Tocilizumab (TCZ) in New-onset Type 1 Diabetes

Type 1 Diabetes Mellitus Clinical Trial

— EXTEND  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02293837
• Other study ID #: DAIT ITN058AI
• Status: Completed
• Phase: Phase 2
• Start date: March 12, 2015
• Est. completion date: August 31, 2020

Study information

• Verified date: August 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 136
• Est. completion date: August 31, 2020
• Est. primary completion date: July 10, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Tocilizumab (TCZ)
Subjects assigned to this group will receive tocilizumab intravenous (IV) infusions of either 8.0 mg/kg (body weight = 30kg) or 10.0 mg/kg (body weight <30kg) every 4 weeks for 24 weeks.
• Placebo
Subjects assigned to this group will receive placebo intravenous (IV) infusions of either 8.0 mg/kg (body weight = 30kg) or 10.0 mg/kg (body weight <30kg) every 4 weeks for 24 weeks.

Other:
• Standard of Care
Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines [Standard of Care, SOC])

Locations

Country	Name	City	State
Australia	Lady Cilento Children's Hospital: Department of Endocrinology	South Brisbane	Queensland
Australia	The Children's Hospital at Westmead: Kids Research Institute	Westmead	New South Wales
United States	Harvard University, Joslin Diabetes Center	Boston	Massachusetts
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of Florida	Gainesville	Florida
United States	Indiana University Health - Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	University of Miami: Diabetes Research Institute	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University	Nashville	Tennessee
United States	Yale University School of Medicine: Diabetes Endocrinology Research Center	New Haven	Connecticut
United States	Columbia University, Naomi Berrie Diabetes Center	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of California San Francisco	San Francisco	California
United States	Benaroya Research Institute	Seattle	Washington
United States	Sanford Research	Sioux Falls	South Dakota
United States	Stanford University	Stanford	California
United States	University of South Florida: Diabetes Center	Tampa	Florida

Sponsors (4)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Immune Tolerance Network (ITN), PPD, Rho Federal Systems Division, Inc.

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline (Pre-treatment) to Week 52
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.	Baseline (Pre-treatment) to Weeks 24, 52, and 104
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.	Baseline (Pre-treatment), Weeks 12, 24, 39, 52, 78, and 104
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.	Baseline (Pre-treatment) to Weeks 52 and 104
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.	Baseline (Pre-treatment) to Weeks 24, 52, and 104
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.	Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
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.	Baseline (Pre-treatment) to Weeks 24, 52, and 104
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.	Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
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	Day 0 (Treatment Initiation) to Weeks 52 and 104
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.	Day 0 (Treatment Initiation) to Week 52
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	Day 0 (Treatment Initiation) to Week 52

External Links

•   American Diabetes Association information on Type 1 Diabetes
•   Division of Allergy, Immunology, and Transplantation (DAIT) website
•   EXTEND's study-specific ITN website
•   Immune Tolerance Network (ITN) website
•   National Institute of Allergy and Infectious Diseases (NIAID) website