Janus Kinase (JAK) Inhibitors to Preserve C-Peptide Production in New Onset Type 1 Diabetes (T1D)

• ClinicalTrials.gov Identifier: NCT05743244
• Recruitment Status: Not yet recruiting
• First Posted: February 24, 2023
• Last Update Posted: February 24, 2023
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborator: Pfizer
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Description

Brief Summary:

A multi-center, placebo-controlled, double blind, 1:1:1 randomized control clinical trial testing two different JAK Inhibitors abrocitnib, ritlecitinib, and placebo in subjects with recent onset Stage 3 Type 1 Diabetes within 100 days of diagnosis.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Drug: Abrocitinib 200 MG Oral Tablet; Drug: Ritlecitinib; Drug: Placebo	Phase 2

Detailed Description:

This study has a total sample size of 78 participants. Of that 78, 52 participants will receive active treatment, and a total of 26 participants will receive placebo. Participants will receive 12 months of active treatment with abrocitinib, ritlecitinib, or placebo with up to 12 months of additional follow-up. During the study, participants will undergo frequent assessments of their insulin production, immunologic status, overall health and well-being and diabetes care.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants aged 12-35 years will be randomized 1:1:1 to receive abrocitinib, ritlecitinib, and placebo. The planned design is to enroll 26 participants in each of the 3 arms: the abrocitinib arm, the ritlecitinib arm, and the shared placebo arm. Within the shared placebo arm, participants will be randomized 1:1 to receive placebo matched to abrocitinib or placebo matched to ritlecitinib. Randomization will be stratified by the following two age categories: 12-17 years old, and 18 years or above. Within each stratum, participants will be randomized to either the abrocitinib arm, ritlecitinib arm, or the shared placebo arm using random block sizes. The total number of enrolled participants from the older age stratum (18 years or above) will be limited to 33 to replicate the age distribution in previous new-onset trials. Participants will receive 12 months of active treatment with abrocitinib, ritlecitinib, or placebo then enter a follow-up period of up to 12 months.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: The randomization method will be stratified by TrialNet study site. The participants will not be informed regarding the intervention assignment until the end of the study. The investigator and clinic personnel will also be masked as to study assignment. Laboratories performing assays for this protocol will be masked as to the identity of biological material to be studied.
• Primary Purpose: Treatment
• Official Title: A Phase 2 Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Subtype-Selective JAK Inhibitors for Preservation of Pancreatic β Cell Function in Newly Diagnosed Type 1 Diabetes Mellitus
• Estimated Study Start Date: May 30, 2023
• Estimated Primary Completion Date: June 30, 2026
• Estimated Study Completion Date: June 30, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Abrocitinib; Abrocitinib will be self-administered as 200-milligram (mg) tablet daily for 52 weeks (12 months). The final prepared product is to be labeled to protect the blind.	Drug: Abrocitinib 200 MG Oral Tablet; Abrocitinib; Other Name: CIBINQO
Experimental: Ritlecitinib; Ritlecitnib will be self-administered via oral administration as a 100-mg capsule daily for 52 weeks (12 months). The final prepared product is to be labeled to protect the blind.	Drug: Ritlecitinib; Ritlecitinib
Placebo Comparator: Placebo; 200 mg tablet or 100 mg capsule matching either abrocitinib or ritlecitinib will be self-administered via oral administration daily for 52 weeks (12 months). The final product is to be labeled to protect the blind.	Drug: Placebo; Placebo for Abrocitinib or Ritlecitinib

Outcome Measures

Primary Outcome Measures :

1. The area under the stimulated C-peptide curve (Y_AUC) [ Time Frame: 12 Months ]
   The primary outcome of interest is the area under the stimulated C-peptide curve over the 2-hour mixed meal glucose tolerance test conducted at the 12-month visit (Y_AUC) over the 2-hour mixed meal glucose tolerance test conducted at the 12-month visit.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 35 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Provide informed consent or assent as appropriate and, if < 18 years of age have a parent or legal guardian provide informed consent
2. Age 12-35 years (both inclusive) at the time of signing informed consent and assent
3. Diagnosis of T1D within 100 days of randomization.
4. Positive for at least one islet cell autoantibody; Glutamate decarboxylase (GAD)65A, mIAA (if obtained within 10 days of the onset of insulin therapy), IA-2A, ICA, or ZnT8A
5. Stimulated C-peptide of ≥0.2 pmol/mL measured during mixed-meal tolerance test (MMTT) conducted at least 21 days from diagnosis of diabetes
6. HbA1c ≤ 10 %
7. Body weight ≥ 35kg at screening
8. Willing to comply with intensive diabetes management and wear a Continuous Glucose Monitoring Device (CGM)
9. Participants who are Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) seronegative at screening must be CMV and/or EBV Polymerase chain reaction (PCR) negative within 30 days of randomization and may not have had signs or symptoms of a CMV and/or EBV-compatible illness lasting longer than 7 days within 30 days of randomization
10. Be up to date on recommended immunizations; participants are required to receive killed influenza vaccination at least 2 weeks prior to randomization when vaccine for the current or upcoming flu season is available. Enrollment must be delayed at least 4 weeks from administration of a killed vaccine other than influenza and 6 weeks from a live vaccination. Vaccinations should not be given while on study drug and be postponed at least 3 months after the last dose of study drug.
11. Participants are required to be fully vaccinated including eligible boosters and should receive an authorized non-live COVID-19 vaccination series or COVID-19 vaccine at least 2 weeks prior to randomization
12. If participant is female with reproductive potential, she must have a negative pregnancy test at screening and be willing to avoid pregnancy using a highly-effective contraceptive method for the duration of the study
13. Males of reproductive age must use a highly-effective contraceptive method during the treatment phase and for 3 months following last dose of study drug

