Use of tofacitinib in patients with treatment-refractory rheumatoid arthritis.

• Register: EUCTR
• Last refreshed on: 17 August 2021
• Main ID: EUCTR2021-001560-14-ES
• Date of registration: 11/06/2021
• Prospective Registration: Yes
• Primary sponsor: FUNDACION JIMENEZ DIAZ HEALTH RESEARCH INSTITUTE
• Public title: Use of tofacitinib in patients with treatment-refractory rheumatoid arthritis.
• Scientific title: Single-center, open-label, uncontrolled clinical trial to evaluate the association between the expression of the JAK / STAT pathway and the response to tofacitinib in patients with refractory rheumatoid arthritis.
• Date of first enrolment: 13/08/2021
• Target sample size: 42
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-001560-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Spain

Contacts

• Name: UNIDAD DE INVESTIGACION CLINICA
• Affiliation: FUNDACION JIMENEZ DIAZ HEALTH RESEARCH INSTITUTE

• Name: UNIDAD DE INVESTIGACION CLINICA
• Affiliation: FUNDACION JIMENEZ DIAZ HEALTH RESEARCH INSTITUTE

Key inclusion & exclusion criteria

Inclusion criteria:
1. Patients, male or female, over 18 years of age.
2. Patients capable of providing written informed consent.
3. Patients mentally competent to understand and agree to carry out the study procedures, as well as tolerate blood draws, local anesthesia, and synovial biopsy.
4. Patients diagnosed with rheumatoid arthritis according to the ACR / EULAR 2010 classification criteria.
5. Patients with active rheumatoid arthritis (DAS28> 3.2) with at least 3 painful and swollen joints out of the 28 joints evaluated in the DAS28 (shoulders, elbows, carpals, metacarpophalangeal, proximal interphalangeal of the hands and knees), in which at least one of them is among the following: carpals, 2nd metacarpophalangeal and knees, and in which the presence of synovial hypertrophy at least grade 2 (on a scale of 0-3) is confirmed by ultrasound.
6. Patients with refractory rheumatoid arthritis, defined as failure to one or more classic synthetic DMARDs (methotrexate, leflunomide, sulfasalazine, leflunomide, or hydroxychloroquine) followed by failure to one or more biological DMARDs (TNF, abatacept, tocilizumab, rituximab).
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 42
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 42

Exclusion criteria:
1. Diagnosis of another type of arthritis other than rheumatoid arthritis.
2. Contraindication to the use of targeted synthetic DMARDs (active infection, previously untreated latent tuberculosis, neoplasia). In cases of latent tuberculosis, after 1 month of tuberculosis treatment, the inclusion of the patient in the study could be considered.
3. Known allergy or hypersensitivity to tofacitinib.
4. Patients taking medications that may interact with tofacitinib or any other contrindication to the use of tofacitinib.
5. Patients in treatment with any drug that may affect the evaluation of the study. Patients must have a washout period prior to the start of the study. Unless there is intolerance, adverse effects, or other specific reason, patients can continue their treatment with classic synthetic DMARDs. In relation to the use of NSAIDs or corticosteroids, concomitant stable doses of NSAIDs or corticosteroids (less than / equal to 10mg of prednisone per day or its equivalent) will be allowed.
6. Anticoagulated patients.
7. Pregnant or lactating patients.
8. Patients participating in another clinical trial or who have participated in another clinical trial in the 3 months prior to signing the IC.
9. Known HIV, HBV, or HCV infection.
10. Patients considered in the investigator's judgment as ineligible for the study based on their medical history, physical examination, medication, and concomitant pathologies.
11. Potentially fertile women who are unwilling to use a contraceptive method that is considered effective *.

* A woman is considered to have reproductive potential (WOCBP), that is, fertile, after menarche and until she becomes postmenopausal, unless she is permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
Highly effective methods are considered: combined hormonal contraception (containing estrogens and progestogens) associated with inhibition of ovulation (oral, intravaginal, transdermal route), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable ), intrauterine device (IUD), intrauterine hormone releasing system (IUS), bilateral tubal occlusion, vasectomized couple, sexual abstinence.
12. Patients who do not want to participate or are not willing to give their IC in writing.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Refractory rheumatoid arthritis

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Trade Name: XELJANZ
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: TOFACITINIB
CAS Number: 477600-75-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 12 weeks

Secondary Objective: To study the association of JAK / STAT protein expression in synovial tissue with the clinical response to tofacitinib.
Define the synovial pathotype (lymphoid-myeloid, diffuse myeloid, and pauci-immune) associated with the clinical response to tofacitinib.
To study the association of the synovial JAK / STAT signature with the ultrasound response in the biopsied joint.

Main Objective: To evaluate in patients with rheumatoid arthritis refractory to classic synthetic DMARDs and one or more biological DMARDs, the association of the JAK / STAT gene signature in synovial tissue with the clinical response to tofacitinib.

Primary end point(s): The primary analysis of the study will be the specific clinical response to treatment with tofacitinib at 12 weeks, measured by the ACR response criteria (number of swollen joints, number of painful joints, HAQ-DI, global assessment of the disease by the patient and the physician, C-reactive protein value) and DAS28 (1,2), and their association with the JAK / STAT signature in synovial tissue.

Secondary Outcome(s)

Secondary end point(s): - The specific synovial tissue pathotype, through the cellular infiltrated analysis (Defined as lynfoid-myeloid, difusse myeloid and pauci-inmune pathotype) and its association with tofacitinib response.
- The distribution of patients with refractary RA in the different pathotypes to check if this distribution is similar or different from the distribution in cohorts of early arthritis already described.
- The protein synthesis of mediators of the JAK/STAT signature in synovial tissue and its association with the tofacitinib
- The cellular infiltrate and its association with the indicated gene expression markers and the analysis of a posible clinical prediction model of response to tofacitinib integrating these findings.
- The intensity of the synovial JAK/STAT signature at baseline and its association with the intensity global and/or local inflammation in the biopsed joint of the pacient, measured by ultrasound.

Timepoint(s) of evaluation of this end point: 4, 8 and 12 weeks

Secondary ID(s)

FJD-RA-TOF-60418809

Source(s) of Monetary Support

INSTITUTO DE SALUD CARLOS III

Ethics review

Status: Approved
Approval date: 30/07/2021
Contact: