Tocilizumab (TCZ) in New-onset Type 1 Diabetes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Preserving Beta-Cell Function With Tocilizumab in New-onset Type 1 Diabetes (ITN058AI)

Conditions
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Type 1 Diabetes Mellitus, New-onset Type 1 Diabetes Mellitus, T1DM, T1D

Intervention / Treatment
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* Drug: Tocilizumab (TCZ)
* Drug: Placebo
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Exclusion Criteria: 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 Hemoglobin <8.5 g/dL . Neutrophil count <2,000 cells/microL. Females who are pregnant, lactating, or planning on pregnancy during the 2- year study period History or diagnoses of other autoimmune diseases with the exception of stable thyroid or celiac disease History of alcohol, drug or chemical abuse within 1 year prior to study eligibility screening evaluation Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial Prior participation in a clinical trial that could increase risks associated with this clinical trial 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 High lipid levels (fasting Low-density lipoprotein (LDL) cholesterol ≥160 mg/dL) History of significant allergy (e.g. anaphylaxis) to milk or soy proteins.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab (TCZ) + SOC<br>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)<br>* 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.<br>* Other names: Actemra®;Other: Standard of Care<br>* Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC])<br>* Other names: SOC;|
| Placebo Comparator: Tocilizumab Placebo Group + SOC<br>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<br>* 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.<br>* Other names: Placebo for Tocilizumab;Other: Standard of Care<br>* Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC])<br>* Other names: SOC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | 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 Weeks 24, 52, and 104 | 
| 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | 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), Weeks 12, 24, 39, 52, 78, and 104 | 
| Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | 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. | Baseline (Pre-treatment) to Weeks 52 and 104 | 
| Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | 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. | Baseline (Pre-treatment) to Weeks 24, 52, and 104 | 
| Change From Baseline in Average Insulin Use Per Kg, Mixed Model | 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. | Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104 | 
| Change From Baseline in Hemoglobin A1c | 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. | Baseline (Pre-treatment) to Weeks 24, 52, and 104 | 
| Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | 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. | Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104 | 
| Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | 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 | Day 0 (Treatment Initiation) to Weeks 52 and 104 | 
| Number of Participants Who Experienced Infusion-Related Adverse Events | 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. | Day 0 (Treatment Initiation) to Week 52 | 
| Number of Participants Who Experienced Hypersensitivity Adverse Events | 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 | Day 0 (Treatment Initiation) to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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interleukin-6 (IL-6) receptor inhibitor