Exclusion Criteria:

1. Current or ongoing use of non-insulin pharmaceuticals or medication that affect glycemic control or glucose homeostasis within 7 days prior to screening or any prohibited concomitant medication listed in section 4.8
2. Untreated hypothyroidism or active Graves' disease
3. Concurrent treatment with other immunosuppressive agents (including biologics or steroids), other than inhaled or topical glucocorticoids
4. Active acute or chronic infection requiring treatment with oral antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 1 month prior to Day 0 or superficial skin infection within 1 week prior to Day 0

5. Active acute or chronic infection requiring treatment with intravenous therapy (IV) within a minimum 1 month prior to Day 0

   a. Specific cases should be reviewed by Infectious Disease Committee prior to enrollment

6. Significant trauma or major surgery within 1 month of signing informed consent.
7. Considered in imminent need for surgery or with elective surgery scheduled to occur during the study
8. History of disseminated herpes zoster or disseminated herpes simplex or a recurrent (more than one episode of) localized, dermatomal herpes zoster
9. Have evidence of prior or current tuberculosis infection as assessed by Purified Protein Derivative (PPD), interferon gamma release assay (IGRA) or by history
10. Have evidence of current or past HIV or Hepatitis B infection
11. Have evidence of active Hepatitis C infection
12. Have current, confirmed COVID-19 infection
13. Current or history of Deep vein thrombosis (DVT), Pulmonary embolism (PE), or other thromboembolic events or history of inherited coagulopathies
14. First degree relative with a history of unprovoked venous thromboembolism (i.e. without known underlying cause such as trauma, surgery, immobilization, prolonged travel, pregnancy, hormone use, or plaster cast), which suggests that a participant may be at increased risk of inherited coagulation disorder
15. Any present malignancies or history of malignancy, other than a successfully treated nonmelanoma skin cancer
16. History of any lymphoproliferative disorder such as EBV-related lymphoproliferative disorder, history of lymphoma, history of leukemia, or signs and symptoms suggestive of current lymphatic or lymphoid disease

17. One or more screening laboratory values as stated

    1. Neutrophils < 1,500 /μL
    2. Lymphocytes < 800 /μL
    3. Platelets < 150,000 / μL
    4. Hemoglobin < 6.2 mmol/L (10.0 g/dL)
    5. Potassium > 5.5 mmol/L or <3.0 mmol/L
    6. Sodium > 150mmol/L or < 130mmol/L
    7. AST or ALT ≥ 2.5 times the upper limit of normal
    8. Bilirubin ≥ 1.5 times upper limit of normal unless diagnosed with Gilbert's syndrome
    9. LDL >160 mg/dL
18. Vaccination with a live virus within the last 6 weeks and killed vaccine within 4 weeks (except 2 weeks for flu vaccine and COVID vaccine)
19. Be currently pregnant or lactating or anticipate becoming pregnant during the study
20. Male participants able to father children and female participants of childbearing potential who are unwilling or unable to use 2 effective methods (at least 1 highly effective method) of contraception, including abstinence, as outlined in this protocol for the duration of the study and for at least 3 months after the last dose of investigational product
21. Be currently participating in another T1D treatment study
22. Have hearing loss with progression over the previous 5 years, or sudden hearing loss, or middle or inner ear disease such as otitis media, cholesteatoma, Meniere's disease, labyrinthitis, or other auditory condition that is considered acute, fluctuating, or progressive
23. Acute coronary syndrome (e.g., myocardial infarction, unstable angina pectoris) and any history of cerebrovascular disease within 24 weeks before screening; Heart failure NYHA (New York Heart Association) III, NYHA IV

24. ANY of the following conditions at screening:

    a. Screening 12-lead electrocardiogram (ECG) that demonstrates: i. Clinically significant abnormalities requiring treatment (eg, acute myocardial infarction, serious tachy- or brady-arrhythmias) or indicating serious underlying heart disease (eg, cardiomyopathy, Wolff-Parkinson- White syndrome); ii. Confirmed QT corrected using Fridericia's correction factor (QTcF) prolongation (>450 milliseconds).

    b. Long QT Syndrome, a family history of Long QT Syndrome, or a history of Torsades de Pointes (TdP).

25. History of chronic alcohol abuse or intravenous drug abuse or other illicit drug abuse within 2 years prior to screening
26. Current or past use of tobacco or nicotine containing products more than the equivalent of 5 cigarettes per day
27. Participant is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the trial
28. Have any complicating medical issues or abnormal clinical laboratory results that may interfere with study conduct, or cause increased risk
29. Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results

Contacts and Locations

Contacts

Contact: Jessica S Conaty; 8133969234; Jessica.Conaty@epi.usf.edu

Contact: Melissa Parker; 8133969378; Melissa.Parker@epi.usf.edu

Sponsors and Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Pfizer

More Information

Additional Information:

TrialNet 

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT05743244
• Other Study ID Numbers: TN31 JAK Inhibitors
• First Posted: February 24, 2023
• Last Update Posted: February 24, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data will be available at the NIDDK Central Repository

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

TrialNet; T1D

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Abrocitinib; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action