| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint inflammation |
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| E.1.1.1 | Medical condition in easily understood language |
| Inflammation of the joints |
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| 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 | 23.1 |
| 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 each of 2 combinations (PF 06650833 + PF-06651600, PF-06650833 + tofacitinib) individually to tofacitinib alone at Week 12 in participants with moderately - severely active RA who have had an inadequate response to MTX |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives
1. To compare the remission rates of each of 2 combinations (PF 06650833 + PF-06651600, PF 06650833 + tofacitinib) individually to tofacitinib alone at Week 24 in participants with moderately to severely active RA who have had an inadequate response to MTX.
Other Secondary Objectives
2. To assess the safety of PF 06650833, PF-06651600, and tofacitinib alone and of the combinations of PF-06650833 with PF-06651600 and tofacitinib
3. To evaluate other signs of clinical efficacy of all treatment arms
Exploratory
1. To estimate other signs of clinical efficacy
2. To collect blood for potential exploratory analyses of pharmacodynamic activity
3. To evaluate PK
4. To collect banked biospecimens for exploratory research
5. To evaluate the effects on joint inflammation assessed by magnetic resonance imaging (MRI), in a subset of participants. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female participants between the ages of 18 and 70 years, inclusive, at time of randomization (Visit 2).
2. Participants who are willing and able to comply with all scheduled visits, treatment plan (including washout of MTX at randomization), laboratory tests, lifestyle considerations, and other study procedures.
3. Diagnosis of RA and meeting the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria 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 MTX inadequate response (MTX IR)
4. The participant has active disease at both Screening and Randomization, as defined by both:
• equal to or greater than 6 joints tender or painful on motion, AND
• equal to or greater than 6 joints swollen;
and fulfills 1 of the following 2 criteria at or before randomization:
• High sensitivity C reactive protein (hsCRP) >7 mg/L at Screening (Visit 1) as performed by the central laboratory.
OR
• Erythrocyte sedimentation rate (ESR) (Westergren method) >28 mm h.
5. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA
6. Participants must be seropositive at the time of randomization (ACPA or RF positive).
7. Participants must have been taking oral MTX (or equivalent parenteral MTX) at an adequate dose and for a sufficient duration (generally at least 3 months but may be as short as at least 8 weeks if consistent with local standard of care treatment guidelines) prior to Screening (Visit 1) to determine that the participant had an inadequate response to MTX, defined, for the purpose of this study, by the investigator’s and participant’s opinions that the participant did not experience adequate benefit from MTX plus the presence of sufficient residual disease activity to meet the entry criteria.
8. Participants 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.
9. Body weight must be >40 kg.
10. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol.
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|
| E.4 | Principal exclusion criteria |
1. Other acute or chronic medical or psychiatric condition including recent or active suicidal ideation or behavior or laboratory abnormality
2. Participants with a known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency.
3. Participants with any of the following infections
a. Any infection requiring treatment within 2 weeks prior to screening
b. Any infection requiring hospitalization, parenteral antimicrobial therapy within 60 days, within the past 6 months.
c. Infected joint prosthesis at any time with the prosthesis still in situ.
d. Recurrent herpes zoster; or severe or disseminated herpes simplex.
e. Participants who test positive for HIV will be excluded
4. Participants with positive hepatitis B surface antigen (HBsAg) will be excluded. Participants who are HBsAg negative but HBcAb positive will be reflex tested for hepatitis B virus deoxyribonucleic acid (HBV DNA) and, if HBV DNA is negative, will be allowed to enroll in the study
5. Participants will be screened for hepatitis C virus (HCV Ab). Participants with positive HCV Ab tests will be reflex tested for HCV ribonucleic acid (HCV RNA). Only participants with negative HCV Ab or HCV RNA, and normal liver function will be allowed to enroll
6. Any history of either untreated or inadequately treated latent or active tuberculosis (TB) infection, current treatment for active or latent TB infection or evidence of currently active TB by chest x ray, CT or MRI, residing with or frequent close contact with individual(s) with active TB.
