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Trial registered on ANZCTR


Registration number
ACTRN12620000239965
Ethics application status
Approved
Date submitted
13/02/2020
Date registered
26/02/2020
Date last updated
26/02/2020
Date data sharing statement initially provided
26/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Baricitinib on Insulin Production in Type 1 Diabetes
Scientific title
A Phase 2, Randomised, Placebo Controlled Study Investigating the Efficacy of Baricitinib in New Onset Type 1 Diabetes Mellitus
Secondary ID [1] 300478 0
SVI-BARI-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes Mellitus 316148 0
Condition category
Condition code
Metabolic and Endocrine 314438 314438 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Baricitinib is an oral JAK1/JAK2-selective inhibitor.

Dosage: The dose of baricitinib is 1 x 4mg tablet once daily

Duration of administration: 48 weeks

Mode of administration: Orally, with or without food

Assessment of intervention adherence: Tablet counts will be used to assess participant compliance with daily doses of the study medication
Intervention code [1] 316776 0
Treatment: Drugs
Comparator / control treatment
One placebo tablet once daily for a duration of 48 weeks. Placebo tablets contain lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
Control group
Placebo

Outcomes
Primary outcome [1] 322782 0
The primary endpoint of the study is the change from baseline of plasma C-peptide area under the curve (AUC) over 2 hours following a mixed meal.
Timepoint [1] 322782 0
Measured at 48 weeks post commencement of intervention.
Secondary outcome [1] 379712 0
Change from baseline in plasma C-peptide AUC over 2 hours following a mixed meal.
Timepoint [1] 379712 0
Measured at weeks 24, 72 and 96 post commencement of intervention.

Secondary outcome [2] 379713 0
Change from baseline in mean daily insulin use over 7 consecutive days. This data will be recorded by participants on their Insulin Use logs.
Timepoint [2] 379713 0
Measured during the 2 weeks prior to the assessment at weeks 12, 24, 36, 48, 72 and 96 post commencement of intervention.
Secondary outcome [3] 379723 0
Change from baseline in glycosylated haemoglobin (HbA1c) levels.
Timepoint [3] 379723 0
Measured at weeks 12, 24, 36, 48, 72 and 96 post commencement of intervention.
Secondary outcome [4] 379724 0
Number of participants with responder status. A participant will be considered a responder when, at the given time point, the participant has: glycosylated haemoglobin (HbA1c) less than or equal to 6.5 percent and mean daily insulin use less than 0.5 international units per kilogram per day (IU/kg/day) over 7 consecutive days during the 2 weeks preceding the visit. This will be assessed using blood test results and recordings made in the participant diary.
Timepoint [4] 379724 0
Measured at weeks 12, 24, 36, 48, 72 and 96 post commencement of intervention.
Secondary outcome [5] 379725 0
Change in estimated C-peptide (CPEST) from baseline. CPEST is calculated based on six variable routine measures: disease duration, BMI, insulin dose, HbA1c, fasting plasma C-peptide and fasting plasma glucose.
Timepoint [5] 379725 0
Measured at weeks 12, 24, 36, 48, 72 and 96 post commencement of intervention.
Secondary outcome [6] 379726 0
Blinded continuous glucose monitoring (CGM).
Timepoint [6] 379726 0
Measured at baseline, 12, 24, 48 and 96 weeks post commencement of intervention.
Secondary outcome [7] 379727 0
The composite outcome assessing both the frequency, and when relevant, the severity of all adverse events.

Baricitinib is associated with an increased risk of infections including pneumonia, herpes zoster, urinary tract infections and cellulitis. Participants will be closely monitored for the development of signs and symptoms of infection during and after treatment with Baricitinib. This involves assessment by the study doctor and study nurse at each study visit as well as via regular telephone calls. Participants can also report any adverse events at any time via telephone contact, or in the participant diary which will be checked at each study visit.

Other possible adverse events include: low lymphocyte counts, low neutrophil counts, low haemoglobin levels, hepatotoxicity, lipid elevations and renal impairment. Such adverse events will be closely monitored via blood sample analysis for each participant at each study visit.
Timepoint [7] 379727 0
Adverse events will be assessed fortnightly from intervention commencement until 96 weeks post-intervention commencement. At each study visit during both the treatment period and the follow up period, blood samples will also be analysed to monitor for certain adverse events. Participants can also make contact at any point during this period to report any adverse events.

