| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to severely active Rheumatoid Arthritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate to severe Rheumatoid Arthritis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the efficacy of 5 mg BID of tofacitinib (with and without background MTX) to adalimumab with MTX as measured by American College of Rheumatology 50% improvement (ACR50) response rates at Month 6.
To compare the efficacy of 5 mg BID of tofacitinib monotherapy to 5 mg BID tofacitinib with MTX as measured by ACR50 response rates at Month 6. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of tofacitinib 5 mg BID monotherapy vs. 5 mg BID combined with MTX as measured by Disease Activity Score 28-4 (C-reactive protein) (DAS28-4 (CRP)), ACR20, ACR70, Rates of remission, Low Disease Activity (LDA), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), DAS28-4 erythrocyte sedimentation rate (ESR), at Month 6.
2. To compare the efficacy of tofacitinib 5 mg BID with and without MTX vs. adalimumab with MTX for the treatment of signs and symptoms of RA as measured by ACR20, ACR70, Rates of remission, LDA, SDAI, CDAI, DAS28-4 (ESR) and DAS28-4 (CRP) at Month 6.
Items 3-6 detailed in the Protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Must be at least 18 years of age or older.
3. Specific criterion for administration of the zoster vaccine - details contained in the Protocol
4. Has ≥4 tender/painful joints on motion and ≥4 swollen joints (28 joint count) at Screening and Baseline/Visit 2
5. Screening C-reactive protein (CRP) ≥3 mg/L in the central laboratory
6. Has moderate to severe rheumatoid arthritis inadequately controlled with methotrexate
7. Has a score of 6 or greater on the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis (Appendix 1 of Protocol)
8. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA where usual self-care activities including dressing, feeding, bathing, grooming, and toileting; avocational (recreational and/or leisure) and vocational (work, school, homemaking) activities are subject-desired and age- and sex-specific. (Details re Class I, II, III contained in the Protocol)
9. Has been receiving a MTX treatment regimen continuously for at least 4 months prior to the Screening visit and has taken a stable weekly dose of oral methotrexate with supplemental folic or folinic acid for at least 6 weeks prior to the Baseline/Visit 2. (Conversion from parenteral to oral will require “stabilization” over this period of time as well). (Further details contained in the Protocol).
10. Female subjects of childbearing potential must test negative for pregnancy.
11. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and for at least 3 months after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active. (Please refer to Appendix 6 for specific requirements for subjects enrolled in Czech Republic, Estonia, Germany, Hungary, Lithuania, Latvia, Romania, Spain and the United Kingdom).
12. Female subjects who are not of childbearing potential (ie, meet at least one of the following criteria):
a. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
b. Have medically confirmed ovarian failure or;
c. Achieved post-menopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle-stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females
13. Subjects must screen negative for active tuberculosis or inadequately treated tuberculosis infection (active or latent) as evidenced by the following:
a. Negative QuantiFERON Gold®TM In-Tube test performed at screening
- This is required unless the subject has been adequately treated for active or latent tuberculosis or a negative QuantiFERON Gold®TM In-Tube test was
previously performed and documented within the 3 months prior to screening.
- A negative tuberculin skin test (TST) is one that is <5 mm induration and can be substituted for the QuantiFERON Gold ® TM In-Tube test only if the
central laboratory is unable to perform the test or the test is reported as indeterminate after at least 2 successive attempts.
- It is strongly recommended that subjects with a history of Bacille Calmette Guérin (BCG) vaccination be tested with the QuantiFERON Gold®™ In-Tube test.
b. Chest radiograph (or chest computed tomography (CT) scan, if available) taken at screening without changes suggestive of active tuberculosis (TB) infection, unless previously performed and documented within 3 months prior to screening.
c. No history of tuberculosis infection unless one of the following is documented:
- Subject with prior or current latent tuberculosis has no evidence of active tuberculosis and must be taking or have completed an adequate course of
therapy for latent tuberculosis in a locale where rates of primary multi-drug resistant TB infection are <5%, and a chest radiograph is negative for active disease; the chest radiograph must be obtained at screening or, if previously performed and documented, within 3 months prior to screening.
- Subject with prior active tuberculosis has no current evidence of active disease and has completed an adequate course of therapy for active tuberculosis (a multi-drug regimen recognized by the World Health Organization) and a chest radiograph is negative for active disease; the chest radiograph must be obtained at screening or, if previously performed and documented, within 3 months prior to screening.
14. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.
2. Subjects who have an allergy or hypersensitivity to MTX, subjects who have experienced a serious toxicity when administered MTX, or have any contraindication to treatment with MTX according to the local label for treatment of RA with MTX.
3. Subjects who have Class III or Class IV heart failure according to the New York Heart Association (NYHA) functional classification system or any other contraindication to treatment with adalimumab.
4. Pregnant female subjects; breastfeeding female subjects; males and females of childbearing potential who are unwilling or unable to use two methods of highly effective contraception as outlined in this protocol for the duration of the study and for at least 3 months after last dose of investigational product. (Please refer to Appendix 6 for specific requirements for subjects enrolled in Czech Republic, Estonia, Germany, Hungary, Lithuania, Latvia, Romania, Spain and the United Kingdom).
5. Subjects with infections or history of infections (additional details in Protocol) .
6. Subjects with any current malignancy or a history of malignancy, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
7. Subjects with any uncontrolled clinically significant laboratory abnormality or any of the following laboratory abnormalities:
a. Evidence of hematopoietic disorder or hemoglobin <9 g/dL
b. Absolute lymphocyte count <0.75 x 10^9/L (<750/mm3)
c. Absolute neutrophil count <1.2 x 10^9/L (<1200/mm3)
d. Platelet count <100 x 10^9/L (<100,000/mm3)
e. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >1.5 times the upper limit of normal (x ULN)
f. Estimated glomerular filtration rate (GFR) <40 mL/min using the Cockcroft-Gault formula (Appendix 3 of Protocol).
8. Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks or 5 half-lives (whichever is longer) after discontinuation of the investigational compound before the current study begins and/or during study participation, unless further restrictions to class of compound are specified in Section 4.2 and Section 5.8.
9. Subjects requiring or have received any prohibited concomitant medication or dietary supplement as outlined in Appendix 2 of the Protocol.
10. Subjects with a screening 12-lead electrocardiogram that demonstrates clinically significant abnormalities requiring urgent treatment (eg, acute myocardial infarction, serious tachy- or bradyarrhythmias) or that is indicative of serious underlying heart disease (eg, cardiomyopathy, major congenital heart disease, low voltage in all leads).
11. Subjects who had significant trauma or surgical procedure within 1 month prior to the Baseline/Visit 2.
12. Subjects with any rheumatic autoimmune disease, other than RA and Sjogren’s syndrome.
13. Subjects who are classified Class IV of the ACR 1991 Revised Criteria for Global Functional Status in RA (ie, are limited in their ability to perform usual self-care, vocational, and avocational activities).
14. Subjects with lymphoproliferative disorders (eg, Epstein Barr Virus (EBV) related lymphoproliferative disorder), a history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.
15. Alcohol or substance abuse unless in full remission for greater than 6 months prior to first dose of study drug.
16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
17. Specific exclusion criteria for administration of the zoster vaccine in eligible subjects (refer to Protocol) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ACR 50 response rates at Month 6 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Change from Baseline in SDAI, CDAI at Month 6.
2. Change from Baseline in DAS28-4 (CRP) and DAS28-4 (ESR) at Month 6.
3. Rate of remission at Month 6, as assessed by: ACR-EULAR Boolean remission criteria;4 SDAI ≤ 3.3; CDAI ≤2.8; DAS28-4 (ESR) < 2.6 and DAS28-4 (CRP) < 2.6.
4. Rate of LDA at Month 6, as assessed by: SDAI ≤ 11; CDAI ≤10; DAS 28-4 (ESR) <3.2 and DAS28-4 (CRP) <3.2.
5. ACR20 and ACR70 response rates at Month 6.
6. Change from Baseline in HAQ-DI at Month 6.
7. Percentage HAQ-DI responders (decrease of at least 0.22) at Month 6.
8. Change from Baseline in the SF-36 8 domain scores and 2 component scores at Month 6.
9. Change from Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Month 6.
10. Change from Baseline in the EuroQol EQ-5D at Month 6.
11. Change from Baseline in the FACIT-Fatigue scale at Month 6. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Bosnia and Herzegovina |
| Bulgaria |
| Canada |
| Chile |
| Croatia |
| Czech Republic |
| Estonia |
| Israel |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| South Africa |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the Member State. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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