Clinical trial NCT03910543: Open-label Trial of Tofacitinib in Cutaneous Sarcoidosis and Granuloma Annulare
Official title: Open-label Trial of Tofacitinib in Cutaneous Sarcoidosis and Granuloma Annulare
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cutaneous Sarcoidosis
Granuloma Annulare
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2019-04-10
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: open-label trial
Primary purpose: TREATMENT

Brief summary: To investigate the ability of tofacitinib, a Janus kinase (JAK) inhibitor, to treat patients with cutaneous sarcoidosis and granuloma annulare during 6 months of therapy.

Detailed description: An open-label clinical trial of tofacitinib in cutaneous sarcoidosis and GA. The hypothesis is that Janus Kinase (JAK) 1/3 inhibition with tofacitinib will be effective for the treatment these two diseases. Tofacitinib will be administered at a dose of 5 mg twice daily and response to therapy will be assessed at months 1, 3, and 6 of therapy. The primary outcomes will be improvement in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) and Granuloma Activity Scoring Index (GASI) after 6 months of tofacitinib therapy. Secondary outcomes will include improvement in internal organ sarcoidosis (i.e. lung, cardiac) and skin related quality of life. Pre- and on treatment PET-CT scans will be performed in patients with sarcoidosis with internal organ involvement. Pre- and on treatment blood collection and skin biopsies will be performed for correlative scientific studies using RNA sequencing, immunohistochemistry (IHC), and cytokine profiling.

Eligibility criteria: Inclusion Criteria:

* 18 years old or older
* Diagnosis of cutaneous sarcoidosis or granuloma annulare with supportive skin biopsies in which other causes of granulomas (infectious, foreign body) have been ruled out
* Patients with either: Cutaneous Sarcoidosis Activity and Morphology (CSAMI) activity score greater than or equal to 10 (patients with a CSAMI greater than or equal to 10 have active cutaneous sarcoidosis involving several distinct cutaneous sites and would otherwise be considered candidates for systemic therapy), or any CSAMI score and sarcoidosis involvement causing functional impairment (i.e. nasal or visual field obstruction).
* For patients with granuloma annulare, patients with 5% or greater Body Surface Area (BSA) will be enrolled.
* If patients are on other systemic therapies for their sarcoidosis or granuloma annulare, they must be taking a stable dose of the other medication(s) for at least 3 months with no plans to change the regimen in the next 6 months. With the exception of methotrexate and/or low dose prednisone, use of concomitant immunosuppressants, e.g. infliximab, azathioprine, etc., will not be permitted.
* Females of childbearing potential must agree to use birth control during the study and there must be a negative pregnancy test documented prior to starting the medication.
* Patients must be willing to undergo skin biopsies, blood collection, and total body photography and comply with clinic visits

Exclusion Criteria:

* Age \<18 years old
* Patients with a history of malignancy (except history of successfully treated basal cell or squamous cell carcinoma of the skin)
* Patients known to be HIV or hepatitis B (HBV) or C (HCV) positive (prior exposure to but clearance of HBV and HCV is acceptable for study entry as long as patient is being monitored by hepatology)
* Patients with active tuberculosis or untreated latent tuberculosis as determined by positive tuberculin skin test or positive QuantiFERON® Tuberculosis (TB) test and, as necessary, chest X-ray
* Patients with significant hepatic impairment
* Patients with untreated peptic ulcer disease
* Patients taking immunosuppressive medications, with the exception of methotrexate and/or low- dose prednisone, including but not limited to mycophenolate mofetil, azathioprine, tacrolimus, cyclosporine, or Tumor Necrosis Factor (TNF-α) inhibitors
* Women of childbearing potential who are unable or unwilling to use birth control while taking the medication
* Women who are pregnant or nursing. If a woman becomes pregnant during the study, she will stop study medication and be removed from the study. She will be urged to follow up with her Primary Care Physician or OB/GYN. The study doctors will ask to follow the pregnancy to its outcome.

Primary outcomes:
measure: Change in Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI)
timeFrame: 6 - 12 months
measure: Percent Change in Body Surface Area (BSA) involvement by GA lesions
timeFrame: 6 - 12 months
Secondary outcomes:
measure: Change in Skindex-16: a skin-related quality of life metric
timeFrame: 6 - 12 months
measure: Change in Histologic Findings
timeFrame: 6 -12 months
measure: Change in RNA sequencing markers (gene expression analysis)
timeFrame: 6 - 12 months
measure: Change in cytokine biomarkers
timeFrame: 6 - 12 months
measure: Change in activity of internal organ sarcoidosis
timeFrame: 6 - 12 months
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Center for Clinical Investigation
state: Connecticut
Study officials:
affiliation: Yale University
name: William Damsky, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Damsky W, Thakral D, Emeagwali N, Galan A, King B. Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis. N Engl J Med. 2018 Dec 27;379(26):2540-2546. doi: 10.1056/NEJMoa1805958.
citation: Damsky W, Wang A, Kim DJ, Young BD, Singh K, Murphy MJ, Daccache J, Clark A, Ayasun R, Ryu C, McGeary MK, Odell ID, Fazzone-Chettiar R, Pucar D, Homer R, Gulati M, Miller EJ, Bosenberg M, Flavell RA, King B. Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis. Nat Commun. 2022 Jun 6;13(1):3140. doi: 10.1038/s41467-022-30615-x.
citation: Wang A, Rahman NT, McGeary MK, Murphy M, McHenry A, Peterson D, Bosenberg M, Flavell RA, King B, Damsky W. Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib. J Allergy Clin Immunol. 2021 May;147(5):1795-1809. doi: 10.1016/j.jaci.2020.10.012. Epub 2020 Dec 11.