Eligibility
Key inclusion criteria
To be eligible for study entry, participants must satisfy all of the following criteria:
1. Male or female aged between 12 and 30 years (inclusive) at screening;

2. Diagnosis of T1D according to ADA criteria within 100 days prior to starting study drug;

3. Islet autoantibody positivity (one or more of: GADA, IA-2A, IAA (assessed within one week of commencing insulin therapy), ZnT8A);

4. Stimulated (peak or 90 min) C-peptide >0.2 nM during a 2-hour MMTT at the screening visit;

5. Participants of childbearing age who are sexually active must agree to use of effective birth control until the end of the study;

6. Be able to read, understand and give written informed consent;

7. Be willing to comply with intensive diabetes management.
Minimum age
12 Years
Maximum age
30 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded from the study if one or more of the following criteria are applicable:
1. Use of immunosuppressive or immunomodulatory therapies other than inhaled or topical glucocorticoids;

2. Current or past history of deep vein thrombosis or pulmonary embolism;

3. Impaired renal function defined by estimated glomerular filtration rate (according to the CKD-EPI) of < 60 mL/min/1.73 m2;

4. LDL cholesterol >4mmol/l;

5. Elevated liver function tests at screening:
a. Aspartate aminotransferase 2x ULN
b. Alanine aminotransferase 2 x ULN;

6. Clinically significant abnormal laboratory parameters at screening including but not limited to:
a. Hemoglobin < 8 g/L;
b. White blood cells <2500 cells/µl;
c. Lymphocyte count <750 cells/µl;
d. Platelets <50,000 cells/µl;
e. Neutrophils <1200cells/µL;

7. Known hypersensitivity to baricitinib;

8. Known malignancy with the exception of successfully treated non- metastatic basal cell and squamous cell carcinoma;

9. Pregnancy, a desire for pregnancy, breast feeding, or a desire to father a child during the study;

10. Patients with current or recent (within 12 weeks of screening) clinically significant comorbidity, including clinically serious viral, bacterial, fungal, or parasitic infection. Viral infections include HBV, HCV, EBV, HIV, recent herpes zoster and TB;

11. Treatment with any investigational product within 30 days or 5 half - lives (whichever is longer) prior to baseline visit, or concurrent participation in a clinical trial with an investigational product or device;

12. Experienced any of the following within 12 weeks of screening: myocardial infarction, unstable ischemic heart disease, stroke, or New York Heart Association Stage IV heart failure;

13. Any serious medical condition within the previous 4 weeks which places the participant at an unacceptable risk if he or she were to participate in the study or confounds the ability to interpret data from the study, including, but not limited to, symptomatic cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine, haematological and neurological conditions or psychiatric illness/social situations that would limit compliance with study requirements;

14. Have had any major surgery within 8 weeks prior to screening or will require major surgery during the study that, in the opinion of the investigator would pose an unacceptable risk to the participant;

15. History of chronic alcohol abuse or IV drug abuse or other illicit drug abuse within 2 years prior to screening.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment performed.

Prior to study initiation, an independent researcher is responsible for generating the randomization schedule. Opaque envelopes numbered 1 through 80 with group name (active or placebo) will be provided to the pharmacists at each one of the study sites who will open them in sequence to assign the treatment. The study pharmacists will conceal the group assignment from study participants, investigators and study staff including the statistician.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified block randomization with variable block sizes of 3, 6 or 9 will be used to generate the randomization schedule. Age (less than 21 years, and greater than or equal to 21 years) will be used as a stratification factor.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The sample size was selected based on estimates of 2-hour AUC mean C-peptide obtained from prior studies and using standard power calculations for comparison of treated and placebo groups. We propose to enrol 83 participants. Using standard equations for comparison of two means, a sample size of 50 baricitinib treated and 25 placebo treated participants with complete data is needed to provide 80% power to detect 45% increase in mean log(C-peptide+1) (0.306 vs. 0.445, sd of 0.2), in the treated group using a two-sample T-test at 0.05 level of significance (two-sided). With the expected 10% dropout rate the number of participants recruited into the study will be increased to 83 (55 and 28 in the intervention and control arms respectively). Should the number of drop-outs exceed 10%, additional participants may be recruited.

