RHEUMATOID ARTHRITIS

Primary Objectives:  To evaluate the efficacy of PF-06650833 at 12 weeks, in subjects with moderate-severe active RA who have had an inadequate response to methotrexate (MTX). Secondary Objectives:  To assess the safety of PF-06650833 for 12 weeks in subjects with RA.  To explore the dose – response relationship for efficacy in RA.  To assess other signs of clinical efficacy over 12 weeks.  To assess the effect of PF-06650833 on patient reported outcome measurements.

PF-06650833

PF-06650833

film-coated modified release tablets
film-coated modified release tablets

20mg, 100mg

Primary Endpoints
 Change from baseline in the Simplified Disease Activity Index (SDAI) at Week 12.
Secondary Endpoints
Secondary Clinical Efficacy Endpoints
 Change from baseline in SDAI at Weeks 4 and 8.
 SDAI low disease activity score (LDAS) and remission rates at 4, 8 and 12 weeks.
 Disease activitiy score (DAS) 28 LDAS and remission rates at 4, 8 and 12 weeks.
The following will also be calculated at Week 4, 8 and 12:
 Change from baseline, DAS28-3, DAS28-3 CRP, DAS28-4 (Erythrocyte
Sedimentation Rate (ESR)) and DAS28-4 (CRP).
 American College of Rheumatology (ACR) 20, ACR 50 and ACR 70 responder rates.
 Change from baseline in the Tender/Painful and Swollen Joint Counts.
 Change from baseline in high sensitivity C-reactive protein (hsCRP).
 Change from baseline in the Physician’s Global Assessment of Arthritis (PhGA).
Safety Endpoints
 Safety and tolerability of PF-06650833: vital signs (blood pressure (BP), pulse and
temperature), laboratory tests, Adverse Events (AEs) and Serious Adverse Events
(SAEs), 12-lead electrocardiogram (ECG).
 Urinalysis including urine microscopy.
Secondary Patient Reported Outcome Endpoints
 Change from baseline in the Patient’s Assessment of Arthritis Pain (PAAP) VAS and
Patient Global Assessment of Arthritis (PtGA, VAS) at Week 4, 8, and 12.
 Change from baseline in the Health Assessment Questionnaire – Disability Index
(HAQ-DI) at Week 4, 8, and 12.
 Change from baseline in the SF-36v.2 (acute) 8 Domain scores and Physical
Component Score (PCS) and Mental component score (MCS) at Week 12.
 Change from baseline in the European Quality of Life – 5 Dimensions-3 Level
(EQ-5D-3L) score at Week 12.
 Change from baseline in the Functional Assessment of Chronic Illness Therapy
(FACIT-F) total score at Week 12.

1.Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent
aspects of the study.
2.Willing and able to comply with scheduled visits, treatment plan, laboratory, and other study procedures.
3.Male and female (including WOCBP) subjects between the ages of 18 and 75 years,inclusive. For subjects >70 years old, the site must
discuss subject eligibility with the study team to ensure that these subjects are sufficiently healthy to participate.(In Taiwan enrollment is 20 -75 years of age)4.Female subjects of childbearing potential must test negative for pregnancy at screening visit and baseline visit.
5.Female subjects of nonchildbearing potential must meet at least 1 of the following criteria:
a.Achieved postmenopausal status, defined as follows: 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 confirming the postmenopausal state;
b.Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
6.Diagnosis of RA and meeting the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification
criteria (see Appendix 2) for RA with a Total Score ≥ 6/10. The duration of time since diagnosis of RA should minimally be sufficient to
meet the definition of methotrexate inadequate response (MTX-IR) (see below).
7.The subject has active disease at both Screening and Baseline, as defined by both:
•≥ 6 joints tender or painful on motion, AND
•≥ 6 joints swollen;
and fulfills 1 of the following 2 criteria at Screening:
•High sensitivity C reactive protein (hsCRP) >7 mg/L at screening performed by the central laboratory. Subjects who do not meet this entry criterion but satisfy all other study entry criteria may have serum hsCRP concentration re-tested once within 14 days and, if the repeat
hsCRP concentration is >7 mg/L will be eligible to enroll into the study provided all other inclusion/exclusion criteria are met.
•Erythrocyte sedimentation rate (ESR) (Westergren method) >28 mm/hr;
8.Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA (see Appendix 3).
9.Subjects must be seropositive at the time of randomization (ACPA positive). If subjects are RF+ but ACPA- at screening, the subject may
be carried to randomization at risk. The ACPA must be repeated and be positive before the targeted Randomization Visit.
10.Subjects must have been taking oral or equivalent parenteral (IM or SC, only; IV administration is not permitted) MTX for at least 3
months (prior to baseline randomization) at an adequate dose to determine that the subject had an inadequate response to MTX, defined, for the purpose of this study, by the Investigator’s and subject’s opinions that the subject did not experience adequate benefit from
methotrexate plus the presence of sufficient residual disease activity to meet the entry criteria. Allowed methotrexate doses are between 15 and 25 mg weekly (inclusive). Doses between 10 and 15 mg weekly are allowed only in the presence of documented intolerance to or toxicity from higher doses.
•Subjects should be on an adequate and stable dose of folic acid (not less than 5 mg weekly, unless higher doses would violate the local label) for at least 4 weeks prior to the first dose of study medication or oral folinic acid (≥ 5 mg once per week) supplementation for at least 21 days prior to the first dose of study drug. Folic acid must be dosed per local standards of care stably for at least 4 weeks before first study dose. In countries which do not have approved folic acid 1 mg or folinic acid 5 mg presentations, a regimen of folic acid of at least ≥ 5 mg weekly is acceptable.
11.Up to 50 % of subjects may have received one (and only one) approved TNF-inhibiting biologic agent administered in accordance with its
labeling recommendations. The TNF-inhibiting biologic could have been discontinued due to its being deemed inadequately effective and/or
not tolerated as defined, for the purpose of this study, by the Investigator’s and subject’s opinions that the subject did not
experience adequate benefit from the anti-TNF plus the presence of sufficient residual disease activity to meet the entry criteria. The
anti-TNF biologic could also have been discontinued due to lack of continued access.
The anti-TNF s should have been discontinued for a minimum of the washout period defined as follows (biosimilars of the below agents
should be considered the same as the originators):
•entanercept (Enbrel®), adalimumab (Humira®): 6 weeks.
•infliximab (Remicade®), golimumab (Simponi®): 10 weeks.
•certolizumab pegol (Cimzia®): 12 weeks.
12.Subjects receiving non-prohibited concomitant medications for any reason must be on a stable regimen, which is defined as not starting
a new drug or changing dosage within 7 days or 5 half-lives (whichever is longer) prior to first study dose.

