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Clinical Phase II/III Trial of Ustekinumab to Treat Type 1 Diabetes (UST1D2) (UST1D2)

Primary Purpose

Type 1 Diabetes Mellitus

Status

Recruiting

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Ustekinumab

Placebo

About this trial

This is an interventional treatment trial for Type 1 Diabetes Mellitus focused on measuring T1D, Ustekinumab, new-onset, diabetes

Eligibility Criteria

18 Years - 35 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

A diagnosis of type 1 diabetes mellitus in accordance with the ADA/CDA criteria.
An interval of ≤100 days between the diagnosis and the first dose of the study drug.
Ability to provide documented informed consent.
Male or female, aged 18-35 years inclusive, at the time of the anticipated first dose of the study drug.
Evidence of residual functioning β cells. This will be assessed by a C-peptide level over 0.2nmol/L in the MMTT test.
Positive for at least one diabetes-related autoantibody.
Willing to record all insulin taken and blood glucose levels that are required for monitoring during the study, including reporting any hypoglycaemic events.

Exclusion Criteria:

No condition that, in the investigators' judgment, is likely to cause the subject to not be able to understand information in order to provide informed consent.
History of malignancy.
No significant and/or active disease in any body system that is likely to increase the risk to the subject or interfere with the subject's participation in the study.
No significant systemic infection during the 6 weeks before the first dose of the study drug.
No history of current or past active tuberculosis infection and no latent tuberculosis as per CDC guidelines.
Have used any other investigational drug within the 3 months prior to the first dose and/or intend on using any investigational drug for the duration of the study.
Prior or current treatment that is known to cause a significant, ongoing change in the course of T1D or immunological status.
Current or prior (within 30 days prior to first study drug dose) use of medications known to influence glucose tolerance.
No significant abnormal laboratory values during the screening period, other than those due to T1D.
Not pregnant, breastfeeding or planning to become pregnant during the 60 days after the last dose of the study drug.
Have not received any live vaccines within 30 days prior to the first study drug dose and are not expected to need to receive a vaccine during the study.
No prior allergic reaction, including anaphylaxis, to any component of the study drug product.
No prior allergic reaction, including anaphylaxis, to any human, humanized, chimeric or rodent antibody treatment.
Have not undergone any major surgery within the 30 day period prior to the first drug dose and not anticipating requiring surgery during the study period.
Negative results for Hepatitis B surface antigen and for antibodies to Hepatitis B core antigen, or evidence of Hepatitis B surface antibody > 10 IU, and negative for Hepatitis C. Negative results for HIV and not considered by the investigator to be at high risk for HIV infection.

Sites / Locations

Mount Sinai Hospital/UHNRecruiting
BCDiabetesRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ustekinumab

Saline Solution - Placebo

Arm Description

Week 0: Loading dose of 6mg/kg Ustekinumab Intravenously. Weeks 8, 16, 24, 32, 40, and 48 (6 visits): 90mg Ustekinumab subcutaneously. Weeks 28, 52, 78: Non-dosing visits where a Mixed Meal Tolerance Test will be administered. Total of 11 visits

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. Weeks 28, 52, 78: Non-dosing visits where a Mixed Meal Tolerance Test will be administered. Total of 11 visits

Outcomes

Primary Outcome Measures

Baseline change in 2-hour mixed meal-stimulated C-peptide AUC at week 52.

Rate, frequency and severity of all adverse events including; hypoglycemic episodes; injection reactions; hypersensitivity reactions; evidence of infection and posterior leukoencephalopathy syndrome.

Secondary Outcome Measures

2-hour MMTT-stimulated C-peptide AUC at 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.

Immune phenotyping via flow cytometry of all IL-12, IL-23, IL-17, IFN-γ secreting immune subsets at weeks 0, 32, 52, 78).