7. History of a major organ transplant (eg, heart, lung, kidney and liver) or hematopoietic stem cell/marrow transplant.
8. History of severe allergic or anaphylactoid reaction to kinase inhibitors, or corticosteroid preparations.
9. Known history of diverticulitis or symptomatic diverticulosis, perineal abscess or fistulae.
10. Participants with malignancy or history of malignancy (including lymphoma, leukemia, or lymphoproliferative disease), with the exception of participants with adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
11. Pre existing chronic autoimmune disease (eg, inflammatory bowel disease, systemic lupus erythematosus, moderate severe atopic dermatitis, dermatomyositis) other than RA. Secondary Sjogren’s Syndrome (due to RA) may be included.
12. Participants with fibromyalgia
13. Major surgery within 4 weeks of screening or planned surgery scheduled to occur during the study.
14. Previous treatment with total lymphoid irradiation.
15. Participants with any condition possibly affecting oral drug absorption (eg, bariatric/obesity surgery, gastrectomy, or clinically significant diabetic gastroenteropathy).
16. Participants with an oral, tympanic, or temporal temperature of 38°C (100.4°F) or higher at baseline.
17. Participants may not receive any live/attenuated vaccine from 30 days prior to randomization during the course of the study, or for 30 days after the last dose of study medication. Participants excluded who have current routine household contact with children who have received varicella or oral polio vaccine within 2 months of first study dose.
18. History of any lymphoproliferative disorder
19. Have hearing loss with progression over the previous 5 years
20. Deep vein thrombosis (DVT) or pulmonary embolism [PE].
21. Recent myocardial infarction, coronary revascularization, or percutaneous angioplasty with or without placement of a coronary artery stent.
22. Current severe chronic renal insufficiency or renal failure
23. Any known coagulopathy or hypercoagulant syndrome.
24. Presence of any laboratory abnormalities at screening or within the 3 months prior to first study dose
26. Participants previously treated with a biologic DMARD
27. Prior use of tofacitinib or other JAK inhibitor in the context of a clinical trial.
28. Prior use of PF-06650833 or PF-06651600 in the context of a clinical trial.
29. Participants who have previously been treated with other, non TNF inhibiting biologic DMARDs or other selective B lymphocyte depleting agents.
30. Previous administration with an investigational drug within 30 days or 5 half lives preceding the first dose of IP used in this study.
31. up to 25% of participants may have previously taken a TNF inhibitor (originator or biosimilar), which includes prior use in the context of a clinical trial.
32. Any 12 lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities
33. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees, including their family members.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in Disease Activity Score (DAS)28-C Reactive protein (CRP) at Week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint
1. DAS28-CRP remission (2.6) at Week 24.
Secondary Endpoints
2. Incidence and severity of adverse events, serious adverse events, and withdrawals due to adverse events.
3. Change from baseline in clinical laboratory values (chemistry, hematology parameters).
4. Change from baseline in vital signs (blood pressure, pulse rate and temperature measurements).
5. Incidences of severe and opportunistic infection AEs; herpes virus infection AEs; clinically significant categorical increases in hepatic enzymes Aspartate aminotransferase (AST), and Alanine aminotransferase (ALT) and total bilirubin, and potential cases meeting Hy’s Law criteria for increased risk of drug induced liver injury [DILI]; major adverse cardiovascular events (MACE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), Cerebrovascular accident (CVA); Adverse events (AEs) for decreased renal function, acute kidney injury, clinically significant increases in serum creatinine (Scr) and decreases in estimated glomerular filtration rate (eGFR).
6. Change from baseline in DAS28-CRP at Week 24.
7. American College of Rheumatology (ACR)20, ACR 50, ACR 70, and ACR 90 responder rates at Week 12 and Week 24.
8. Change from baseline in the Tender/Painful and Swollen Joint Count at Week 12 and Week 24.
9. Change from baseline in the Physician’s Global Assessment (PhGA) of Arthritis at Week 12 and Week 24.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 12 and 24 respectively |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Placebo is used to ensure dosing is blinded. No subject is treated with placebo |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| 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 |
| Bosnia and Herzegovina |
| Canada |
| Chile |
| Colombia |
| Georgia |
| Mexico |
| Russian Federation |
| Serbia |
| Ukraine |
| Bulgaria |
| Hungary |
| Poland |
| Romania |
| Slovakia |
| Spain |
| Sweden |
| Czechia |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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