This study is a phase 2 multi-center, double-blind, randomized, placebo-controlled clinical trial of male and female adolescent and adult participants (ages 12-35 years) with newly diagnosed Stage 3 type 1 diabetes (T1D) within 100 days of diagnosis. Enrollment into abrocitinib and ritlecitinib arms and the shared placebo arm occur in a 1:1:1 allocation. Participants receive 12 months of active treatment with abrocitinib, ritlecitinib, or placebo with up to 12 months of additional follow-up.

The primary objective is to evaluate the efficacy of subtype-selective Janus kinase (JAK) inhibitors in the preservation of beta cell function in participants with recent onset Stage 3 T1D (diagnosed within 100 days).

Secondary objectives include change from baseline of the 2-hour C-peptide area under the curve (AUC) during a mixed meal tolerance test (MMTT), change in MMTT-derived glucose measures, HbA1c, blood glucose patterns obtained from continuous glucose monitoring (CGM), total daily insulin dose (adjusted for weight), and adverse events.

The primary outcome measure for each participant is the area under the stimulated C-peptide curve (AUC) over the 2-hour mixed meal glucose tolerance test conducted at the 12-month visit.

Secondary outcome measures include change from baseline in MMTT-stimulated 2-hour C-peptide AUC at 3, 6, 9, 12, 18, and 24 months, change in glucose measures at baseline and 3, 6, 9, 12, 18, and 24 months during the MMTTs, assessment of HbA1c over time, continuous glucose monitoring data, total daily insulin use, and adverse events per treatment arm.

• Age 12-35 years (both inclusive) at the time of signing informed consent or assent
• Diagnosis of T1D within 100 days of the baseline visit
• Positive for at least one islet cell autoantibody: GAD65A, mIAA (if obtained within 10 days of the onset of insulin therapy), IA-2A, ICA, or ZnT8A
• Stimulated C-peptide of ≥ 0.2 pmol/mL measured during MMTT conducted at least 21 days from diagnosis of diabetes
• HbA1c ≤ 10 %
• Body weight ≥ 35 kg at screening
• Willing to comply with intensive diabetes management and wear a continuous glucose monitor
• Participants who are CMV and/or EBV seronegative at screening must be CMV and/or EBV PCR negative within 37 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 37 days of the baseline visit
• Participants who are CMV and/or EBV seropositive at screening must be CMV PCR negative and/or EBV PCR < 2,000 IU/mL and must have no signs or symptoms of acute infection at the time of the baseline visit
• Participants are required to receive killed influenza vaccination at least 2 weeks prior to the baseline visit when vaccine for the current or upcoming flu season is available
• 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
• 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

• Current or ongoing use of non-insulin pharmaceuticals or medication that affect glycemic control or glucose homeostasis within 7 days prior to screening
• Untreated hypothyroidism or active Graves’ disease
• Concurrent treatment with other immunosuppressive agents (including biologics or steroids), other than inhaled or topical glucocorticoids
• 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, or intravenous therapy (IV) within a minimum 1 month prior to Day 0
• Significant trauma or major surgery within 1 month of signing informed consent
• History of disseminated herpes zoster or disseminated herpes simplex or a recurrent (more than one episode of) localized, dermatomal herpes zoster
• Have evidence of current or past HIV, Hepatitis B, or tuberculosis infection
• Have evidence of active Hepatitis C or COVID-19 infection
• Current or history of deep vein thrombosis (DVT), pulmonary embolism (PE), or other thromboembolic events or history of inherited coagulopathies, or first degree relative with a history of unprovoked venous thromboembolism
• 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
• Have renal impairment (eGFR < 60 mL/min)
• Currently on anti-platelet therapies, excluding low dose aspirin
• One or more screening laboratory values: neutrophils < 1,500 /μL, lymphocytes < 800 /μL, platelets < 150,000 / μL, hemoglobin < 6.2 mmol/L (10.0 g/dL), potassium > 5.5 mmol/L or < 3.0 mmol/L, sodium > 150mmol/L or < 130mmol/L, AST or ALT ≥ 2.5 times the upper limit of normal, bilirubin ≥ 1.5 times upper limit of normal unless diagnosed with Gilbert’s syndrome, or LDL > 160 mg/dL
• 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)
• Currently pregnant or lactating or anticipate becoming pregnant during the study
• Currently participating in another T1D treatment study
• Have had previous clinical use of Tzield (Teplizumab) not part of a T1D treatment study
• Acute coronary syndrome (e.g., myocardial infarction, unstable angina pectoris) and any history of cerebrovascular disease within 24 weeks before screening
• History of chronic alcohol abuse, intravenous drug abuse, or other illicit drug abuse within 2 years prior to screening
• Current or past use of tobacco or nicotine containing products more than the equivalent of 5 cigarettes per day

This study is ongoing.