Clinical trial NCT02293837: Tocilizumab (TCZ) in New-onset Type 1 Diabetes
Official title: Preserving Beta-Cell Function With Tocilizumab in New-onset Type 1 Diabetes (ITN058AI)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus
New-onset Type 1 Diabetes Mellitus
T1DM
T1D
Keywords: interleukin-6 (IL-6) receptor inhibitor
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
name: PPD Development, LP
name: Rho Federal Systems Division, Inc.
First posted: 2014-11-18
Enrollment: 136
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC) in Pediatric Participants
timeFrame: Baseline (Pre-treatment) to Week 52
Secondary outcomes:
measure: Change From Baseline in 2-Hour C-peptide Mean Area Under the Curve (mAUC)
timeFrame: Baseline (Pre-treatment) to Weeks 24, 52, and 104
measure: 2-Hour C-peptide Mean Area Under the Curve (mAUC), Mixed Model
timeFrame: Baseline (Pre-treatment), Weeks 12, 24, 39, 52, 78, and 104
measure: Change From Baseline in 4-Hour C-peptide Mean Area Under the Curve (mAUC)
timeFrame: Baseline (Pre-treatment) to Weeks 52 and 104
measure: Change From Baseline in Average Insulin Use in Units Per Kilogram Body Weight Per Day
timeFrame: Baseline (Pre-treatment) to Weeks 24, 52, and 104
measure: Change From Baseline in Average Insulin Use Per Kg, Mixed Model
timeFrame: Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
measure: Change From Baseline in Hemoglobin A1c
timeFrame: Baseline (Pre-treatment) to Weeks 24, 52, and 104
measure: Change From Baseline in Hemoglobin A1C (HbA1c) Level in Participants, Mixed Model
timeFrame: Baseline (Pre-treatment) to Weeks 12, 24, 39, 52, 78, and 104
measure: Number of Participants Who Experienced at Least One Major Hypoglycemic Event After Treatment Initiation
timeFrame: Day 0 (Treatment Initiation) to Weeks 52 and 104
measure: Number of Participants Who Experienced Infusion-Related Adverse Events
timeFrame: Day 0 (Treatment Initiation) to Week 52
measure: Number of Participants Who Experienced Hypersensitivity Adverse Events
timeFrame: Day 0 (Treatment Initiation) to Week 52
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine: Diabetes Endocrinology Research Center
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami: Diabetes Research Institute
state: Florida
city: Tampa
country: United States
facility: University of South Florida: Diabetes Center
state: Florida
city: Indianapolis
country: United States
facility: Indiana University Health - Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Harvard University, Joslin Diabetes Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: New York
country: United States
facility: Columbia University, Naomi Berrie Diabetes Center
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Research
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute
state: Washington
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead: Kids Research Institute
state: New South Wales
city: South Brisbane
country: Australia
facility: Lady Cilento Children's Hospital: Department of Endocrinology
state: Queensland
Study officials:
affiliation: Benaroya Research Institute at Virginia Mason: Diabetes Research Program
name: Carla Greenbaum
role: STUDY_CHAIR
affiliation: Benaroya Research Institute at Virginia Mason: Diabetes Research Program
name: Jane Buckner, M.D.
role: STUDY_CHAIR
References:
citation: Greenbaum CJ, Serti E, Lambert K, Weiner LJ, Kanaparthi S, Lord S, Gitelman SE, Wilson DM, Gaglia JL, Griffin KJ, Russell WE, Raskin P, Moran A, Willi SM, Tsalikian E, DiMeglio LA, Herold KC, Moore WV, Goland R, Harris M, Craig ME, Schatz DA, Baidal DA, Rodriguez H, Utzschneider KM, Nel HJ, Soppe CL, Boyle KD, Cerosaletti K, Keyes-Elstein L, Long SA, Thomas R, McNamara JG, Buckner JH, Sanda S; ITN058AI EXTEND Study Team. IL-6 receptor blockade does not slow beta cell loss in new-onset type 1 diabetes. JCI Insight. 2021 Nov 8;6(21):e150074. doi: 10.1172/jci.insight.150074.
citation: Hundhausen C, Roth A, Whalen E, Chen J, Schneider A, Long SA, Wei S, Rawlings R, Kinsman M, Evanko SP, Wight TN, Greenbaum CJ, Cerosaletti K, Buckner JH. Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression. Sci Transl Med. 2016 Sep 14;8(356):356ra119. doi: 10.1126/scitranslmed.aad9943.