Janus Kinase Inhibition in Granuloma Annulare

JAK1 Inhibition in Granuloma Annulare: an Opportunity for Pathogenesis Directed Therapy

The primary objective is to determine if JAK1 specific inhibition is effective in treating granuloma annulare (GA), a problematic inflammatory skin disease without an FDA approved treatment. The primary outcome will be the percentage change in the body surface area (BSA) involvement by GA after 6 months of treatment with abrocitinib 200 mg daily in 10 patients with moderate to severe GA affecting at least 5% body surface area (BSA).

Study Overview

• Status: Active, not recruiting
• Conditions: Granuloma Annulare
• Intervention / Treatment: Drug: Abrocitinib 200 mg

Detailed Description

There are no effective treatments for GA. Systemic corticosteroids can be effective in temporarily controlling GA; however, GA patients are almost never treated with systemic steroids due to the myriad potential adverse effects of this drug class and its transient effect on disease control. Intralesional (intradermal) steroid injections can be effective in patients with localized GA but are not really an option for patients with BSA > 1-2%, require frequent clinic visits for injection, are painful, and also only transiently control disease. A variety of other treatment approaches have been described and include: antibiotics (minocycline, doxycycline, others), hydroxychloroquine, phototherapy, tumor necrosis factor inhibitors, among others. However, these therapies are rarely effective. GA is notoriously recalcitrant to treatment.

With no FDA approved therapies for GA and current approaches being broadly ineffective; there is a large unmet need for an effective treatment. Likely in part because of under recognition, GA is designated as a rare disease by the National Organization for Rare Disorders. Progress in the treatment of GA has been impaired by a poor understanding of disease pathogenesis. Not only will this study allow for greater clarity regarding the pathogenesis of GA, but an oral treatment option for patients that is easier to administer compared to other therapies (such as injections) and with less potential systemic side effects.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent
• Male and female patients 18 years old or older
• Diagnosis of GA with supportive skin biopsy
• BSA involvement of at least 5%
• If patients are on systemic therapies or phototherapy for their GA, they must discontinue these therapies with a washout period of 4 weeks and must remain off them during the study
• If patients are on topical therapies for their GA, they must discontinue these therapies with a washout period of 2 weeks and must remain off them during the study
• 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 have skin biopsies, blood collection, and total body photography and to 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 or C positive, or have an active, serious infection herpes simplex, herpes zoster, and pneumonia. This would also include localized infections.
• Patients with positive tuberculin skin test or positive QuantiFERON® Tuberculosis test
• Patients with significant hepatic impairment
• Patients with moderate renal impairment
• Patients with uncontrolled peptic ulcer disease
• Patients with a history of deep vein thrombosis and/or pulmonary embolism and/or clotting disorder
• Patients with any history of myocardial infarction or stroke.
• Patients taking concomitant immunosuppressive medications, with the exception of methotrexate and/or low-dose prednisone, including but not limited to mycophenolate mofetil, azathioprine, tacrolimus, cyclosporine, or 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
• Current smoker or history of any tobacco use

• Screening labs outside the normal range for parameters associated with potential risk for treatment under investigation. Including but not limited to:

  i. Platelets <150,000/mm3 ii. Absolute neutrophil count <1,000/mm3 iii. Hemoglobin levels <8 g/dL iv. Absolute lymphocyte count <500/mm3

• Patients who are taking moderate to strong inhibitors of both CYP2C19 and CYP2C9, or strong CYP2C19 or CYP2C9 inducers, as well as P-gp substrate where small concentration changes may lead to serious or life-threatening toxicities.
• Patients who have received a live vaccine. Patients should wait a minimum of 2 weeks, if recently vaccinated, prior to initiating treatment and should not receive a live vaccine during treatment or 2 weeks post-treatment.
• Patients with any medical, psychiatric, or social condition that is likely to unfavorably affect the risk-benefit of continued study participation, interfere with study compliance or confound safety or efficacy assessments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Abrocitinib 200 mg daily; 6 months of treatment with abrocitinib 200 mg daily	Drug: Abrocitinib 200 mg; Abrocitinib (Cibinqo) is FDA approved at 200 mg dose once daily for the treatment of atopic dermatitis. It is not currently FDA approved for the treatment of GA.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in BSA involvement by active GA	The percentage change in the body surface area (BSA) involvement by GA after 6 months of treatment with abrocitinib 200 mg daily in 10 patients with moderate to severe GA affecting at least 5% body surface area (BSA).	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in molecular signatures in skin and blood before and after treatment	Changes in molecular signatures in skin and blood at baseline vs. after 6 months of treatment. Molecular signatures will be assessed in the skin and in the blood. RNA-sequencing will be used to examine transcriptional profiles in this skin. A high throughput proteomic assay will be used to examine molecular profiles in the blood.	Baseline and 6 months
Changes in Granuloma Annulare Severity and Morphology Instrument (GASMI) score	Changes in GASMI score baseline vs. after 6 months of treatment. The Granuloma Annulare Severity and Morphology Instrument is a clinical severity scoring tool for GA. The score is determined by the study team who will examine the participants skin to determine the severity of the GA in different anatomic areas. Scores range from 0-165 with higher score indicating a worse outcome.	Baseline and 6 months
Changes in Skindex-16 (Skin related quality of life index)	Changes in Skindex-16 (Skin related quality of life index) baseline vs. after 6 months of treatment. This is a 16 item validated skin related Quality of Life questionnaire which will be administered by the study team to assess how GA affects the participants quality of life. Scores range from 0-96, higher scores indicating more significant impact on quality of life.	Baseline and 6 months

Collaborators and Investigators

• Sponsor: William Damsky
• Collaborators: Yale University; Pfizer
• Investigators: Principal Investigator: William Damsky, M.D., Yale University

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2023
• Primary Completion (Actual): May 7, 2024
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: December 6, 2022
• First Posted (Actual): December 14, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 2, 2025
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Inhibition; Granuloma Annulare
• Additional Relevant MeSH Terms: Pathologic Processes; Connective Tissue Diseases; Skin Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Collagen Diseases; Necrobiotic Disorders; Granuloma; Granuloma Annulare; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Abrocitinib
• Other Study ID Numbers: 2000033312; No NIH funding (Other Identifier: 11.09.23)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No