| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10039075 |
| E.1.2 | Term | Rheumatoid arthritis and associated conditions |
| E.1.2 | System Organ Class | 100000004870 |
|
| 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 evaluate the efficacy of PF-06651600
at 8 weeks in subjects with moderate to
severe active RA. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of PF-06651600.
- To assess other signs of clinical efficacy
over 8 weeks.
- To assess the effect of PF-06651600 on
patient reported outcome measurements. |
|
| 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 has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
3. Male and female subjects (including Women of Childbearing Potential (WOCBP)) 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.
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 rheumatoid arthritis (RA) and meeting the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism
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 (see below).
7. Meets Class I, II or III of the ACR 1991 Revised Criteria for the classification of Global Functional Status in RA (see Appendix 2).
8. 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 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 and, if the repeat hsCRP concentration is ≥7 mg/L prior to the baseline visit, will be eligible to enroll into the study provided all other inclusion/exclusion criteria are
met.
9. Subjects must be seropositive (rheumatoid factor positive and/or anti-citrullinated protein antibody positive) at the screening visit.
10. Subjects must have been taking oral MTX for at least 3 months 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 15 to 25 mg, inclusive, weekly, unless there is documented (in the source documentation) intolerance to or toxicity from these doses, in which case a dose between 10 and <15 mg, inclusive, may be used (See Section 5.8). The dose must have been stable for at least 4 weeks before first dose of study drug, and the dose must remain stable during the study.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 investigational product or oral folinic acid
(≥5 mg once per week) supplementation for at least 4 weeks 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 and the dose must remain stable during the study. 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 approved TNF α-inhibiting biologic agent administered in accordance with its labeling recommendations that was inadequately effective and/or not tolerated. For the purpose of this study, inadequate efficacy is defined by the investigator’s and subject’s opinions that the subject did not experience adequate benefit from the anti-TNFα inhibitor and the presence of sufficient residual disease activity to meet the entry criteria. The anti-TNFα inhibitor should have been discontinued for a minimum of the washout period defined as follows:
- entanercept (Enbrel): 4 weeks.
- infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), certolizumab (Cimzia): 10 weeks.
12. Subjects receiving non-prohibited medications (See Section 5.8) 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 and the dose must remain stable during the study. |
|
| E.4 | Principal exclusion criteria |
1. Investigator site staff members 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 30 days or 5 half-lives prior to study entry and/or during study participation.
3. Other acute or chronic medical or psychiatric condition including recent or active suicidal ideation or behavior 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.
4. Any major condition or evidence of an unstable clinical condition that will substantially increase the risk to the subject if he or she participates in the study
5. Acute coronary syndrome and any history of cerebrovascular disease within 24 weeks before screening or in the period between the Screening Visit and the Baseline Visit.
6. Subjects with a known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency.
7. Subjects with acute or active chronic dermatological disorders within 4 weeks prior to study entry or in the period between the Screening Visit and the Baseline Visit
8. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects of childbearing potential who wish to become pregnant or who are unwilling or unable to use 2 highly effective methods of contraception
9. History of alcohol or drug abuse with less than 6 months of abstinence prior to the Baseline Visit
11. Subjects treated with prohibited medications will be excluded unless appropriate washout has been performed
12. Any current evidence of untreated latent or active TB infection, evidence of currently active TB by chest x-ray, residing with or frequent close contact with individual(s) with active TB.
13. Current routine household contact with children or anyone else who have received varicella or oral polio or any other live vaccine within 6 weeks of first study dose, or during the course of the study
14. Any live vaccines from 30 days prior to the Baseline Visit and through the Follow Up Visit
15. Subjects who have been in contact with people with acute infections within 2 weeks prior to the Screening Visit or in the period between the Screening Visit and the Baseline Visit
16. History of any lymphoproliferative disorder, history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease
17. Have a history of a major organ transplant or hematopoietic stem cell/marrow transplant. Skin grafts are allowed.
18. History of severe allergic or anaphylactoid reaction to kinase inhibitors, or corticosteroid preparations
19. Subjects with malignancy or history of malignancy, 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
20. Preexisting chronic autoimmune disease other than RA. Secondary Sjogren’s-Syndrome associated with RA may be included.
21. Major surgery within 4 weeks of the Screening Visit or if scheduled to occur during the study, excluding diagnostic surgical procedures.
22. Previous treatment with total lymphoid irradiation
23. Subjects with any condition possibly affecting oral drug absorption. Procedures such as gastric banding that simply divide the stomach into separate chambers are not exclusionary
24. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subjects’ safety or interpretation of study results.
25. Have current or recent history of clinically significant severe or progressive hearing loss or auditory disease. Subjects with hearing aids will be allowed to enter the study provided their hearing impairment is considered controlled/clinically stable.
26. Subjects with an oral or tympanic temperature at the Baseline Visit of 38°C or higher.
27. Presence of any of the following laboratory abnormalities at the Screening Visit or within the 3 months prior to first study dose:
ALT and AST levels 1.5 times the upper limit of normal
Total bilirubin level ≥1.5 times the ULN;
Hemoglobin level ≥90 g/L
Platelet count ≤100 x 109/L or ≥1000 x 109/L
White blood cell count ≥3.0 x 109/L or absolute neutrophil count <1500 cells/mm3 or absolute lymphocyte count of<0.5 x 109/L
Serum creatinine level ≥177 μmol/L
Glycosylated hemoglobin (HbA1C) >10%.
28. have any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the subject’s participation in the study.
29. Grade 3 or greater laboratory abnormality based on the CTC for AE version 4.03 toxicity scale. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline in simple disease activity index
(SDAI) at Week 8. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-Safety and tolerability of PF-06651600 versus placebo;
vital signs, laboratory tests, adverse events (AEs)
including infections, and Serious Adverse Events
(SAEs).
-Change from baseline in SDAI at Weeks 1, 2, 4 and 6.
-Change from baseline in SDAI low disease activity
scale (LDAS) and remission rates at Week 4, Week 6
and Week 8
-Change from baseline in DAS28 LDAS and remission
rates at Week 4, Week 6 and Week 8.
The following will also be calculated at Weeks 1, 2,4, 6
and 8:
-Change from baseline in DAS28-3 (ESR), DAS28-3
(CRP), DAS28 -4 (ESR), and DAS28-4 (CRP).
-Change from baseline in hsCRP.
-Change from baseline in the Tender/Painful and
Swollen Joint Count (28).
-Change from baseline in the Physician’s Global
Assessment of Arthritis.
Change from baseline in the Patient’s Assessment of
Arthritis Pain (VAS) and Patient’s Global Assessment
of Arthritis (VAS) at Weeks 1, 2, 4, 6 and 8.
-Change from baseline in the HAQ-DI at Weeks 1, 2, 4,
6 and 8. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Bulgaria |
| Czech Republic |
| Georgia |
| Germany |
| Hungary |
| Poland |
| Romania |
| Serbia |
| Slovakia |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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