In type 1 diabetes (T1D), immune defense cells in the body attack and destroy insulin-producing beta cells leaving affected people with a lifelong need for daily insulin injections. Even with insulin injections, blood glucose (sugar) control is imperfect and leads to many health complications and a shortened life span. Our pilot study (NCT02117765) has informed us that Ustekinumab is safe in the treatment of participants with recent-onset T1D. Ustekinumab is currently licensed for use in psoriasis where it has proven to be both highly effective and safe. The investigators hope that if the drug can block immune cells soon after the development of diabetes, any remaining insulin-producing cells may be protected, and regenerate, thus producing more insulin so that individuals may be insulin free, or require less insulin. This trial will assess the efficacy of Ustekinumab in decreasing C-peptide decline (proxy for endogenous insulin production) in participants with recent onset T1D.
This is a randomized, placebo-controlled, double-blinded, multi-centre phase II/II study to assess efficacy and safety of Ustekinumab (STELARA®) in patients with T1D. The investigators will perform a phase II/III clinical trial with a total of 66 adult (18-35 years old) subjects with recent-onset T1D. There will be two study cohorts, with a drug:placebo ratio of 2:1. Patients receiving the study drug will receive a loading dose of 6mg/kg Ustekinumab IV given at week 0. Thereafter, 90mg Ustekinumab subcutaneously given at weeks 8, 16, 24, 32, 40, 48 (total of 7 doses). Patients randomized to receive placebo will receive respective amounts of a saline-placebo. An additional non-dosing visit at the midpoint (week 28) is required to measure 2-hour C-peptide during a MMTT. Patients will be followed for 78 weeks following the first dose. There will be a total of 10 study visits over 78 weeks, three of which are non-dosing and follow-up visits. Recruitment and screening for the study will be completed within the first 24 months. The follow up period is 1 and 1.5 years from the first dose.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
66
Week 0: Loading dose of 6mg/kg Ustekinumab Intravenously. Weeks 8, 16, 24, 32, 40, and 48 (6 visits): 90mg Ustekinumab subcutaneously.
Patients allocated to receive placebo will receive respective amounts of a saline-placebo at the same intervals. Week 0: Loading dose of 6mg/kg saline intravenously. Weeks 8, 16, 24, 32, 40, and 48 (6 visits): 90mg saline subcutaneously.
Mount Sinai Hospital/UHN
Toronto, British Columbia, Canada
BCDiabetes
Vancouver, British Columbia, Canada
Baseline change in 2-hour mixed meal-stimulated C-peptide AUC at week 52.
Time frame: Week 52
Rate, frequency and severity of all adverse events including; hypoglycemic episodes; injection reactions; hypersensitivity reactions; evidence of infection and posterior leukoencephalopathy syndrome.
Time frame: Week 52
2-hour MMTT-stimulated C-peptide AUC at weeks 28 and 78)
Time frame: Weeks 28 and 78
HbA1C and insulin use in units per kg body weight per day at weeks 0, 8, 16, 24, 28, 32, 40, 48, 52, 78.
Time frame: 78 Weeks
Immune phenotyping via flow cytometry of all IL-12, IL-23, IL-17, IFN-γ secreting immune subsets at weeks 0, 32, 52, 78).
Time frame: 78 Weeks
Basic immune phenotyping of WBC subsets
Time frame: 78 Weeks
HLA- A, B, C, DR, DP, DQ typing at weeks 0, 8 ,16, 32, 52, 78)
Time frame: 78 Weeks
Fluorospot (ELISpot) analysis for IL-17 and IFN-γ secretion in response to whole insulin and antigens for CD8+ and CD4+ T cells.
Time frame: 78 Weeks
Luminex/Mesoscale assessment of serum cytokines IL-17, IFN-γ, IL-12p40, IL-12p70 and IL-23.
Time frame: 78 Weeks
Regulatory T cell (CD4+ FOXP3+): Effector T cell (CD4+ FOXP3-CD25+) ratio.
Time frame: 78 Weeks
CD154 and CD134 (OX40) based assays to determine diabetogenic antigen specific responses of T helper cells.
Time frame: 52 Weeks
Nanostring assessment of whole blood and PBMC RNA gene expression of IL-17 and IFN-γ family genes.
Time frame: 78 Weeks
Epigenetic assessment of Treg phenotype and function.
Time frame: 78 Weeks
Sequencing and profiling of microbiome.
Time frame: 78 Weeks
Glycaemic variability in continuous glucose monitoring and hypoglycaemia rates.
Time frame: 78 Weeks
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