Statistical methods and analysis plan: The primary statistical hypothesis to be assessed is whether residual beta cell function (CPave at 48 weeks) will differ between those treated with baricitinib and placebo. The primary analysis will be performed based on intention to treat (ITT) with sensitivity analysis based on a per protocol basis to confirm the robustness of the findings.

Secondary outcomes will be assessed using ANOVA or Fisher’s exact test for continuous and categorical data respectively.

Safety results will be listed, tabulated using descriptive statistics, and plotted when appropriate.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 15814 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 15815 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 29251 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 304898 0
Charities/Societies/Foundations
Name [1] 304898 0
Juvenile Diabetes Research Foundation (JDRF) International
Address [1] 304898 0
200 Vesey Street,
28th Floor
New York,
NY 10281.
Country [1] 304898 0
United States of America
Primary sponsor type
Other
Name
St Vincent’s Institute of Medical Research
Address
9 Princes Street,
Fitzroy,
Victoria,
Australia,
3065
Country
Australia
Secondary sponsor category [1] 305240 0
None
Name [1] 305240 0
Address [1] 305240 0
Country [1] 305240 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305308 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 305308 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050
Australia
Ethics committee country [1] 305308 0
Australia
Date submitted for ethics approval [1] 305308 0
22/11/2019
Approval date [1] 305308 0
14/02/2020
Ethics approval number [1] 305308 0
HREC/59210/MH-2019

Summary
Brief summary
Type 1 diabetes (T1D) results from the killing of insulin-producing pancreatic beta cells by cells of the immune system. We aim to slow the progressive, immune-mediated loss of insulin-producing beta cells that occurs after clinical presentation. We have identified a pathway that is important for immune cells to kill beta cells, and a drug that will block this pathway and prevent beta cell death. This drug, baricitinib, is already in clinical use for rheumatoid arthritis, and is currently in clinical trials for other diseases, including childhood autoimmune diseases. We hypothesize that baricitinib treatment for 48 weeks will preserve beta cell function in children and young adults with recently-diagnosed T1D.

The trial aims to recruit 83 participants aged 12-30 years who have been recently diagnosed with T1D. Two thirds of the participants will be randomly assigned to receive baricitinib, one third will receive placebo. Our trial will test if baricitinib can slow the progressive loss of insulin-producing beta cells in these patients. The primary objective is to determine if baricitinib can reduce the loss of meal-stimulated plasma C-peptide, a measure of beta-cell function. Maintaining endogenous insulin in recent-onset T1D improves glucose control and may lead to long-term improvements in glucose and lower rates of serious diabetes complications and death.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99938 0
Prof Thomas WH Kay
Address 99938 0
St Vincent’s Institute of Medical Research,
9 Princes Street,
Fitzroy,
Victoria,
3065.
Country 99938 0
Australia
Phone 99938 0
+61 3 9231 2480
Fax 99938 0
Email 99938 0
tkay@svi.edu.au
Contact person for public queries
Name 99939 0
Dr Michaela Waibel
Address 99939 0
St Vincent’s Institute of Medical Research,
9 Princes Street,
Fitzroy,
Victoria,
3065.
Country 99939 0
Australia
Phone 99939 0
+61 3 9231 2502
Fax 99939 0
Email 99939 0
mwaibel@svi.edu.au
Contact person for scientific queries
Name 99940 0
Dr Michaela Waibel
Address 99940 0
St Vincent’s Institute of Medical Research,
9 Princes Street,
Fitzroy,
Victoria,
3065.
Country 99940 0
Australia
Phone 99940 0
+61 3 9231 2502
Fax 99940 0
Email 99940 0
mwaibel@svi.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification
When will data be available (start and end dates)?
Immediately following publication, and for at least 15 years after the end of the study.
Available to whom?
On case-by-case basis at the discretion of primary sponsor and only to researchers who have obtained ethical approval to access it.
Available for what types of analyses?
The data will be available for analyses that are only to achieve the aims in the approved proposal.
How or where can data be obtained?
Access subject to approvals by the Principal Investigator, Prof Thomas Kay. Enquiries should be directed to tkay@svi.edu.au
What supporting documents are/will be available?
No other documents available
Summary results
No Results