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

Primary Purpose

Chronic Granulomatous Disease, Inflammatory Gastrointestinal Disease, Inflammatory Skin Disease

Status
Enrolling by invitation
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
XELJANZ (tofacitinib)
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Granulomatous Disease focused on measuring Inflammatory Bowel Disease, Interferon (IFN)-induced gene expression, JAK Inhibitor, Ulcerative Colitis, Inflammatory skin/ lung disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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 product, 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.

Sites / Locations

  • National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

XELJANZ (tofacitinib)

Arm Description

Tofacitinib is self-administered orally at 5 mg twice per day for 3 months.

Outcomes

Primary Outcome Measures

Rate of treatment-related toxicities.
To assess the safety of tofacitinib during the study period in patients with CGD.
Rate of infection.
To assess the safety of tofacitinib during the study period in patients with CGD.
Rate of AEs
To assess the safety of tofacitinib during the study period in patients with CGD.
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.

Secondary Outcome Measures

CGD-related IBD: 1.Change in modified HBI. 2.Change in histopathological endoscopy.
To assess the overall clinical response for the specific inflammatory manifestations.
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.
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.
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.

Full Information

First Posted
November 2, 2021
Last Updated
August 10, 2023
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT05104723
Brief Title
Safety and Efficacy of Tofacitinib for Chronic Granulomatous Disease With Inflammatory Complications
Official Title
A Phase 1/2 Open-label Study to Evaluate the Safety and Efficacy of Tofacitinib for Chronic Granulomatous Disease With Inflammatory Complications
Study Type
Interventional

2. Study Status

Record Verification Date
August 8, 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
August 12, 2022 (Actual)
Primary Completion Date
January 1, 2026 (Anticipated)
Study Completion Date
January 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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 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.
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: To assess the overall clinical response for the specific inflammatory manifestations. To assess the biological effect of tofacitinib on interferon (IFN)-induced gene expression in CGD. Primary Endpoints: Rate of infection. Rate of treatment-related toxicities. Rate of adverse events (AEs). 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): Change in modified Harvey-Bradshaw Index (HBI). Change in histopathological endoscopy. Inflammatory lung disease: Change in forced expiratory volume (FEV1). Change in diffusing capacity for carbon monoxide (DLCO). Change in computed tomography (CT) radiography. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Granulomatous Disease, Inflammatory Gastrointestinal Disease, Inflammatory Skin Disease, Inflammatory Lung Disease
Keywords
Inflammatory Bowel Disease, Interferon (IFN)-induced gene expression, JAK Inhibitor, Ulcerative Colitis, Inflammatory skin/ lung disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
XELJANZ (tofacitinib)
Arm Type
Experimental
Arm Description
Tofacitinib is self-administered orally at 5 mg twice per day for 3 months.
Intervention Type
Drug
Intervention Name(s)
XELJANZ (tofacitinib)
Intervention Description
The XELJANZ 5-mg tablets will taken orally twice daily in this study.
Primary Outcome Measure Information:
Title
Rate of treatment-related toxicities.
Description
To assess the safety of tofacitinib during the study period in patients with CGD.
Time Frame
Day 1 through Day 120
Title
Rate of infection.
Description
To assess the safety of tofacitinib during the study period in patients with CGD.
Time Frame
Day 1 through Day 120
Title
Rate of AEs
Description
To assess the safety of tofacitinib during the study period in patients with CGD.
Time Frame
Day 1 through Day 120
Title
Incidence of serious bacterial, mycobacterial, fungal, or viral infections defined as infections that require medical assessment or hospitalization.
Description
To assess the safety of tofacitinib during the study period in patients with CGD.
Time Frame
Day 1 through Day 120
Secondary Outcome Measure Information:
Title
CGD-related IBD: 1.Change in modified HBI. 2.Change in histopathological endoscopy.
Description
To assess the overall clinical response for the specific inflammatory manifestations.
Time Frame
Day 90
Title
Skin disease: 1.Change in presence of skin flares or ulcerations by objective photography evaluation.
Description
To assess the overall clinical response for the specific inflammatory manifestations.
Time Frame
Day 90
Title
Inflammatory lung disease: 1. Change in FEV1. 2. Change in DLCO. 3.Change in CT radiography. 4. Change in 6-minute walk.
Description
To assess the overall clinical response for the specific inflammatory manifestations.
Time Frame
Day 90
Title
Gene expression: 1.Change in IFN gene module enrichment score derived from whole blood RNA expression data.
Description
To assess the biological effect of tofacitinib on IFN-induced gene expression in CGD.
Time Frame
Day 90

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Aged >=18 years. Enrolled on NIH study 93-I-0119. Has a documented diagnosis of one or more of the following and is not controlled under current therapy (per investigator assessment): Endoscopically diagnosed mild-to-severe CGD-related IBD. Radiographic or PFT changes (DLCO<60%, FEV1<70%) consistent with CGD-related inflammatory lung disease. Any inflammatory skin disease related to CGD (eg, hidradenitis suppurativa or granulomatous skin disease). Able to provide informed consent. 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: Known allergy or hypersensitivity to any component of the tofacitinib formulation. Known allergy or hypersensitivity to any component of the acyclovir or valacyclovir formulation. Active or latent tuberculosis. Infection with hepatitis B or C, or HIV. Active EBV infection. History of GI perforation. History of malignancy (except for nonmelanoma skin cancer). Concomitant use of acetylsalicylic acid and/or NSAIDs that cannot be safely discontinued. History of connective tissue disease. End-stage renal disease or chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m^2. Evidence of other invasive or systemic fungal, bacterial, or viral infections requiring therapy. Pregnant. Breastfeeding. Current use of inhaled tobacco products, vaping product, inhaled cannabis, or other illicit inhaled drugs. Current use of strong CYP3A4 inducer and unable to discontinue at least 14 days before beginning of tofacitinib regimen. 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. Any of the following laboratory abnormalities: Alkaline phosphatase and either ALT or AST >2.5 times the upper limit of normal (ULN). Serum creatinine level >5 mg/dL. Absolute neutrophil count (ANC) <1000 cells/microL. Lymphocyte count <500 cells/microL. History of unprovoked deep vein thrombosis, pulmonary embolism, or other thrombotic events. History of heart failure. Current immobilization, ie, bed-bound and unable to ambulate. Exposure to any investigational agent within the last 4 weeks. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christa S Zerbe, M.D.
Organizational Affiliation
National Institute of Allergy and Infectious Diseases (NIAID)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
28209624
Citation
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.
Results Reference
background
PubMed Identifier
29746679
Citation
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.
Results Reference
background
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_000064-I.html
Description
NIH Clinical Center Detailed Web Page

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

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