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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02293837
Registration number
NCT02293837
Ethics application status
Date submitted
13/11/2014
Date registered
18/11/2014
Date last updated
8/09/2021
Titles & IDs
Public title
Tocilizumab (TCZ) in New-onset Type 1 Diabetes
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Scientific title
Preserving Beta-Cell Function With Tocilizumab in New-onset Type 1 Diabetes (ITN058AI)
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Secondary ID [1]
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DAIT ITN058AI
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Universal Trial Number (UTN)
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Trial acronym
EXTEND
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes Mellitus
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New-onset Type 1 Diabetes Mellitus
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T1DM
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T1D
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Condition category
Condition code
Metabolic and Endocrine
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Diabetes
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Tocilizumab (TCZ)
Treatment: Drugs - Placebo
Other interventions - Standard of Care
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])
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])
Treatment: Drugs: 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.
Treatment: Drugs: 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 interventions: Standard of Care
Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC])
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) in Pediatric Participants
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline (Pre-treatment) to Week 52
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Secondary outcome [1]
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Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC)
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline (Pre-treatment) to Weeks 24, 52, and 104
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Secondary outcome [2]
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2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline (Pre-treatment), Weeks 12, 24, 39, 52, 78, and 104
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Secondary outcome [3]
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Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC)
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline (Pre-treatment) to Weeks 52 and 104
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Secondary outcome [4]
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Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day
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Assessment method [4]
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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.
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Timepoint [4]
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Baseline (Pre-treatment) to Weeks 24, 52, and 104
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Secondary outcome [5]
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Change From Baseline in Average Insulin Use Per Kg, Mixed Model
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Assessment method [5]
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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.
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Timepoint [5]
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Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
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Secondary outcome [6]
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Change From Baseline in Hemoglobin A1c
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Assessment method [6]
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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.
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Timepoint [6]
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Baseline (Pre-treatment) to Weeks 24, 52, and 104
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Secondary outcome [7]
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Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model
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Assessment method [7]
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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.
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Timepoint [7]
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Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
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Secondary outcome [8]
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Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation
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Assessment method [8]
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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
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Timepoint [8]
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Day 0 (Treatment Initiation) to Weeks 52 and 104
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Secondary outcome [9]
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Number of Participants Who Experienced Infusion-Related Adverse Events
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Assessment method [9]
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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.
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Timepoint [9]
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Day 0 (Treatment Initiation) to Week 52
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Secondary outcome [10]
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Number of Participants Who Experienced Hypersensitivity Adverse Events
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Assessment method [10]
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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
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Timepoint [10]
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Day 0 (Treatment Initiation) to Week 52
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Eligibility
Key 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).
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Minimum age
6
Years
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Maximum age
17
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
12/03/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
31/08/2020
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Sample size
Target
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Accrual to date
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Final
136
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Recruitment in Australia
Recruitment state(s)
NSW,QLD
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Recruitment hospital [1]
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The Children's Hospital at Westmead: Kids Research Institute - Westmead
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Recruitment hospital [2]
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Lady Cilento Children's Hospital: Department of Endocrinology - South Brisbane
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Recruitment postcode(s) [1]
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Westmead 2145 - Westmead
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Recruitment postcode(s) [2]
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4101 - South Brisbane
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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United States of America
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State/province [2]
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Connecticut
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United States of America
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State/province [3]
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Florida
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Country [4]
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United States of America
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State/province [4]
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Indiana
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Country [5]
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United States of America
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State/province [5]
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Iowa
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Country [6]
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United States of America
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State/province [6]
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Massachusetts
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Country [7]
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United States of America
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State/province [7]
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Minnesota
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Country [8]
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United States of America
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State/province [8]
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Missouri
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Country [9]
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United States of America
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State/province [9]
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New York
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Country [10]
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United States of America
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State/province [10]
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Pennsylvania
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Country [11]
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United States of America
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State/province [11]
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South Dakota
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Country [12]
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United States of America
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State/province [12]
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Tennessee
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Country [13]
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United States of America
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State/province [13]
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Texas
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Country [14]
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United States of America
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State/province [14]
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Washington
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Funding & Sponsors
Primary sponsor type
Government body
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Name
National Institute of Allergy and Infectious Diseases (NIAID)
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Address
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Other collaborator category [1]
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Other
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Name [1]
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Immune Tolerance Network (ITN)
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Address [1]
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Other collaborator category [2]
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Commercial sector/Industry
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Name [2]
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PPD
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Address [2]
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Other collaborator category [3]
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Commercial sector/Industry
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Name [3]
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Rho Federal Systems Division, Inc.
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Address [3]
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02293837
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Carla Greenbaum
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Address
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Benaroya Research Institute at Virginia Mason: Diabetes Research Program
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Fax
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02293837
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