| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inflammation of the joints |
|
| 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.
Participants who do not meet this entry criterion but satisfy all other study entry criteria may have ESR or serum hsCRP concentration re
tested once within 14 days and, if the repeat hsCRP concentration is >7 mg/L or ESR >28 mm/h, will be eligible to enroll into the study provided
all other inclusion/exclusion criteria are met.
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 (generally between 15 and 25 mg weekly
[inclusive] unless documented to be intolerant to these doses) 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;. Current treatment with methotrexate is not required for participant eligibility, provided documentation of prior inadequate
response to or intolerance of MTX is available and provided in source documentation.
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.
|
|
| 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. Active COVID-19 as defined by a positive test for SARS-CoV-2 or an exposure history with compatible symptoms (as defined by WHO).
c. Asymptomatic participants with an exposure history while under quarantine or pending results of a SARS-CoV-2 test (which if negative
would allow the patient to be eligible),
d. Participants with a history of COVID-19 in the last 3 months unless asymptomatic for at least the last 30 days with a negative SARS-CoV-2
test in the last 7 days. Asymptomatic patients with a more remote (> 3 months) history of COVID-19 do not need a confirmatory SARS-CoV-2
test to be eligible.
e. Participants with COVID-19 who are symptomatic irrespective of the interval since infection.
f. Any infection requiring hospitalization, parenteral antimicrobial therapy within 60 days of randomization, or as otherwise judged by the
investigator to be an opportunistic infection or clinically significant, within the past 6 months.
g. Infected joint prosthesis at any time with the prosthesis still in situ.
h. Recurrent (1 or more lifetime episodes after the initial episode) herpes zoster; or severe or disseminated (a single lifetime episode of
either) herpes simplex. Note that for the purposes of this study the initial infection (eg, chicken pox) is considered the initial episode of
herpes zoster. A recurrent episode of herpes zoster is any subsequent manifestation of active herpes zoster (eg, shingles).
i. Participants will be screened for HIV (unless local regulations prohibitmandatory testing). Participants who test positive for HIV will be
excluded from the study.
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. History of any medical condition associated with an increased risk of venothromboembolism (eg, paroxysmal atrial fibrillation) unless
properly anti coagulated
please see exclusion criteria on section 5.2 on Protocol 02 dated 07july2021.
|
|
| 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 | 9 |
| 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 | 17 |
| 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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