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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Collaborators:
Immune Tolerance Network (ITN)
PPD
Rho Federal Systems Division, Inc.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.

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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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1
Drug Information available for: Tocilizumab

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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02293837


Locations
Show Show 19 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
PPD
Rho Federal Systems Division, Inc.
Investigators
Layout table for investigator information
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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
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    Key Record Dates
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:
Layout table for MeSH terms
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases