Research with the drug tofacitinib for patients with refractory celiac disease type II

Phase 1

Conditions: Refractory celiac disease type II
Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Registration Number: EUCTR2018-001678-10-NL

Lead Sponsor: VU Medical Center

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 5

Inclusion Criteria

1. Adult patients = 18 years old
2. Given informed consent
3. Diagnosis of RCDII
4. Total adherence to a glutenfree diet for at least 6 consecutive months prior to screening. Subjects must also agree to make no changes to their current GFD for the duration of study participation.
5. Anti-tissue transglutaminase (IgA and IgG) at screening < 2x the diagnostic level for celiac disease (weak positive or negative)
6. In case of female fertile patients: negative serum pregnancy test prior to study enrollment; adequate contraception, up to 4 weeks after final dose.
7. Laboratory values:
a) Total WBC > 0.75 x 10^9/L (i.e. > 750/mm3)
n) Hemoglobin > 5.5 mmol/L (i.e. 8.86 g/dL)
c) Absolute neutrophil count > 1 x 10^9 / L (i.e. > 1000 cells/mm3.)
d) Estimated eGFR > 30mL/min/1.73m2 using the Cockcroft-Gault equation.
e) Platelets > 50 x 109/L (i.e. 50000/mm3)
8. PET/CT-scan without signs of abnormalities suggestive for EATL within 3 months.
9. Willingness and ability to comply with study procedures.
10. Willingness to return for all scheduled follow-up visits.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 2
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3

Exclusion Criteria

1. Diagnosis of RCDI, EATL
2. Presence of any of the following diagnosis:
a) Active acute infections, which require systemic treatments (specific attention for treatment with ketoconazol or fluconazole (as well CYP3A4 metabolizers).
b) Severe infection prior to screening
c) Active tuberculosis (TBC) (as confirmed in PET/CT-scan; chest radiography)
d) Untreated or inadequately treated latent TB (as confirmed with a positive IGRA test (QuantiFERON-TB Gold Plus test)).
- NB. Subjects are permitted to enroll in study after = 4 months treatment with rifampicine)
e) History within 3 years of opportunistic infections typical of those seen in immunocomprised patients, such as systemic candida infection.
f) Severe liver insufficiency (Child Pugh Score 10-15)
3. Positive Hep B, Hep C or HIV test results at the time of screening.
4. Vaccination with live, attenuated vaccines (such as varicella zoster vaccine, yellow fever, oral typhoid vaccine) within 2 weeks before start of tofacitinib.
5. History of significant immune suppression:
a) BMT therapy less than 6 months prior to baseline
b) Potent systemic immune suppressants (e.g., azathioprine, within specified time periods per drug type) prior to baseline.
6. Subjects receiving moderate/potent CYP3A inducers or inhibitors in the specified time periods prior to the first dose of study drug:
- Moderate/potent CYP3A inducers, within 28 days of 5 half-lives, whichever is longer, prior to first dose of study drug;
- Moderate/potent CYP3A inhibitors, within 7 days or 5 half-lives, whichever is longer, prior to first dose of study drug.
i. NB.Topical (including skin or mucous membranes) application of antimicriobial and antifungal medications is permitted.
7. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results.
8. History or presence of clinically significant disease that in the opinion of the investigator would confound the subject’s participation and follow-up in the clinical trial or put the subject at unnecessary risk (e.g. uncontrolled cardiac diseases, uncontrolled/chronic pulmonary, renal, endocrine, hematological, gastrointestinal, immunologic, dermatological, neurological or psychiatric dysfunction).
9. History of drug or alcohol abuse that would interfere with the ability to comply with the study protocol.
10. History of clinically significant hypersensitivity to the study drug or to any of the excipients
11. Females who are pregnant, becoming pregnant or are currently breastfeeding.
12. Participation in any other investigational drug study in the past 30 days/5 half-lives.
13. Any additional reason which would endanger safety of the subject for participation in this study, in the opinion of the investigator.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy of tofacitinib treatment in patients with RCDII with persistent or recurrent villous atrophy (Marsh III ABC) and aberrant IEL T-cells (> 20% as assessed by flow cytometry). ;Secondary Objective: - To assess the safety of tofacitinib in patients with RCDII. <br>- To evaluate the effect of of tofacitinib on quality-of-life of patients with RCDII when treated with tofacitinib.<br>- To evaluate predictability of response to tofacitinib therapy with an in vitro assay. <br>;Primary end point(s): Primary efficacy endpoint: <br><br>- Immunological response, as defined by: <br>reduction from baseline of aberrant IELs (%) with respect to total IELs in duodenal biopsies at week 12, as assessed by flow cytometry. ;Timepoint(s) of evaluation of this end point: 12 weeks

Secondary Outcome Measures