Type 1 Diabetes Mellitus, New-onset Type 1 Diabetes Mellitus, T1DM, T1D
Conditions
Keywords
interleukin-6 (IL-6) receptor inhibitor
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.
Interventions
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.
DRUGPlacebo
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.
OTHERStandard of Care
Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines \[Standard of Care, SOC\])
Sponsors
Immune Tolerance Network (ITN)
PPD Development, LP
Rho Federal Systems Division, Inc.
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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. |
| 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. |
| 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 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 |
| 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 hypertension |
| 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. |
Countries
Australia, United States
Participant flow
Recruitment details
Participants were screened from February 11, 2015 to Jun 21, 2018 at 17 sites in the US and two sites in Australia. March 12, 2015 was the actual date on which the first participant was enrolled in this clinical study.
Pre-assignment details
Before initiating the study in the pediatric group (6-17 years old), adults (18-45 years old) were randomized 2:1 to tocilizumab or placebo, respectively. After at least 30 adults completed 12 weeks of treatment, the Data and Safety Monitoring Board (DSMB) and FDA reviewed the available data and allowed the enrollment of children 6-17 years old.
Participants by arm
| Arm | Count |
|---|---|
| Tocilizumab (TCZ) in Pediatric Participants Participants received 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. The dose was capped at 800 mg. Pediatric participants were 6 to 17 years old inclusive. | 54 |
| Placebo in Pediatric Participants Participants received IV placebo infusions of saline of equal volume and appearance to the treatment. Pediatric participants were 6 to 17 years old inclusive. | 27 |
| Tocilizumab (TCZ) in Adult Participants Participants received 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. The dose was capped at 800 mg. Adult participants were 18 to 45 years old inclusive. | 35 |
| Placebo in Adult Participants Participants received IV placebo infusions of saline of equal volume and appearance to the treatment. Adult participants were 18 to 45 years old inclusive. | 20 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | COVID-19 Related | 1 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 | 1 | 0 |
| Overall Study | Participant ill and could not be infused | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | Tocilizumab (TCZ) in Pediatric Participants | Placebo in Pediatric Participants | Tocilizumab (TCZ) in Adult Participants | Placebo in Adult Participants | Total |
|---|---|---|---|---|---|
| 2-hour C-peptide Mean Area Under the Curve (mAUC) Result in Response to Standardized Mixed Meal Tol | 0.73 pmol/mL STANDARD_DEVIATION 0.44 | 0.66 pmol/mL STANDARD_DEVIATION 0.32 | 0.77 pmol/mL STANDARD_DEVIATION 0.24 | 0.97 pmol/mL STANDARD_DEVIATION 0.69 | 0.76 pmol/mL STANDARD_DEVIATION 0.43 |
| Age, Continuous | 11.1 years STANDARD_DEVIATION 2.9 | 11.1 years STANDARD_DEVIATION 2.5 | 27.9 years STANDARD_DEVIATION 7.4 | 29.2 years STANDARD_DEVIATION 9.3 | 18.1 years STANDARD_DEVIATION 10.2 |
| Average Insulin Use Per Kilogram Body Weight | 0.39 Units per Kilogram Body Weight per Day STANDARD_DEVIATION 0.24 | 0.38 Units per Kilogram Body Weight per Day STANDARD_DEVIATION 0.19 | 0.28 Units per Kilogram Body Weight per Day STANDARD_DEVIATION 0.15 | 0.30 Units per Kilogram Body Weight per Day STANDARD_DEVIATION 0.21 | 0.35 Units per Kilogram Body Weight per Day STANDARD_DEVIATION 0.21 |
| Body Mass Index (BMI) | 19.8 kg/m^2 STANDARD_DEVIATION 3.8 | 19.1 kg/m^2 STANDARD_DEVIATION 3.3 | 24.2 kg/m^2 STANDARD_DEVIATION 3.9 | 25.4 kg/m^2 STANDARD_DEVIATION 3.5 | 21.6 kg/m^2 STANDARD_DEVIATION 4.4 |
| Days from Type 1 Diabetes Mellitus (T1DM) Diagnosis to Randomization | 85.9 Days STANDARD_DEVIATION 15.5 | 83.9 Days STANDARD_DEVIATION 16.7 | 82.5 Days STANDARD_DEVIATION 13.6 | 84.6 Days STANDARD_DEVIATION 12.4 | 84.4 Days STANDARD_DEVIATION 14.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants | 1 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants | 21 Participants | 32 Participants | 19 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Hemoglobin A1C (HbA1c) Level | 6.79 percent (%) STANDARD_DEVIATION 1.03 | 6.86 percent (%) STANDARD_DEVIATION 0.55 | 6.48 percent (%) STANDARD_DEVIATION 1.08 | 6.28 percent (%) STANDARD_DEVIATION 0.73 | 6.65 percent (%) STANDARD_DEVIATION 0.94 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 47 Participants | 20 Participants | 32 Participants | 19 Participants | 118 Participants |
| Region of Enrollment Australia | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Region of Enrollment United States | 52 Participants | 24 Participants | 35 Participants | 20 Participants | 131 Participants |
| Sex: Female, Male Female | 26 Participants | 12 Participants | 12 Participants | 7 Participants | 57 Participants |
| Sex: Female, Male Male | 28 Participants | 15 Participants | 23 Participants | 13 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 27 | 0 / 34 | 0 / 20 | 0 / 88 | 0 / 27 |
| other Total, other adverse events | 52 / 54 | 26 / 27 | 31 / 34 | 19 / 20 | 83 / 88 | 45 / 47 |
| serious Total, serious adverse events | 3 / 54 | 3 / 27 | 2 / 34 | 2 / 20 | 5 / 88 | 5 / 47 |
Outcome results
Primary
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.
Time frame: Baseline (Pre-treatment) to Week 52
Population: The modified intent to treat population includes all randomized participants who received any dose of assigned study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) in Pediatric Participants | -0.337 pmol/mL |
| Placebo in Pediatric Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) in Pediatric Participants | -0.391 pmol/mL |
Comparison: Week 52; Primary imputation method used for missing Week 52 mAUC.p-value: 0.277ANCOVA
Secondary
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.
Time frame: Baseline (Pre-treatment), Weeks 12, 24, 39, 52, 78, and 104
Population: The modified intent to treat population includes all randomized participants who received any dose of assigned study treatment. The model only included subjects with at least 1 post-screening assessment. One mITT subject did not have a post-screening MMTT and this subject is not included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 52 | 0.42 pmol/mL |
| Tocilizumab (TCZ) in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 12 | 0.60 pmol/mL |
| Tocilizumab (TCZ) in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 104 | 0.18 pmol/mL |
| Tocilizumab (TCZ) in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 24 | 0.55 pmol/mL |
| Tocilizumab (TCZ) in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 39 | 0.48 pmol/mL |
| Tocilizumab (TCZ) in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 78 | 0.30 pmol/mL |
| Placebo in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 39 | 0.42 pmol/mL |
| Placebo in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 78 | 0.23 pmol/mL |
| Placebo in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 104 | 0.10 pmol/mL |
| Placebo in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 24 | 0.49 pmol/mL |
| Placebo in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 12 | 0.55 pmol/mL |
| Placebo in Pediatric Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 52 | 0.35 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 52 | 0.59 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 24 | 0.68 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 78 | 0.50 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 104 | 0.41 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 12 | 0.72 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 39 | 0.63 pmol/mL |
| Placebo in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 12 | 0.88 pmol/mL |
| Placebo in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 52 | 0.72 pmol/mL |
| Placebo in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 39 | 0.77 pmol/mL |
| Placebo in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 24 | 0.83 pmol/mL |
| Placebo in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 78 | 0.61 pmol/mL |
| Placebo in Adult Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 104 | 0.50 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 39 | 0.54 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 24 | 0.60 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 12 | 0.65 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 52 | 0.49 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 78 | 0.38 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 104 | 0.27 pmol/mL |
| Placebo in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 12 | 0.69 pmol/mL |
| Placebo in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 52 | 0.50 pmol/mL |
| Placebo in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 39 | 0.56 pmol/mL |
| Placebo in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 24 | 0.63 pmol/mL |
| Placebo in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 104 | 0.27 pmol/mL |
| Placebo in Pooled Participants | 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model | Week 78 | 0.38 pmol/mL |
Comparison: Screening to Week 104p-value: 0.679Longitudinal mixed model
Comparison: Screening to Week 104p-value: 0.373Longitudinal mixed model
Comparison: Screening to Week 104p-value: 0.395Longitudinal mixed model
Secondary
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.
Time frame: Baseline (Pre-treatment) to Weeks 24, 52, and 104
Population: Modified intent to treat population includes all randomized participants who received any dose of assigned study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 24 | -0.200 pmol/mL |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.339 pmol/mL |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.495 pmol/mL |
| Placebo in Pediatric Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 24 | -0.164 pmol/mL |
| Placebo in Pediatric Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.397 pmol/mL |
| Placebo in Pediatric Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.556 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 24 | -0.072 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.186 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.384 pmol/mL |
| Placebo in Adult Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 24 | -0.097 pmol/mL |
| Placebo in Adult Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.267 pmol/mL |
| Placebo in Adult Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.388 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 24 | -0.152 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.287 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.461 pmol/mL |
| Placebo in Pooled Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 24 | -0.134 pmol/mL |
| Placebo in Pooled Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.328 pmol/mL |
| Placebo in Pooled Participants | Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.463 pmol/mL |
Comparison: Week 24p-value: 0.499ANCOVA
Comparison: Week 52p-value: 0.267ANCOVA
Comparison: Week 104p-value: 0.226ANCOVA
Comparison: Week 24p-value: 0.758ANCOVA
Comparison: Week 52p-value: 0.341ANCOVA
Comparison: Week 104p-value: 0.969ANCOVA
Comparison: Week 24p-value: 0.689ANCOVA
Comparison: Week 52p-value: 0.4ANCOVA
Comparison: Week 104p-value: 0.969ANCOVA
Secondary
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.
Time frame: Baseline (Pre-treatment) to Weeks 52 and 104
Population: The modified intent to treat population includes all randomized participants who received any dose of assigned study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.325 pmol/mL |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.521 pmol/mL |
| Placebo in Pediatric Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.448 pmol/mL |
| Placebo in Pediatric Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.635 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.195 pmol/mL |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.382 pmol/mL |
| Placebo in Adult Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.262 pmol/mL |
| Placebo in Adult Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.390 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.252 pmol/mL |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.449 pmol/mL |
| Placebo in Pooled Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 52 | -0.321 pmol/mL |
| Placebo in Pooled Participants | Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC) | Week 104 | -0.448 pmol/mL |
Comparison: Week 52. Only participants \>=12 years old had the 4-hour MMTT performed.p-value: 0.176ANCOVA
Comparison: Week 104. Only participants \>=12 years old had the 4-hour MMTT performed.p-value: 0.285ANCOVA
Comparison: Week 52p-value: 0.435ANCOVA
Comparison: Week 104p-value: 0.931ANCOVA
Comparison: Week 52. Only participants \>=12 years old had the 4-hour MMTT performed.p-value: 0.28ANCOVA
Comparison: Week 104. Only participants \>=12 years old had the 4-hour MMTT performed.p-value: 0.985ANCOVA
Secondary
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.
Time frame: Baseline (Pre-treatment) to Weeks 24, 52, and 104
Population: The modified intent to treat population includes all randomized participants who received any dose of assigned study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 52 | 0.300 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 24 | 0.139 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 104 | 0.403 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 52 | 0.326 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 24 | 0.126 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 104 | 0.493 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 52 | 0.081 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 24 | 0.015 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 104 | 0.116 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 52 | 0.112 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 24 | 0.146 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 104 | 0.129 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 52 | 0.211 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 24 | 0.090 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 104 | 0.288 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 24 | 0.139 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 104 | 0.354 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day | Week 52 | 0.243 Units per Kilogram Body Weight per Day |
Comparison: Week 24p-value: 0.762ANCOVA
Comparison: Week 52p-value: 0.64ANCOVA
Comparison: Week 104p-value: 0.145ANCOVA
Comparison: Week 24p-value: 0.033ANCOVA
Comparison: Week 52p-value: 0.591ANCOVA
Comparison: Week 104p-value: 0.81ANCOVA
Comparison: Week 24p-value: 0.178ANCOVA
Comparison: Week 52p-value: 0.43ANCOVA
Comparison: Week 104p-value: 0.149ANCOVA
Secondary
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.
