Tocilizumab (TCZ) in New-onset Type 1 Diabetes
- Conditions
- T1DMT1DType 1 Diabetes MellitusNew-onset Type 1 Diabetes Mellitus
- Interventions
- Registration Number
- NCT02293837
- 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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 136
-
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).
-
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Tocilizumab (TCZ) + SOC Tocilizumab (TCZ) 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 \[Standard of Care, SOC\]) Tocilizumab (TCZ) + SOC Standard of Care 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 \[Standard of Care, SOC\]) Tocilizumab Placebo Group + SOC Placebo 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 \[Standard of Care, SOC\]) Tocilizumab Placebo Group + SOC Standard of Care 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 \[Standard of Care, SOC\])
- Primary Outcome Measures
Name Time Method Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) in Pediatric Participants 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
Name Time Method Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) 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-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model 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.
Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day 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.
Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) 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.
Change From Baseline in Hemoglobin A1c 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.
Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model 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.
Number of Participants Who Experienced Infusion-Related Adverse Events 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.
Number of Participants Who Experienced Hypersensitivity Adverse Events 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 hypertensionChange From Baseline in Average Insulin Use Per Kg, Mixed Model 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.
Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation 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
Trial Locations
- Locations (19)
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Benaroya Research Institute
🇺🇸Seattle, Washington, United States
Indiana University Health - Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
University of South Florida: Diabetes Center
🇺🇸Tampa, Florida, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Vanderbilt University
🇺🇸Nashville, Tennessee, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
University of Florida
🇺🇸Gainesville, Florida, United States
University of Miami: Diabetes Research Institute
🇺🇸Miami, Florida, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Harvard University, Joslin Diabetes Center
🇺🇸Boston, Massachusetts, United States
Columbia University, Naomi Berrie Diabetes Center
🇺🇸New York, New York, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
The Children's Hospital at Westmead: Kids Research Institute
🇦🇺Westmead, New South Wales, Australia
Lady Cilento Children's Hospital: Department of Endocrinology
🇦🇺South Brisbane, Queensland, Australia
Sanford Research
🇺🇸Sioux Falls, South Dakota, United States
Stanford University
🇺🇸Stanford, California, United States
Yale University School of Medicine: Diabetes Endocrinology Research Center
🇺🇸New Haven, Connecticut, United States
Children's Mercy Hospital
🇺🇸Kansas City, Missouri, United States