Baricitinib for the Treatment of Ocular Mucous Membrane Pemphigoid
Condition: Mucous Membrane Pemphigoid; Cicatrizing Conjunctivitis
MeSH terms: Conjunctivitis; Pemphigoid, Benign Mucous Membrane; Pemphigoid, Bullous
Intervention: Baricitinib 2 MG [Olumiant]; Methotrexate; Azathioprine; Mycophenolate
Intervention description: Two tabs daily; Target dose: 20mg weekly; Target dose: 2mg/kg daily; Target Dose: 1g twice daily
Intervention MeSH terms: Methotrexate; Azathioprine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Ocular mucous membrane pemphigoid (MMP) is an autoimmune, scarring conjunctivitis that can
      lead to vision loss and permanent disability. It is a rare disorder with an estimated
      incidence of 1 in 60,000. There are currently no FDA-approved medications for the treatment
      of mucous membrane pemphigoid, highlighting a clear unmet need.

      At present, moderate to severe disease requires off-label use of potent immunosuppressive
      agents, such as oral anti-proliferatives (methotrexate, azathioprine, and mycophenolate),
      rituximab (RTX) or cyclophosphamide (CyC). Recently, Janus kinase (JAK) inhibition with
      baricitinib or tofacitinib been reported to be successful in one case of ocular MMP.

      This is a randomized, single-masked, two-arm study of baricitinib vs anti-proliferatives for
      ocular MMP.
    

Eligibility criteria:

        Inclusion Criteria:

        Patients are eligible to be included in the study only if they meet all the following
        criteria:

        Type of Patient and Disease Characteristics

          1. Are at least 18 years of age

          2. Have a clinical diagnosis of Ocular Mucous Membrane Pemphigoid

             a. The treating ophthalmologist will have excluded alternative etiologies that can
             cause cicatrizing conjunctivitis such as:

               -  Rosacea

               -  Atopic dermatitis

               -  Lichen Planus

               -  Iatrogenic interventions, e.g. glaucoma eye drops

               -  Stevens-Johnsons Syndrome

               -  Graft vs Host Disease

          3. Have active disease based on ophthalmologic exam

             Patient Characteristics

          4. Nonpregnant, nonbreastfeeding female or male patient

               1. Female patients of child-bearing potential who are abstinent (if this is complete
                  abstinence, as their preferred and usual lifestyle) or in a same-sex relationship
                  (as part of their preferred and usual lifestyle) must agree to either remain
                  abstinent or stay in a same-sex relationship without sexual relationships with
                  the opposite sex.

               2. Total abstinence is defined as refraining from intercourse during the entirety of
                  the study and for at least 1 week following the last dose of investigational
                  product. Periodic abstinence such as calendar, ovulation, symptothermal,
                  post-ovulation methods and withdrawal are not acceptable methods of
                  contraception.

               3. Otherwise, female patients of childbearing potential must agree to use 2
                  effective methods of contraception, where at least 1 form is highly effective,
                  for the entirety of the study and for at least 1 week following the last dose of
                  investigational product.

               4. The following contraception methods are considered acceptable (the patient should
                  choose 2, and 1 must be highly effective [defined as less than 1% failure rate
                  per year when used consistently and correctly]):

                    -  Highly effective birth control methods:

                         -  Combined (estrogen and progestogen containing) hormonal contraception
                            associated with inhibition of ovulation: oral, intravaginal, or
                            transdermal

                         -  Progestogen- only containing hormonal contraception associated with
                            inhibition of ovulation: oral, intravaginal, or transdermal

                         -  intrauterine device (IUD)/intrauterine hormone-releasing system (IUS)

                         -  vasectomized male (with appropriate post-vasectomy documentation of the
                            absence of sperm in the ejaculate).

                    -  Effective birth control methods:

                       o Male or female condom with spermicide. It should be noted that the use of
                       male and female condoms as a double barrier method is not considered
                       acceptable due to the high failure rate when these methods are combined.

                    -  Diaphragm with spermicide

                    -  Cervical sponge

                    -  Cervical cap with spermicide Note: When local guidelines concerning highly
                       effective or effective methods of birth control differ from the above, the
                       local guidelines must be followed.

             Female patients of non-child-bearing potential are not required to use birth control
             and they are defined as:

               -  Women who are infertile due to surgical sterilization (hysterectomy, bilateral
                  oophorectomy, or tubal ligation)

               -  Post-menopausal - defined either as

                  o A woman at least 50 years of age with an intact uterus, not on hormone therapy,
                  who has either

               -  Cessation of menses for at least 1 year

               -  At least 6 months of spontaneous menorrhea with follicle-stimulating hormone >40
                  mIU/mL

                    -  Women aged 55 years or older who are not on hormone therapy, and who have
                       had at least 6 months of spontaneous amenorrhea

                    -  Women aged 55 years or older who have a diagnosis of menopause

             Informed Consent

          5. Must read and understand the informed consent approved by the institutional review
             board (IRB)/ethics review board (ERB) governing the site and provide written informed
             consent.

             Exclusion Criteria:

             Patients will be excluded from study enrollment if they meet any of the following
             criteria:

             Disease Characteristics

          6. Have rapidly progressive disease, as determined by the treating ophthalmologist, that
             places the patient at an unacceptable risk for participating in the study

             Medical Conditions

          7. 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 patient.

          8. Have experienced any of the following within 12 weeks of screening: VTE (DVT/pulmonary
             embolism [PE]), myocardial infarction (MI), unstable ischemic heart disease, stroke,
             or New York Heart Association Stage III/IV heart failure.

          9. Have a history of recurrent (≥ 2) VTE (DVT/PE).

         10. Have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal,
             endocrine, hematological, neurological, or neuropsychiatric disorders or any other
             serious and/or unstable illness that in the opinion of the investigator, could
             constitute an unacceptable risk when taking investigational product or interfere with
             the interpretation of data.

         11. Have a history of lymphoproliferative disease; have signs or symptoms suggestive of
             possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; have
             active primary or recurrent malignant disease; or have been in remission from
             clinically significant malignancy for <5 years prior to randomization.

             The following may be exempted:

               1. Patients with cervical carcinoma in situ that has been resected with no evidence
                  of recurrence or metastatic disease for at least 3 years may participate in the
                  study.

               2. Patients with basal cell or squamous epithelial skin cancers that have been
                  completely resected with no evidence of recurrence for at least 3 years may
                  participate in the study.

         12. Have a current or recent (<4 weeks prior to randomization) clinically serious viral,
             bacterial, fungal, or parasitic infection or any other active or recent infection that
             in the opinion of the investigator, would pose an unacceptable risk to the patient if
             participating in the study.

             Note: For example, a recent viral upper respiratory tract infection or uncomplicated
             urinary tract infection need not be considered clinically serious.

         13. Have symptomatic herpes simplex at the time of randomization

         14. Have had symptomatic herpes zoster infection within 12 weeks prior to randomization

         15. Have a history of disseminated/complicated herpes zoster (for example, ophthalmic
             zoster or CNS involvement).

         16. Have a positive test for hepatitis B virus (HBV) defined as:

               1. positive for hepatitis B surface antigen (HBsAg), or

               2. positive for hepatitis B core antibody (HBcAb) and positive for hepatitis B virus
                  deoxyribonucleic acid (HBV DNA)

             Note: Patients who are HBcAb-positive and HBV DNA-negative may be enrolled in the
             study but will require additional HBV DNA monitoring during the study.

         17. Have hepatitis C virus (HCV) infection (hepatitis C antibody-positive and HCV
             ribonucleic acid [RNA]-positive).

             Note: Patients who have documented anti-HCV treatment for a past HCV infection AND are
             HCV RNA-negative may be enrolled in the study.

         18. Have evidence of HIV infection and/or positive HIV antibodies

         19. Have had household contact with a person with active TB and did not receive
             appropriate and documented prophylaxis for TB

         20. Have evidence of active TB or latent TB

               1. Have evidence of active TB, defined in this study as the following:

                    -  Positive purified protein derivative (PPD) test (≥5 mm induration between
                       approximately 2 and 3 days after application, regardless of vaccination
                       history), medical history, clinical features, and abnormal chest x-ray at
                       screening

                    -  QuantiFERON®-TB Gold test or T-SPOT®.TB test (as available and if compliant
                       with local TB guidelines) may be used instead of the PPD test. Patients are
                       excluded from the study if the test is not negative and there is clinical
                       evidence of active TB

                  Exception: patients with a history of active TB who have documented evidence of
                  appropriate treatment, have no history of re-exposure since their treatment was
                  completed, have no clinical features of active TB, and have a screening chest
                  x-ray with no evidence of active TB may be enrolled if other entry criteria met.
                  Such patients would not be required to undergo the protocol-specific TB testing
                  for PPD, QuantiFERON®-TB Gold test, or T-SPOT®.TB test but must have a chest
                  x-ray at screening (i.e., chest imaging performed within the past 6 months will
                  not be accepted).

               2. Have evidence of untreated/inadequately or inappropriately treated latent TB,
                  defined in this study as the following:

                    -  Positive PPD test, no clinical features consistent with active TB, and a
                       chest x-ray with no evidence of active TB at screening; or

                    -  If the PPD test is positive and the patient has no medical history or chest
                       x-ray findings consistent with active TB, the patient may have a
                       QuantiFERON®-TB Gold test or T-SPOT®.TB test (as available and if compliant
                       with local TB guidelines). If the test results are not negative, the patient
                       will be considered to have latent TB (for purposes of this study); or

                    -  QuantiFERON®-TB Gold test or T- SPOT®.TB test (as available and if compliant
                       with local TB guidelines) may be used instead of the PPD test. If the test
                       results are positive, the patient will be considered to have latent TB. If
                       the test is not negative, the test may be repeated once within approximately
                       2 weeks of the initial value. If the repeat test results are again not
                       negative, the patient will be considered to have latent TB (for purposes of
                       this study).

             Exception: Patients who have evidence of latent TB may be enrolled if he or she
             completes at least 4 weeks of appropriate treatment prior to randomization and agrees
             to complete the remainder of treatment while in the trial.

             Exception: Patients with a history of latent TB who have documented evidence of
             appropriate treatment, have no history of re-exposure since their treatment was
             completed, have no clinical features of active TB, and have a screening chest x-ray
             with no evidence of active TB may be enrolled if other entry criteria met. Such
             patients would not be required to undergo the protocol-specific TB testing for PPD,
             QuantiFERON®-TB Gold test, or T-SPOT®.TB test but must have a chest x-ray at screening
             (i.e., chest imaging performed within the past 6 months will not be accepted).

         21. Have received any of the following medications:

               1. Cyclophosphamide (or any other cytotoxic agent) within 4 weeks of screening.

               2. Rituximab or any other B cell depleting therapies within 12 weeks of screening.

         22. Have been treated with probenecid that cannot be discontinued for the duration of the
             study.

         23. Have been exposed to a live vaccine within 12 weeks of randomization or are expected
             to need/receive a live vaccine during the course of the study (with the exception of
             herpes zoster vaccination).

             Note: All patients who have not previously received the herpes zoster vaccine by
             screening will be encouraged (per local guidelines) to do so prior to randomization;
             vaccination with live herpes zoster vaccine must occur >4 weeks prior to randomization
             and start of investigational product. Patients will not be randomized if they were
             exposed to a live herpes zoster vaccination within 4 weeks of planned randomization.
             Investigators should review the vaccination status of their patients and follow the
             local guidelines for vaccination of patients ≥18 years of age with nonlive vaccines
             intended to prevent infectious disease prior to entering patients into the study.

         24. Are currently enrolled in or have discontinued within 4 weeks of screening from any
             other clinical trial involving an investigational product or nonapproved use of a drug
             or device or any other type of medical research judged not to be scientifically or
             medically compatible with this study.

         25. Have screening laboratory test values, including thyroid-stimulating hormone (TSH),
             outside the reference range for the population that, in the opinion of the
             investigator, pose an unacceptable risk for the patient's participation in the study.
             Patients who are receiving thyroxine as replacement therapy may participate in the
             study, provided stable therapy has been administered for ≥12 weeks and TSH is within
             the laboratory's reference range. Patients who have TSH marginally outside the
             laboratory's normal reference range and are receiving stable thyroxine replacement
             therapy may participate if the treating physician has documented that the thyroxine
             replacement therapy is adequate for the patient

         26. Have any of the following specific abnormalities on screening laboratory tests from
             the central or local laboratory

               1. ALT or AST >2 x upper limits of normal (ULN)

               2. alkaline phosphatase (ALP) ≥2 x ULN

               3. total bilirubin ≥1.5 x ULN

               4. hemoglobin <10 g/dL (100.0 g/L)

               5. total white blood cell count <3000 cells/μL (<3.00 x 103/μL or <3.00 billion/L)

               6. neutropenia (absolute neutrophil count [ANC] <1500 cells/uL) (<1.50 x 103/uL or
                  <1.50 billion/L)

               7. lymphopenia (lymphocyte count <1000 cells/uL) (<1.00 x 103/μL or <1.00 bilion/L)

               8. thrombocytopenia (platelets <100,000 cells/uL) (<100 x 103/μL or <100 billion/L)

               9. eGFR <60 mL/min/1.73 m2 (Bedside Schwartz formula 2009) In the case of any of the
                  aforementioned laboratory abnormalities, the tests may be repeated once during
                  screening, and values resulting from repeat testing may be accepted for
                  enrollment eligibility if they meet the eligibility criterion

             Other Exclusions

         27. Are largely or wholly incapacitated permitting little or no self-care, such as being
             bedridden or confined to wheelchair

         28. In the opinion of the investigator, are at an unacceptable risk for participating in
             the study

         29. Have donated more than a single unit of blood within 4 weeks prior to screening or
             intend to donate blood during the course of the study

         30. Have a history of intravenous drug abuse, other illicit drug abuse, or chronic alcohol
             abuse within the 2 years prior to screening or are concurrently using, or expected to
             use during the study, illicit drugs (including marijuana)

             Note: Patients who are prescribed medical marijuana by a physician are not excluded
             from the study.

         31. Are unable or unwilling to make themselves available for the duration of the study
             and/or are unwilling to follow study restrictions/procedures

         32. Are investigator site personnel directly affiliated with this study and/or their
             immediate families. Immediate family is defined as a spouse, parent, child, or
             sibling, whether biological or legally adopted