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

Sponsor
National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
Overall Status
Enrolling by invitation
CT.gov ID
NCT05104723
Collaborator
(none)
20
Enrollment
1
Location
1
Arm
38.2
Anticipated Duration (Months)
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 of tofacitinib, participants inflammatory complications will be objectively assessed. Samples collected before, during, and after therapy will be evaluated for pathologic, molecular, and cellular changes in response to therapy, thereby refining our knowledge of the mechanisms driving inflammatory complications in CGD patients while evaluating the safety of this novel therapy. Inhibition of Janus kinase (JAK) pathways is a novel therapeutic intervention for CGD patients with inflammatory complications that are not responsive to standard therapies. Preliminary data highlight the potential role of increased activation of the JAK/signal transducer and activator of transcription (STAT) pathway in the pathogenesis of CGD. These data, paired with the success in treating other monogenic immune disorders characterized by JAK/STAT pathway activation (ie, STAT1 gain-of-function, STING-associated vasculopathy of infancy) with JAK inhibitors (JAKIs), suggest that JAKIs are a reasonable candidate therapy for the difficult-to-treat inflammatory manifestations of CGD. Tofacitinib, a first generation JAKI, is an attractive candidate for this purpose given the following: 1) it is FDA-approved for treatment of moderate to severe ulcerative colitis, 2) CGD colitis shares many clinical and pathologic features of inflammatory bowel disease, and 3) the GI, pulmonary, and skin inflammatory complications of CGD respond poorly to standard therapies and cause significant morbidity. Patients taking tofacitinib are at increased risk for developing serious infections, so participants will maintain their current antifungal and antibacterial medications, and will start a shingles prophylaxis regimen. Major adverse cardiovascular (CV) events, such as heart attack, stroke, blot clots, cancer, and death have also been reported in patients with preexisting CV risk factors. Patients with CV risk factors or a history of major adverse CV events will be excluded from the study, and participants will be closely monitored for signs and symptoms. The hypothesis of this study is that CGD patients with poorly controlled GI, skin, and pulmonary inflammatory manifestations can be safely treated with tofacitinib and will experience improvement in clinical symptoms, pathological findings, and molecular and cellular biomarkers.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: XELJANZ (tofacitinib)
Phase 1/Phase 2

Detailed 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 of tofacitinib, participants inflammatory complications will be objectively assessed. Samples collected before, during, and after therapy will be evaluated for pathologic, molecular, and cellular changes in response to therapy, thereby refining our knowledge of the mechanisms driving inflammatory complications in CGD patients while evaluating the safety of this novel therapy. Inhibition of Janus kinase (JAK) pathways is a novel therapeutic intervention for CGD patients with inflammatory complications that are not responsive to standard therapies. Preliminary data highlight the potential role of increased activation of the JAK/signal transducer and activator of transcription (STAT) pathway in the pathogenesis of CGD. These data, paired with the success in treating other monogenic immune disorders characterized by JAK/STAT pathway activation (ie, STAT1 gain-of-function, STING-associated vasculopathy of infancy) with JAK inhibitors (JAKIs), suggest that JAKIs are a reasonable candidate therapy for the difficult-to-treat inflammatory manifestations of CGD. Tofacitinib, a first generation JAKI, is an attractive candidate for this purpose given the following: 1) it is FDA-approved for treatment of moderate to severe ulcerative colitis, 2) CGD colitis shares many clinical and pathologic features of inflammatory bowel disease, and 3) the GI, pulmonary, and skin inflammatory complications of CGD respond poorly to standard therapies and cause significant morbidity. Patients taking tofacitinib are at increased risk for developing serious infections, so participants will maintain their current antifungal and antibacterial medications, and will start a shingles prophylaxis regimen. Major adverse cardiovascular (CV) events, such as heart attack, stroke, blot clots, cancer, and death have also been reported in patients with preexisting CV risk factors. Patients with CV risk factors or a history of major adverse CV events will be excluded from the study, and participants will be closely monitored for signs and symptoms. The hypothesis of this study is that CGD patients with poorly controlled GI, skin, and pulmonary inflammatory manifestations can be safely treated with tofacitinib and will experience improvement in clinical symptoms, pathological findings, and molecular and cellular biomarkers.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
20 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Open-label Study to Evaluate the Safety and Efficacy of Tofacitinib for Chronic Granulomatous Disease With Inflammatory Complications
Anticipated Study Start Date :
Nov 24, 2021
Anticipated Primary Completion Date :
Jan 31, 2025
Anticipated Study Completion Date :
Jan 31, 2025

Arms and Interventions

ArmIntervention/Treatment
Experimental: XELJANZ (tofacitinib)

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

Drug: XELJANZ (tofacitinib)
The XELJANZ 5-mg tablets will taken orally twice daily in this study.

Outcome Measures

Primary Outcome Measures

  1. Rate of treatment-related toxicities. [Day 1 through Day 120]

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

  2. Rate of infection. [Day 1 through Day 120]

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

  3. Rate of AEs [Day 1 through Day 120]

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

  4. Incidence of serious bacterial, mycobacterial, fungal, or viral infections defined as infections that require medical assessment or hospitalization. [Day 1 through Day 120]

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

Secondary Outcome Measures

  1. CGD-related IBD: 1.Change in modified HBI. 2.Change in histopathological endoscopy. [Day 90]

    To assess the overall clinical response for the specific inflammatory manifestations.

  2. Skin disease: 1.Change in presence of skin flares or ulcerations by objective photography evaluation. [Day 90]

    To assess the overall clinical response for the specific inflammatory manifestations.

  3. Inflammatory lung disease: 1. Change in FEV1. 2. Change in DLCO. 3.Change in CT radiography. 4. Change in 6-minute walk. [Day 90]

    To assess the overall clinical response for the specific inflammatory manifestations.

  4. Gene expression: 1.Change in IFN gene module enrichment score derived from whole blood RNA expression data. [Day 90]

    To assess the biological effect of tofacitinib on IFN-induced gene expression in CGD.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
  • 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):

  4. Endoscopically diagnosed mild-to-severe CGD-related IBD.

  5. Radiographic or PFT changes (DLCO<60%, FEV1<70%) consistent with CGD-related inflammatory lung disease.

  6. Any inflammatory skin disease related to CGD (eg, hidradenitis suppurativa or granulomatous skin disease).

  7. Able to provide informed consent.

  8. 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 tobacco products.

  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:

  18. Alkaline phosphatase and either ALT or AST >2.5 times the upper limit of normal (ULN).

  19. Serum creatinine level >5 mg/dL.

  20. Absolute neutrophil count (ANC) <1000 cells/microL.

  21. Lymphocyte count <500 cells/microL.

  22. History of unprovoked deep vein thrombosis, pulmonary embolism, or other thrombotic events.

  23. History of heart failure.

  24. Current immobilization, ie, bed-bound and unable to ambulate.

  25. Exposure to any investigational agent within the last 4 weeks.

  26. 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.

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1National Institutes of Health Clinical CenterBethesdaMarylandUnited States20892

Sponsors and Collaborators

  • National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

Responsible Party:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT05104723
Other Study ID Numbers:
  • 10000064
  • 000064-I
First Posted:
Nov 3, 2021
Last Update Posted:
Nov 19, 2021
Last Verified:
Nov 1, 2021
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID)
Additional relevant MeSH terms:

Study Results

No Results Posted as of Nov 19, 2021