1.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, including their family members, directly involved in the conduct of
the study.
2.Participation in other studies involving investigational drug(s) within 4 weeks or 5 half-lives (whichever is longer) prior to study
entry.
3.Female subjects who are pregnant or wish to become pregnant, breastfeeding female subjects; male subjects with partners currently
pregnant; male subjects able to father children and female subjects of childbearing potential who are unwilling or unable to use at least 1 highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days (90 days
for male subjects) after the last dose of investigational product.4.Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior,
known drug or alcohol abuse, 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.
5.Subjects with a known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency.
6.Subjects with any of the following infections or infections history:
a.Any infection requiring treatment within 2 weeks prior to screening (Visit 1).
b.Any infection requiring hospitalization, parenteral antimicrobial therapy within 60 days, or as otherwise judged to be an opportunistic
infection or 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 HIV (unless local regulations prohibit mandatory testing). Subjects who test positive for HIV will be
excluded from the study.
f.Subjects will be screened for hepatitis B virus infection and will be excluded if positive for hepatitis B surface antigen (HBsAg).
Subjects with 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 with clinically significant active hepatic disease or hepatic impairment by laboratory assessment.
h.Subjects will be screened for hepatitis C virus (HCV Ab). Subjects with positive HCV Ab tests will be reflex tested for HCV ribonucleic
acid (HCV RNA). Only subjects with negative HCV Ab or HCV RNA will be allowed to enroll in the study.
7.Evidence of active or latent, untreated or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by the
following:
•A positive QuantiFERON-TB Gold (QFT-G) test performed at or within the 3 months prior to Screening;or
•A chest radiograph (taken at or within the 3 months prior to Screening) with changes
suggestive of active TB infection;
Subject who is currently being treated for either latent or active TB infection is to be excluded.
Subjects with prior active tuberculosis (except for multi drug resistant TB) that 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 to which
the organism has demonstrated appropriate sensitivity) has a chest radiograph that is negative for active disease, and has a negative QFT-G are eligible; the chest radiograph must be obtained at screening or, if previously performed and documented, within 3 months prior to
screening. Subjects that have an indeterminate QFT-G may have QFT-G test repeated and, will be eligible if the repeat (QFT-G) test is
negative at time of randomization.
8.Subjects may not receive any live/attenuated vaccine from 30 days prior to screening, during the course of the study, or for 30 days
after the last dose of study medication. Subjects who have current routine household contact with children who have received varicella or
oral polio vaccine within 2 months of first study dose are also excluded.
9.History of any lymphoproliferative disorder (such as EBV-related lymphoproliferative disorder, as reported in some subjects on
immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative disorders,multiple myeloma, or signs and symptoms suggestive
of current lymphatic disease.
10.Subjects treated with prohibited medications will be excluded (see Section 5.7.2).
11.Have a history of a major organ transplant (eg, heart, lung, kidney and liver) or hematopoietic stem cell/marrow transplant.
12.History of severe allergic or anaphylactoid reaction to kinase inhibitors, or corticosteroid preparations.
13.Known history of diverticulitis or symptomatic diverticulosis, perineal abscess or fistulae.
14.Subjects with malignancy or history of malignancy (including lymphoma, leukemia, or lymphoproliferative disease), with the exception of
subjects with adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
15.Pre-existing chronic autoimmune disease (eg, inflammatory bowel disease, SLE,moderate-severe atopic dermatitis, dermatomyositis) other than RA.
Secondary Sjogren’s Syndrome (due to RA) may be included.
16.Subjects with fibromyalgia will be excluded.
17.Major surgery within 4 weeks of screening or scheduled to occur during the study,excluding diagnostic surgery.
18.Previous treatment with total lymphoid irradiation.
19.Subjects with any condition possibly affecting oral drug absorption (eg,bariatric/obesity surgery (such as gastric bypass or gastric
banding), gastrectomy, or clinically significant diabetic gastroenteropathy).
20.Screening 12-lead ECG that demonstrates clinically relevant abnormalities (eg, QTc >450 msec or a QRS interval >120 msec) which may
affect subject safety or interpretation of study results. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two
more times and the average of the three QTc or QRS values should be used to determine the subject’s eligibility.
21.Subjects with an oral, tympanic, temporal, or axillary temperature of 38C or higher at baseline.
22.Renal disease manifested by eGFR <80 mL/min per 1.73 m2 ( based on MDRD calculation), creatinine >1.5 X ULN, proteinuria 500 mg/day (or spot urine albumin to creatinine ratio ≥ 3mg/mmol or ≥ 30 mg/g). (Sites may use either MDRD or Cockroft/Gault methods for estimating
GFR for local, real-time monitoring of subject safety, provided the same method is used for a subject throughout the study. However, the
eGFR derived by the Central Laboratory using the MDRD method will be the definitive value entered into the clinical database and used for
adverse event reporting.)
23.Presence of any of the following laboratory abnormalities at screening or within the 3 months prior to first
study dose:
•Alanine aminotransferase (ALT) or asparatate aminotransferease (AST) levels 1.5 x the upper limit of normal (ULN).
•Subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the
direct bilirubin is ≤ ULN and other liver function assessments are normal.
•Absolute neutrophil count of <1.5 x 109/L (<1500/mm3).
•Absolute lymphocyte count of <0.5 x 109/L (<500/mm3).
•Absolute white blood cell (WBC) count of < 3.0 x 109/L (<3000/mm3).
•Hemoglobin <9.0 g/dL (90 g/L).
•Thrombocytopenia, as defined by a platelet count <100 x 109/L (< 100,000/mm3) at screening visit or within the 3 months prior to first
study dose.
•Atypical, needle-like, urine crystals [(>15/high power field (hpf)] on urine microscopy (amorphous, or typical, clearly recognizable,
urate, oxalate, phosphate, or other normally occurring crystals are acceptable).
Screening laboratory tests with abnormal results may be repeated once to confirm abnormal results. If results return to normal protocol
acceptable limits within the 4-week screening period, the subject may enter the study.
24.Grade 3 or greater laboratory abnormality based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 toxicity scale except for the following that are allowed:
•Grade 3 prothrombin time (PT) secondary to warfarin treatment.
•Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not related to liver disease or anti-coagulant therapy.