A clinical trial to assess a novel medicine in the treatment of patients with moderately to severely active rheumatoid arthritis

• Register: EUCTR
• Last refreshed on: 3 April 2017
• Main ID: EUCTR2014-000358-13-LV
• Date of registration: 11/09/2014
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc. 235 East 42nd Street, New York, NY 10017
• Public title: A clinical trial to assess a novel medicine in the treatment of patients with moderately to severely active rheumatoid arthritis
• Scientific title: A PHASE 3b/4 RANDOMIZED DOUBLE BLIND STUDY OF 5 MG OF TOFACITINIB WITH AND WITHOUT METHOTREXATE IN COMPARISON TO ADALIMUMAB WITH METHOTREXATE IN SUBJECTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS - N/A
• Date of first enrolment: 26/09/2014
• Target sample size: 1080
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000358-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): yes

Countries of recruitment

Argentina, Australia, Bosnia and Herzegovina, Bulgaria, Canada, Chile, Croatia, Czech Republic, Estonia, Germany, Israel, Korea, Republic of, Latvia, Lithuania, Mexico, Peru, Philippines, Poland, Romania, Russian Federation, Serbia, South Africa, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States

Contacts

• Name: Clinical Trials.gov Call Centre
• Affiliation: Pfizer Inc.

• Name: Clinical Trials.gov Call Centre
• Affiliation: Pfizer Inc.

Key inclusion & exclusion criteria

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 s
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, l

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

Health Condition(s) or Problem(s) studied

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

Moderately to severely active Rheumatoid Arthritis
MedDRA version: 18.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Intervention(s)

Product Name: Tofacitinib citrate
Product Code: CP-690, 550 - 10
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Tofacitinib
CAS Number: 477600-75-2
Current Sponsor code: CP-690550
Other descriptive name: TOFACITINIB CITRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Humira ® (Adalimumab) 40mg/0.8mL Pre-filled Syringe
Product Name: Adalimumab
Product Code: L04AB04
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: ADALIMUMAB
CAS Number: 331731-18-1
Other descriptive name: Humira
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Trade Name: Humira® 40 mg/ 0.8 ml solution for injection in pre-filled syringe
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: ADALIMUMAB
CAS Number: 331731-18-1
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Trade Name: Methotrexate sodium 2.5mg tablets
Product Name: Methotrexate sodium 2.5mg tablets
Pharmaceutical Form: Tablet
INN or Proposed INN: Methotrexate
Other descriptive name: METHOTREXATE SODIUM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): ACR 50 response rates at Month 6

Secondary Objective: 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.

Main Objective: 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.

Timepoint(s) of evaluation of this end point: Month 6

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Month 6

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.

Secondary ID(s)

A3921187

2014-000358-13-CZ

Source(s) of Monetary Support

Pfizer Inc.