions.
10. Number of Participants Who Experienced Hypersensitivity Adverse Events [ Time Frame: Day 0 (Treatment Initiation) to Week 52 ]

    Signs of a possible hypersensitivity reaction to the study drug include but are not limited to:

    • Fever, chills, pruritus, urticaria, angioedema, and skin rash
    • Cardiopulmonary reactions, including chest pain, dyspnea, hypotension or hypertension

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 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

2. Diagnosis of type 1 diabetes mellitus (T1DM), using the American Diabetes Association T1DM criteria, within 100 days of study enrollment

3. Positive for at least one diabetes-related autoantibody, including but not limited to:

   1. Glutamate decarboxylase (GAD-65)
   2. Insulin, if obtained within 10 days of the onset of exogenous insulin therapy
   3. Insulinoma antigen-2 (IA-2)
   4. Zinc transporter-8 (ZnT8)
4. 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)
5. Signed informed consent (and informed assent of minor, if applicable).

Exclusion Criteria:

1. Severe reaction or anaphylaxis to human, humanized or murine monoclonal antibodies
2. History of malignancy or serious uncontrolled cardiovascular, nervous system, pulmonary, renal, or gastrointestinal disease, or significant dyslipidemia
3. Any history of recent serious bacterial, viral, fungal, or other opportunistic infections
4. Have serologic evidence of current or past HIV (Human immunodeficiency virus), Hepatitis B, or Hepatitis C
5. Positive QuantiFERON Tuberculosis (TB) test, history of TB, or active TB infection
6. Active infection with Epstein-Barr virus (EBV) as defined by EBV viral load ≥10,000 copies per mL of whole blood
7. Active infection with Cytomegalovirus (CMV) as defined by CMV viral load ≥10,000 copies per mL of whole blood
8. 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
9. Current or prior treatment that is known to cause a significant, ongoing change in the course of T1D or immunologic status
10. 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)
11. Current use of any medication known to significantly influence glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, niacin)

12. Any of the following hematologic abnormalities, confirmed by repeat tests:

    1. White blood count <3,000/microL or >14,000/microL
    2. Lymphocyte count <500/microL
    3. Platelet count <150,000 /microL
    4. Hemoglobin <8.5 g/dL
    5. . Neutrophil count <2,000 cells/microL.
13. Females who are pregnant, lactating, or planning on pregnancy during the 2- year study period
14. History or diagnoses of other autoimmune diseases with the exception of stable thyroid or celiac disease
15. History of alcohol, drug or chemical abuse within 1 year prior to study eligibility screening evaluation
16. Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial
17. Prior participation in a clinical trial that could increase risks associated with this clinical trial
18. Receipt of live vaccine (e.g. varicella, measles, mumps, rubella, cold-attenuated intranasal influenza vaccine, bacillus Calmette-Guérin, and small pox) in the 6 weeks before randomization
19. High lipid levels (fasting Low-density lipoprotein (LDL) cholesterol ≥160 mg/dL)
20. History of significant allergy (e.g. anaphylaxis) to milk or soy proteins.

Contacts and Locations

Locations

United States, California

University of California San Francisco

San Francisco, California, United States, 94143

Stanford University

Stanford, California, United States, 94305

United States, Connecticut

Yale University School of Medicine: Diabetes Endocrinology Research Center

New Haven, Connecticut, United States, 06519

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

University of Miami: Diabetes Research Institute

Miami, Florida, United States, 33136

University of South Florida: Diabetes Center

Tampa, Florida, United States, 33612

United States, Indiana

Indiana University Health - Riley Hospital for Children

Indianapolis, Indiana, United States, 46202

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Massachusetts

Harvard University, Joslin Diabetes Center

Boston, Massachusetts, United States, 002215

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64111

United States, New York

Columbia University, Naomi Berrie Diabetes Center

New York, New York, United States, 10032

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, South Dakota

Sanford Research

Sioux Falls, South Dakota, United States, 57104

United States, Tennessee

Vanderbilt University

Nashville, Tennessee, United States, 37232

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

United States, Washington

Benaroya Research Institute

Seattle, Washington, United States, 98101

Australia, New South Wales

The Children's Hospital at Westmead: Kids Research Institute

Westmead, New South Wales, Australia, Westmead 2145

Australia, Queensland

Lady Cilento Children's Hospital: Department of Endocrinology

South Brisbane, Queensland, Australia, 4101

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Immune Tolerance Network (ITN)

PPD

Rho Federal Systems Division, Inc.

Investigators

• Study Chair: 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 Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol  [PDF] June 13, 2018

Statistical Analysis Plan  [PDF] October 2, 2020

More Information

Additional Information:

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 

American Diabetes Association information on Type 1 Diabetes 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02293837
• Other Study ID Numbers: DAIT ITN058AI
• First Posted: November 18, 2014
• Results First Posted: August 17, 2021
• Last Update Posted: September 8, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• Time Frame: On average, within 24 months after database lock for the trial.
• Access Criteria: Open access.
• URL: https://www.immport.org/home

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

interleukin-6 (IL-6) receptor inhibitor

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases