Safety and Efficacy of Tofacitinib for Chronic Granulomatous Disease With Inflammatory Complications

A Phase 1/2 Open-label Study to Evaluate the Safety and Efficacy of Tofacitinib for Chronic Granulomatous Disease With Inflammatory Complications

Background:

Chronic granulomatous disease (CGD) is a disease of the immune system, which is how the body fights germs. People with CGD get infections easily and have other health problems. Some medicines to treat CGD have a lot of side effects and do not always work. Researchers want to see if a new drug can help.

Objective:

To see if tofacitinib is safe to use for treating chronic CGD.

Eligibility:

Adults aged 18 and older with CGD who have not had success with other treatments and who are enrolled on NIH study # 93-I-0119.

Design:

Participants will be screened with the following:

Physical exam

Medical history

Blood, urine, and stool tests

Pregnancy test, if needed

An upper gastrointestinal endoscopy and/or colonoscopy, if needed for their symptoms. Tissue samples will be collected.

Skin assessment, if needed

Participants will repeat some screening tests at visits.

Participants will complete questionnaires about their general health and how CGD affects their daily life. Photographs will be taken of their skin, if needed. They will have lung function tests, if needed. They will have a computed tomography (CT) scan of the chest, abdomen, and pelvis, if needed. A CT scan uses X-rays to create pictures of the inside of the body.

Participants will gradually reduce the amount of some CGD medicines they take. Then they will take tofacitinib as a pill twice a day or once a day for 3 months. They will keep a drug diary. They will have monthly study visits. They will have a follow-up visit about 1 month after their last study drug visit.

Participation will last for about 6 months....

Study Overview

• Status: Completed
• Conditions: Chronic Granulomatous Disease; Inflammatory Gastrointestinal Disease; Inflammatory Skin Disease; Inflammatory Lung Disease
• Intervention / Treatment: Drug: XELJANZ (tofacitinib)

Detailed Description

Study Description:

This is a phase 1/2 open-label trial to study the safety and to explore the biological efficacy of tofacitinib in patients with confirmed and symptomatic inflammatory complications (gastrointestinal [GI], skin, lung) related to chronic granulomatous disease (CGD). After a 3-month regimen, participants inflammatory complications will be objectively assessed.

Primary Objective:

To assess the safety of tofacitinib during the study period in patients with CGD.

Secondary Objectives:

1. To assess the overall clinical response for the specific inflammatory manifestations.
2. To assess the biological effect of tofacitinib on interferon (IFN)-induced gene expression in CGD.

Primary Endpoints:

1. Rate of infection.
2. Rate of treatment-related toxicities.
3. Rate of adverse events (AEs).
4. Incidence of serious bacterial, mycobacterial, fungal, or viral infections defined as infections that require medical assessment or hospitalization.

Secondary Endpoints:

CGD-related inflammatory bowel disease (IBD):

1. Change in modified Harvey-Bradshaw Index (HBI).
2. Change in histopathological endoscopy.

Inflammatory lung disease:

1. Change in forced expiratory volume (FEV1).
2. Change in diffusing capacity for carbon monoxide (DLCO).
3. Change in computed tomography (CT) radiography.
4. Change in 6-minute walk.

Skin disease:

1. Change in presence of skin flares or ulcerations by objective photography evaluation.

Gene expression:

1.Change in IFN gene module enrichment score derived from whole blood RNA expression data.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

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

Description

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Aged >=18 years.
2. Enrolled on NIH study 93-I-0119.

3. Has a documented diagnosis of one or more of the following and is not controlled under current therapy (per investigator assessment):

   1. Endoscopically diagnosed mild-to-severe CGD-related IBD.
   2. Radiographic or PFT changes (DLCO<60%, FEV1<70%) consistent with CGD-related inflammatory lung disease.
   3. Any inflammatory skin disease related to CGD (eg, hidradenitis suppurativa or granulomatous skin disease).
4. Able to provide informed consent.
5. Participants who can become pregnant or who can impregnate their partner must agree to use at least one highly effective method of contraception when engaging in sexual activities that can result in pregnancy, starting at the first dose of tofacitinib until 2 days after the last dose. Highly effective methods include a barrier (eg, condom, diaphragm, cervical cap), intrauterine device, or hormonal contraception.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Known allergy or hypersensitivity to any component of the tofacitinib formulation.
2. Known allergy or hypersensitivity to any component of the acyclovir or valacyclovir formulation.
3. Active or latent tuberculosis.
4. Infection with hepatitis B or C, or HIV.
5. Active EBV infection.
6. History of GI perforation.
7. History of malignancy (except for nonmelanoma skin cancer).
8. Concomitant use of acetylsalicylic acid and/or NSAIDs that cannot be safely discontinued.
9. History of connective tissue disease.
10. End-stage renal disease or chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m^2.
11. Evidence of other invasive or systemic fungal, bacterial, or viral infections requiring therapy.
12. Pregnant.
13. Breastfeeding.
14. Current use of inhaled tobacco products, vaping products, inhaled cannabis, or other illicit inhaled drugs.
15. Current use of strong CYP3A4 inducer and unable to discontinue at least 14 days before beginning of tofacitinib regimen.
16. Concomitant medical condition that could interfere with study drug evaluation or that is a contraindication to the proposed investigational treatment based upon known agent safety profile or toxicities.

17. Any of the following laboratory abnormalities:

    1. Alkaline phosphatase and either ALT or AST >2.5 times the upper limit of normal (ULN).
    2. Serum creatinine level >5 mg/dL.
    3. Absolute neutrophil count (ANC) <1000 cells/microL.
    4. Lymphocyte count <500 cells/microL.
18. History of unprovoked deep vein thrombosis, pulmonary embolism, or other thrombotic events.
19. History of heart failure.
20. Current immobilization, ie, bed-bound and unable to ambulate.
21. Exposure to any investigational agent within the last 4 weeks.
22. Any other finding that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety or reactogenicity, or a participant s ability to give informed consent, or increase the risk of having an adverse outcome from participating in the study.

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: XELJANZ (tofacitinib); Tofacitinib is self-administered orally at 5 mg twice per day or 11 mg once per day for 3 months.	Drug: XELJANZ (tofacitinib); The XELJANZ 5-mg tablets or 11-mg XR tablets will taken orally twice daily or once daily, respectively, in this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of treatment-related toxicities.	To assess the safety of tofacitinib during the study period in patients with CGD.	Day 1 through Day 120
Rate of infection.	To assess the safety of tofacitinib during the study period in patients with CGD.	Day 1 through Day 120
Rate of AEs	To assess the safety of tofacitinib during the study period in patients with CGD.	Day 1 through Day 120
Incidence of serious bacterial, mycobacterial, fungal, or viral infections defined as infections that require medical assessment or hospitalization.	To assess the safety of tofacitinib during the study period in patients with CGD.	Day 1 through Day 120

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CGD-related IBD: 1.Change in modified HBI. 2.Change in histopathological endoscopy.	To assess the overall clinical response for the specific inflammatory manifestations.	Day 90
Skin disease: 1.Change in presence of skin flares or ulcerations by objective photography evaluation.	To assess the overall clinical response for the specific inflammatory manifestations.	Day 90
Inflammatory lung disease: 1. Change in FEV1. 2. Change in DLCO. 3.Change in CT radiography. 4. Change in 6-minute walk.	To assess the overall clinical response for the specific inflammatory manifestations.	Day 90
Gene expression: 1.Change in IFN gene module enrichment score derived from whole blood RNA expression data.	To assess the biological effect of tofacitinib on IFN-induced gene expression in CGD.	Day 90

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Christa S Zerbe, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Panes J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D'Haens G, Panaccione R, Higgins PDR, Colombel JF, Feagan BG, Chan G, Moscariello M, Wang W, Niezychowski W, Marren A, Healey P, Maller E. Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials. Gut. 2017 Jun;66(6):1049-1059. doi: 10.1136/gutjnl-2016-312735. Epub 2017 Feb 16.
• Henrickson SE, Jongco AM, Thomsen KF, Garabedian EK, Thomsen IP. Noninfectious Manifestations and Complications of Chronic Granulomatous Disease. J Pediatric Infect Dis Soc. 2018 May 9;7(suppl_1):S18-S24. doi: 10.1093/jpids/piy014.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2022
• Primary Completion (Actual): May 4, 2026
• Study Completion (Actual): May 4, 2026

Study Registration Dates

• First Submitted: November 2, 2021
• First Submitted That Met QC Criteria: November 2, 2021
• First Posted (Actual): November 3, 2021

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 5, 2026

More Information

Terms related to this study

• Keywords: Ulcerative Colitis; Inflammatory Bowel Disease; JAK Inhibitor; Interferon (IFN)-induced gene expression; Inflammatory skin/ lung disease
• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Genetic Diseases, Inborn; Intestinal Diseases; Immune System Diseases; Digestive System Diseases; Gastrointestinal Diseases; Leukocyte Disorders; Hematologic Diseases; Colonic Diseases; Immunologic Deficiency Syndromes; Skin Diseases; Gastroenteritis; Genetic Diseases, X-Linked; Phagocyte Bactericidal Dysfunction; Colitis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Colitis, Ulcerative; Dermatitis; Granulomatous Disease, Chronic; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; tofacitinib
• Other Study ID Numbers: 10000064; 000064-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No