Time frame: Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
Population: The modified intent to treat population includes all randomized participants who received any dose of assigned study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 12 | 0.45 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 78 | 0.73 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 24 | 0.50 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 39 | 0.57 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 104 | 0.84 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 52 | 0.62 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 39 | 0.59 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 104 | 0.94 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 12 | 0.45 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 24 | 0.51 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 52 | 0.66 Units per Kilogram Body Weight per Day |
| Placebo in Pediatric Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 78 | 0.80 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 12 | 0.29 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 52 | 0.35 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 78 | 0.39 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 24 | 0.31 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 39 | 0.33 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 104 | 0.43 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 24 | 0.40 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 52 | 0.46 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 104 | 0.57 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 78 | 0.51 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 39 | 0.43 Units per Kilogram Body Weight per Day |
| Placebo in Adult Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 12 | 0.37 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 104 | 0.68 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 24 | 0.43 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 78 | 0.60 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 39 | 0.47 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 52 | 0.51 Units per Kilogram Body Weight per Day |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 12 | 0.39 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 52 | 0.58 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 78 | 0.68 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 39 | 0.53 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 24 | 0.47 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 12 | 0.42 Units per Kilogram Body Weight per Day |
| Placebo in Pooled Participants | Change From Baseline in Average Insulin Use Per Kg, Mixed Model | Week 104 | 0.79 Units per Kilogram Body Weight per Day |
Comparison: Screening to Week 104p-value: 0.103Longitudinal mixed model
Comparison: Screening to Week 104p-value: 0.452Longitudinal mixed model
Comparison: Screening to Week 104p-value: 0.091Longitudinal mixed model
Secondary
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.
Time frame: Baseline (Pre-treatment) to Weeks 24, 52, and 104
Population: The modified intent to treat population includes all randomized participants who received any dose of assigned study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1c | Week 104 | 0.734 percent (%) |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1c | Week 52 | 0.650 percent (%) |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1c | Week 24 | 0.065 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1c | Week 52 | 1.134 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1c | Week 24 | 0.368 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1c | Week 104 | 1.042 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1c | Week 104 | 0.253 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1c | Week 24 | -0.509 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1c | Week 52 | 0.152 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1c | Week 24 | -0.136 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1c | Week 104 | 0.583 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1c | Week 52 | 0.262 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1c | Week 52 | 0.459 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1c | Week 24 | -0.163 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1c | Week 104 | 0.556 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1c | Week 52 | 0.753 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1c | Week 104 | 0.812 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1c | Week 24 | 0.169 percent (%) |
Comparison: Week 24p-value: 0.154ANCOVA
Comparison: Week 52p-value: 0.193ANCOVA
Comparison: Week 104p-value: 0.397ANCOVA
Comparison: Week 24p-value: 0.125ANCOVA
Comparison: Week 52p-value: 0.705ANCOVA
Comparison: Week 104p-value: 0.378ANCOVA
Comparison: Week 24p-value: 0.035ANCOVA
Comparison: Week 52p-value: 0.262ANCOVA
Comparison: Week 104p-value: 0.338ANCOVA
Secondary
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.