Basic immune phenotyping of WBC subsets

HLA- A, B, C, DR, DP, DQ typing at weeks 0, 8 ,16, 32, 52, 78)

Fluorospot (ELISpot) analysis for IL-17 and IFN-γ secretion in response to whole insulin and antigens for CD8+ and CD4+ T cells.

Luminex/Mesoscale assessment of serum cytokines IL-17, IFN-γ, IL-12p40, IL-12p70 and IL-23.

Regulatory T cell (CD4+ FOXP3+): Effector T cell (CD4+ FOXP3-CD25+) ratio.

CD154 and CD134 (OX40) based assays to determine diabetogenic antigen specific responses of T helper cells.

Nanostring assessment of whole blood and PBMC RNA gene expression of IL-17 and IFN-γ family genes.

Epigenetic assessment of Treg phenotype and function.

Sequencing and profiling of microbiome.

Glycaemic variability in continuous glucose monitoring and hypoglycaemia rates.

Full Information

NCT ID

NCT03941132

First Posted

May 3, 2019

Last Updated

June 3, 2022

Sponsor

University of British Columbia

Collaborators

Juvenile Diabetes Research Foundation, Janssen, LP

1. Study Identification

Unique Protocol Identification Number

NCT03941132

Brief Title

Clinical Phase II/III Trial of Ustekinumab to Treat Type 1 Diabetes (UST1D2)

Acronym

UST1D2

Official Title

Clinical Phase II/III Trial of Ustekinumab to Treat Type 1 Diabetes (UST1D2)

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Recruiting

Study Start Date

January 4, 2021 (Actual)

Primary Completion Date

January 2024 (Anticipated)

Study Completion Date

August 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of British Columbia

Collaborators

Juvenile Diabetes Research Foundation, Janssen, LP

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 1 Diabetes Mellitus

Keywords

T1D, Ustekinumab, new-onset, diabetes

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Model Description

There will be a total of 60 patients enrolled in the study. The study participants will be enrolled at 2 centers (Vancouver and Toronto), and will be referred by adult or pediatric endocrinologists. This sample size estimation is based on results from week 52 C-peptide AUC values observed in the pilot UST1D study and the expected 1-year C-peptide decline in adult-onset T1D patients. Using a 2:1 Ustekinumab vs. placebo randomized assignment, a sample size of 60 yields 85% power to detect improvement in C-peptide function (alpha = 0.05) in the Ustekinumab group for an unstratified analysis at 12 months. Sixty-six participants (44 active: 22 placebo) will be recruited to allow for an approximate 10% loss to follow-up.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

66 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Ustekinumab

Arm Type

Experimental

Arm Description

Arm Title

Saline Solution - Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Ustekinumab

Other Intervention Name(s)

Stelara

Intervention Description

Week 0: Loading dose of 6mg/kg Ustekinumab Intravenously. Weeks 8, 16, 24, 32, 40, and 48 (6 visits): 90mg Ustekinumab subcutaneously.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Saline solution

Intervention Description

Primary Outcome Measure Information:

Title

Baseline change in 2-hour mixed meal-stimulated C-peptide AUC at week 52.

Time Frame

Week 52

Title

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

Secondary Outcome Measure Information:

Title

2-hour MMTT-stimulated C-peptide AUC at weeks 28 and 78)

Time Frame

Weeks 28 and 78

Title

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

Title

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

Title

Basic immune phenotyping of WBC subsets

Time Frame

78 Weeks

Title

HLA- A, B, C, DR, DP, DQ typing at weeks 0, 8 ,16, 32, 52, 78)

Time Frame

78 Weeks

Title

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

Title

Luminex/Mesoscale assessment of serum cytokines IL-17, IFN-γ, IL-12p40, IL-12p70 and IL-23.

Time Frame

78 Weeks

Title

Regulatory T cell (CD4+ FOXP3+): Effector T cell (CD4+ FOXP3-CD25+) ratio.

Time Frame

78 Weeks

Title

CD154 and CD134 (OX40) based assays to determine diabetogenic antigen specific responses of T helper cells.

