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

Prior treatment

• 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
• Active acute or chronic infection requiring treatment with intravenous therapy (IV) within a minimum 1 month prior to Day 0
  • Specific cases should be reviewed by Infectious Disease Committee prior to enrollment
• Significant trauma or major surgery within 1 month of signing informed consent.
• Considered in imminent need for surgery or with elective surgery scheduled to occur during the study
• Have evidence of prior or current tuberculosis infection as assessed by Purified Protein Derivative (PPD), interferon gamma release assay (IGRA) or by history
• 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
• Have had previous clinical use of Tzield (Teplizumab) not part of a T1D treatment study.
• 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
  • Participants with hearing aids will be allowed to enter the study provided their hearing impairment is considered controlled/clinically stable.
• 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
• History of chronic alcohol abuse or intravenous drug abuse or other illicit drug abuse within 2 years prior to screening

Other illness

• Untreated hypothyroidism or active Graves' disease
• Have active signs or symptoms of acute infection at the time of the baseline visit (V0).
• 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 or Hepatitis B infection
• Have evidence of active Hepatitis C infection
• Have current, confirmed COVID-19 infection
• Current or history of Deep vein thrombosis (DVT), Pulmonary embolism (PE), or other thromboembolic events or history of inherited coagulopathies
• 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
• Any present malignancies or history of malignancy, other than a successfully treated nonmelanoma skin cancer
• 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
• 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)
• Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results

Lab values

• 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
• Have renal impairment (eGFR\< 60 mL/min)
• Currently on anti-platelet therapies, excluding low dose aspirin
• One or more screening laboratory values as stated
  • 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
  • LDL \>160 mg/dL
  • Troponin I above the upper limit of normal
• ANY of the following conditions at screening:
  • 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).
  • Long QT Syndrome, a family history of Long QT Syndrome, or a history of Torsades de Pointes (TdP).
• Have any complicating medical issues or abnormal clinical laboratory results that may interfere with study conduct, or cause increased risk

Other

• Known or suspected polymorphism in the Cytochrome P450 2C19 (CYP2C19 gene, resulting in classification as a poor CYP2C19 metabolizer).
• Be currently pregnant or lactating or anticipate becoming pregnant during the study
• Be currently participating in another T1D treatment study
• Current or past use of tobacco or nicotine containing products more than the equivalent of 5 cigarettes per day
• 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

• Provide informed consent or assent as appropriate and, if \< 18 years of age have a parent or legal guardian provide informed consent
• Age 12-35 years (both inclusive) at the time of signing informed consent and assent
• Diagnosis of T1D within 100 days of the baseline visit (V0).
• 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
• Stimulated C-peptide of ≥0.2 pmol/mL measured during mixed-meal tolerance test (MMTT) conducted at least 21 days from diagnosis of diabetes
• HbA1c ≤ 10 %
• Body weight ≥ 35kg at screening
• Willing to comply with intensive diabetes management and wear a Continuous Glucose Monitoring Device (CGM)
• 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 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 (V0).
• 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 (V0).
• Be up to date on recommended vaccinations based on age of participants\*
• Participants are required to receive killed influenza vaccination at least 2 weeks prior to the baseline visit (V0) 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 COVID-19 and 6 weeks from a live vaccination. Live vaccinations and non-live vaccinations (other than influzena and COVID-19) should not be given while on study drug and be postponed at least 3 months after the last dose of study drug.
• 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
  • For COVID-19 vaccination, all participants will be strongly encouraged to be up-to-date with COVID-19 vaccine (s) as indicated by country-specific guidelines at least 2 weeks prior to the baseline visit (V0). HPV vaccine initiation and/or completion of series may be delayed until after completion of study drug in both adult and pediatric participants.