Time frame: Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
Population: The modified intent to treat population includes all randomized participants who received any dose of assigned study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 104 | 7.80 percent (%) |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 39 | 7.05 percent (%) |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 78 | 7.50 percent (%) |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 12 | 6.74 percent (%) |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 24 | 6.87 percent (%) |
| Tocilizumab (TCZ) in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 52 | 7.20 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 104 | 8.62 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 12 | 6.99 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 39 | 7.46 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 78 | 8.16 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 24 | 7.20 percent (%) |
| Placebo in Pediatric Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 52 | 7.69 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 39 | 6.19 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 104 | 6.94 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 24 | 6.02 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 12 | 5.88 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 52 | 6.34 percent (%) |
| Tocilizumab (TCZ) in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 78 | 6.64 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 12 | 6.04 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 78 | 6.86 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 104 | 7.19 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 52 | 6.54 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 39 | 6.38 percent (%) |
| Placebo in Adult Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 24 | 6.19 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 39 | 6.71 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 78 | 7.16 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 52 | 6.86 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 104 | 7.45 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 24 | 6.54 percent (%) |
| Tocilizumab (TCZ) in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 12 | 6.40 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 104 | 8.04 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 12 | 6.60 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 24 | 6.79 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 39 | 7.02 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 52 | 7.23 percent (%) |
| Placebo in Pooled Participants | Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model | Week 78 | 7.63 percent (%) |
Comparison: Screening to Week 104p-value: 0.493Longitudinal mixed model
Comparison: Screening to Week 104p-value: 0.659Longitudinal mixed model
Comparison: Screening to Week 104p-value: 0.407Longitudinal mixed model
Secondary
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
Time frame: Day 0 (Treatment Initiation) to Weeks 52 and 104
Population: The safety population includes all participants who received any degree of study treatment. Safety analyses are based on actual treatment the participants receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 52 | 19 Participants |
| Tocilizumab (TCZ) in Pediatric Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 104 | 28 Participants |
| Placebo in Pediatric Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 52 | 11 Participants |
| Placebo in Pediatric Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 104 | 14 Participants |
| Tocilizumab (TCZ) in Adult Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 52 | 10 Participants |
| Tocilizumab (TCZ) in Adult Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 104 | 15 Participants |
| Placebo in Adult Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 52 | 3 Participants |
| Placebo in Adult Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 104 | 8 Participants |
| Tocilizumab (TCZ) in Pooled Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 52 | 29 Participants |
| Tocilizumab (TCZ) in Pooled Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 104 | 43 Participants |
| Placebo in Pooled Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 52 | 14 Participants |
| Placebo in Pooled Participants | Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation | Day 0 to Week 104 | 22 Participants |
Comparison: Baseline to Week 52p-value: 0.634Fisher Exact
Comparison: Baseline to Week 104/End of Studyp-value: 1Fisher Exact
Comparison: Baseline to Week 52p-value: 0.329Fisher Exact
Comparison: Baseline to Week 104/End of Studyp-value: 1Fisher Exact
Comparison: Baseline to Week 52p-value: 0.847Fisher Exact
Comparison: Baseline to Week 104/End of Studyp-value: 0.858Fisher Exact
Secondary
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
Time frame: Day 0 (Treatment Initiation) to Week 52
Population: The safety population includes all participants who received any degree of study treatment. Safety analyses are based on actual treatment the participants receive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Number of Participants Who Experienced Hypersensitivity Adverse Events | 3 Participants |
| Placebo in Pediatric Participants | Number of Participants Who Experienced Hypersensitivity Adverse Events | 0 Participants |
| Tocilizumab (TCZ) in Adult Participants | Number of Participants Who Experienced Hypersensitivity Adverse Events | 0 Participants |
| Placebo in Adult Participants | Number of Participants Who Experienced Hypersensitivity Adverse Events | 0 Participants |
| Tocilizumab (TCZ) in Pooled Participants | Number of Participants Who Experienced Hypersensitivity Adverse Events | 3 Participants |
| Placebo in Pooled Participants | Number of Participants Who Experienced Hypersensitivity Adverse Events | 0 Participants |
Comparison: Treatment start to Week 52p-value: 0.547Fisher Exact
Comparison: Treatment start to Week 52p-value: 0.551Fisher Exact
Secondary
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.
Time frame: Day 0 (Treatment Initiation) to Week 52
Population: The safety population includes all participants who received any degree of study treatment. Safety analyses are based on actual treatment the participants receive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab (TCZ) in Pediatric Participants | Number of Participants Who Experienced Infusion-Related Adverse Events | 4 Participants |
| Placebo in Pediatric Participants | Number of Participants Who Experienced Infusion-Related Adverse Events | 0 Participants |
| Tocilizumab (TCZ) in Adult Participants | Number of Participants Who Experienced Infusion-Related Adverse Events | 5 Participants |
| Placebo in Adult Participants | Number of Participants Who Experienced Infusion-Related Adverse Events | 0 Participants |
| Tocilizumab (TCZ) in Pooled Participants | Number of Participants Who Experienced Infusion-Related Adverse Events | 9 Participants |
| Placebo in Pooled Participants | Number of Participants Who Experienced Infusion-Related Adverse Events | 0 Participants |
Comparison: Treatment start to Week 52p-value: 0.296Fisher Exact
Comparison: Treatment start to Week 52p-value: 0.145Fisher Exact
Comparison: Treatment start to Week 52p-value: 0.027Fisher Exact