Time Frame

52 Weeks

Title

Nanostring assessment of whole blood and PBMC RNA gene expression of IL-17 and IFN-γ family genes.

Time Frame

78 Weeks

Title

Epigenetic assessment of Treg phenotype and function.

Time Frame

78 Weeks

Title

Sequencing and profiling of microbiome.

Time Frame

78 Weeks

Title

Glycaemic variability in continuous glucose monitoring and hypoglycaemia rates.

Time Frame

78 Weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

35 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: A diagnosis of type 1 diabetes mellitus in accordance with the ADA/CDA criteria. An interval of ≤100 days between the diagnosis and the first dose of the study drug. Ability to provide documented informed consent. Male or female, aged 18-35 years inclusive, at the time of the anticipated first dose of the study drug. Evidence of residual functioning β cells. This will be assessed by a C-peptide level over 0.2nmol/L in the MMTT test. Positive for at least one diabetes-related autoantibody. Willing to record all insulin taken and blood glucose levels that are required for monitoring during the study, including reporting any hypoglycaemic events. Exclusion Criteria: No condition that, in the investigators' judgment, is likely to cause the subject to not be able to understand information in order to provide informed consent. History of malignancy. No significant and/or active disease in any body system that is likely to increase the risk to the subject or interfere with the subject's participation in the study. No significant systemic infection during the 6 weeks before the first dose of the study drug. No history of current or past active tuberculosis infection and no latent tuberculosis as per CDC guidelines. Have used any other investigational drug within the 3 months prior to the first dose and/or intend on using any investigational drug for the duration of the study. Prior or current treatment that is known to cause a significant, ongoing change in the course of T1D or immunological status. Current or prior (within 30 days prior to first study drug dose) use of medications known to influence glucose tolerance. No significant abnormal laboratory values during the screening period, other than those due to T1D. Not pregnant, breastfeeding or planning to become pregnant during the 60 days after the last dose of the study drug. Have not received any live vaccines within 30 days prior to the first study drug dose and are not expected to need to receive a vaccine during the study. No prior allergic reaction, including anaphylaxis, to any component of the study drug product. No prior allergic reaction, including anaphylaxis, to any human, humanized, chimeric or rodent antibody treatment. Have not undergone any major surgery within the 30 day period prior to the first drug dose and not anticipating requiring surgery during the study period. Negative results for Hepatitis B surface antigen and for antibodies to Hepatitis B core antigen, or evidence of Hepatitis B surface antibody > 10 IU, and negative for Hepatitis C. Negative results for HIV and not considered by the investigator to be at high risk for HIV infection.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Tom Elliott, MBBS, FRCPC

Phone

604-683-3734

Ext

1001

telliott@bcdiabetes.ca

First Name & Middle Initial & Last Name or Official Title & Degree

Marla Inducil, Pharm, MD, CCRP

Phone

604 628 7253

Ext

7011

minducil@bcdiabetes.ca

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jan Dutz, MD FRCPC

Organizational Affiliation

University of British Columbia

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Betina F Rasmussen, MSc

Organizational Affiliation

University of British Columbia

Official's Role

Study Director

Facility Information:

Facility Name

Mount Sinai Hospital/UHN

City

Toronto

State/Province

British Columbia

ZIP/Postal Code

M5T 3L9

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Andrej Orszag

Phone

416-586-4800

Ext

7625

Andrej.Orszag@uhn.ca

First Name & Middle Initial & Last Name & Degree

Bruce Perkins, MD

Facility Name

BCDiabetes

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V5Y 3W2

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marla Inducil, Pharm, MD, CCRP

Phone

604 628 7253

Ext

7011

minducil@bcdiabetes.ca

First Name & Middle Initial & Last Name & Degree

Tom Elliott, MBBS, FRCPC

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Clinical Phase II/III Trial of Ustekinumab to Treat Type 1 Diabetes (UST1D2)

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