A clinical study to evaluate the safety of two different doses of Tofacitinib for the treatment of rheumatoid arthritis.

• Register: EUCTR
• Last refreshed on: 16 November 2020
• Main ID: EUCTR2013-003177-99-SE
• Date of registration: 05/02/2014
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc. 235 East 42nd Street, New York, 10017
• Public title: A clinical study to evaluate the safety of two different doses of Tofacitinib for the treatment of rheumatoid arthritis.
• Scientific title: PHASE 3B/4 RANDOMIZED SAFETY ENDPOINT STUDY OF 2 DOSES OF TOFACITINIB IN COMPARISON TO A TUMOR NECROSIS FACTOR (TNF) INHIBITOR IN SUBJECTS WITH RHEUMATOID ARTHRITIS
• Date of first enrolment: 11/04/2014
• Target sample size: 4000
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003177-99
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no 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, Austria, Belgium, Brazil, Bulgaria, Chile, Colombia, Czech Republic, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Malaysia, Mexico, Netherlands, Peru, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States

Contacts

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

• Name: Clinical Trials.gov Call Center
• 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 legal representative) has been informed of all pertinent aspects of the study.
2.Must be at least 50 years of age or older.
3.Has moderate to severe rheumatoid arthritis inadequately controlled with methotrexate alone with a score of 6 or greater on the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis
4.Has =6 tender/painful joints on motion and =6 swollen joints (28 joint count)
5.Has a C-reactive protein measured by a high sensitivity assay (hs-CRP) =0.3 mg/dL in the central laboratory
6.Meets Class I, II or III of the American College of Rheumatology (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.
7.Has taken methotrexate continuously for at least 4 months prior to the Screening visit and has taken a stable weekly dose of methotrexate with supplemental folic or folinic acid for at least 6 weeks prior to the Baseline visit.
•Methotrexate doses less than 15 mg/week are allowed only in the presence of documented intolerance or toxicity from higher doses
•Doses higher than 25 mg/week are not permitted under any circumstances
•Folic acid doses should be at least 5 mg per week; folinic acid doses should be at least 2.5 mg per week.
8.Have at least one of the following cardiovascular risk factors at screening:
•Current cigarette smoker
•Diagnosis of hypertension
•High density lipoprotein (HDL) <40 mg/dL
•Diabetes mellitus
•Family history of premature coronary heart disease
•Presence of extra-articular disease associated with rheumatoid arthritis, which may include nodules, Sjögren’s syndrome, anemia of chronic disease and pulmonary manifestations
•History of coronary artery disease including a history of revascularization procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome
9.Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
10.Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment.
11.Female subjects of childbearing potential must test negative for pregnancy.
12.Female subjects who are not of childbearing potential must meet at least one of the following criteria:
•Have undergone a documented hysterectomy and/or bilateral oophorectomy
•Have medically confirmed ovarian failure or
•Achieved post menopausal status
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®™ 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®™ 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 it can be substituted for the QuantiFERON Gold®™ In-Tube test only if the
Exclusion criteria:
1.Subjects who are investigational site staff members directly involved in the conduct of the trial 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 trial.
2.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).
3.Pregnant females; breastfeeding females; sexually active males and females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after last dose of investigational product.
4.Subjects with infections or history of infections:
a.Any infection requiring treatment within 2 weeks prior to the Baseline visit.
b.Any infection requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator, within the past 6 months.
c.Infected joint prosthesis at any time with the prosthesis still in situ.
d.Recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
e.Subjects will be screened for human immunodeficiency virus (HIV). Subjects who test positive for HIV will be excluded from the study.
f.Subjects will be screened for hepatitis B virus infection. Subjects with hepatitis B surface antigen (HBsAg) negative testing but who test positive for hepatitis B core antibody (HBcAb) must have further testing for hepatitis B surface antibody (HBsAb). If HBsAb is negative, the subject will be excluded from the study.
g.Subjects will be screened for hepatitis C virus antibodies (HCV Ab). Subjects with positive HCV Ab tests will be reflex tested for hepatitis C virus ribonucleic acid (HCV RNA). Only subjects with negative HCV Ab or HCV RNA will be allowed to enroll in the study.
h.Subjects are excluded for current active tuberculosis infection or prior active or latent tuberculosis that was inadequately treated or cannot be documented (See Section 4.1 Inclusion Criteria #13).
5.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.
6.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.White blood cell count <3.0 x 109/L (<3000/mm3)
c.Absolute lymphocyte count <0.5 x 109/L (<500/mm3)
d.Absolute neutrophil count <1.0 x 109/L (<1000/mm3)
e.Platelet count <100 x 109/L (<100,000/mm3)
f.Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >1.5 times the upper limit of normal (x ULN)
g.Estimated glomerular filtration rate (GFR) <60 mL/min using the Cockcroft-Gault formula (Appendix 3).
7.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 Exclusion Criteria and Section 5.5 Concomitant Medication(s).
8.Subjects requir

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

Health Condition(s) or Problem(s) studied

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

Rheumatoid Arthritis
MedDRA version: 19.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Intervention(s)

Trade Name: XELJANZ
Product Name: Tofacitinib citrate (commercial image)
Product Code: CP-690,550-10
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Tofacitinib
CAS Number: 540737-29-9
Current Sponsor code: CP-690,550-10
Other descriptive name: TOFACITINIB CITRATE CP-690550
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Product Name: Tofacitinib citrate (clinical trial image)
Product Code: CP-690,550-10
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Tofacitinib
CAS Number: 540737-29-9
Current Sponsor code: CP-690,550-10
Other descriptive name: TOFACITINIB CITRATE CP-690550
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: Enbrel
Product Name: Etanercept
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ETANERCEPT
CAS Number: 185243-69-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Secondary Objective: Not Applicable

Main Objective: The primary objective of this endpoint study is to evaluate the safety of tofacitinib at two doses versus TNFi; the co-primary endpoints are adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies excluding non-melanoma skin cancers during study participation.

Timepoint(s) of evaluation of this end point: Visit 1 [Day 1]
Visit 2 [Month 2]
Visit 3 [Month 3]
Visit 4 [Month 6]
Visits 5, 9, 13, 17, 21 [Months 9, 21, 33,45, 57]
Visit 6, 10, 14, 18, 22 [Months 12, 24, 36, 48, 60]
Visits 7, 11, 15, 19 [Months 15, 27, 39, 51]
Visits 8, 12, 16, 20 [Months 18, 30, 42, 54]
End of Study Visit [Month 60]

Primary end point(s): Safety Endpoints
The safety endpoints will be collected and analyzed for all subjects in the study, through the end of the study.

Co-Primary Safety Endpoints
The following co-primary safety endpoints will be analyzed to provide comparative rates for tofacitinib vs. the combined TNFi:
•Malignancies, excluding non-melanoma skin cancers (adjudicated)
•Major adverse cardiovascular events (adjudicated) defined as cardiovascular death including deaths due to coronary, cerebrovascular, cardiac (eg, sudden cardiac death) events and non-cardiac vascular deaths (eg, pulmonary embolism), and non-fatal cardiovascular events including myocardial infarction and cerebrovascular events.

Secondary Outcome(s)

Secondary end point(s): Secondary Safety Endpoints
The secondary safety endpoints will include an evaluation of the following events:
•Opportunistic infection events including tuberculosis (adjudicated)
•Hepatic events (adjudicated)
•Cardiovascular events other than MACE (adjudicated)
•All adverse events (AEs), including serious adverse events (SAEs)
•Clinically significant abnormal laboratory parameters
•All cause mortality (adjudicated)
•Reasons for permanent or temporary discontinuation of study medication
Efficacy endpoints will include:
• Change from baseline to each post-baseline scheduled visit in DAS28-4 (CRP).
• Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI).
• Rate of remission at each post-baseline scheduled visit including:
• ACR-EULAR Boolean remission (defined as the subject satisfying all of the
following: tender joint count = 1, swollen joint count =1, C-reactive protein =1 mg/dL, patient global assessment =1 on a 0-10 scale)
• SDAI = 3.3
•CDAI =2.8
• Rate of low disease activity (LDA) at each post-baseline scheduled visit including:
• SDAI = 11
• CDAI =10
• DAS28-4(CRP) =3.2
• ACR20, ACR50, and ACR70 response rate of at each post-baseline scheduled visit
• Change from baseline to each post-baseline scheduled visit in the HAQ-DI

Timepoint(s) of evaluation of this end point: Visit 1 [Day 1]
Visit 2 [Month 2]
Visit 3 [Month 3]
Visit 4 [Month 6]
Visits 5, 9, 13, 17, 21 [Months 9, 21, 33,45, 57]
Visit 6, 10, 14, 18, 22 [Months 12, 24, 36, 48, 60]
Visits 7, 11, 15, 19 [Months 15, 27, 39, 51]
Visits 8, 12, 16, 20 [Months 18, 30, 42, 54]
End of Study Visit [Month 60]

Secondary ID(s)

2013-003177-99-CZ

A3921133

Source(s) of Monetary Support

Pfizer Inc

Ethics review

Status: Approved
Approval date: 11/04/2014
Contact: