| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 17.1 |
| 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 |
| The primary objective is to determine long term safety and tolerability of 5 mg bid and 10 mg bid of CP-690,550 for treatment of signs and symptoms of RA. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective is to evaluate persistence of efficacy of 5 mg BID and 10 mg BID of CP 690,550 for treatment of signs and symptoms of RA.
Exploratory endpoints:
to analyze HAQ-DI score data to model healthcare utilization long term in patients taking CP-690,550;
to assess PK of CP-690,550 in patients on stable dose of CP-690,550 in the setting of this long term, open label study;
to evaluate the lymphocyte subsets in patients from the substudy |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: A3921024 Lymphocyte Substudy
Date and version: as for A3291024 long-term open-lable follow-up study
Primary:
To evaluate the changes in the absolute lymphocyte counts (ALCs) and lymphocyte subset counts (LSCs) over time with long-term tofacitinib treatment
Secondary:
To evaluate the correlation of tofacitinib safety events (eg, infections) with ALCs or LSCs
Exploratory:
To evaluate the reversibility of LSCs and ALCs after temporary discontinuation of tofacitinib and rechallenge;
To evaluate the utility of monitoring LSCs in addition to ALCs to mitigate the risk of infections |
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| E.3 | Principal inclusion criteria |
Patients who enroll from a qualifying study within a 14 day window must meet Inclusion Criteria 1, 2, 4, 6, 7 and 8 below and must continue to meet safety eligibility criteria of their qualifying study for continued participation. Patients who enroll after the 14 day window must meet all Inclusion Criteria including Inclusion Criteria 3 and 5 to be eligible for enrollment into the trial. 1. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the trial. 2. Patient must be at least the legally recognized age of consent or provide assent in writing along with a consent signed by their legally recognized representative. 3. In the opinion of the investigator the patient must have sufficient evidence of RA disease activity to warrant use of CP-690,550 as a DMARD. 4. Patients must have previously completed participation in a qualifying study of CP 690,550 for treatment of RA or have required earlier discontinuation of treatment in a qualifying study for reasons other than CP 690,550 related serious adverse events with the approval of the Pfizer study clinician. 5. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by all of the following: • A negative QuantiFERON Gold®TM In-Tube test performed within the 3 months prior to screening. A negative PPD test can be substituted for the QuantiFERON TB Gold In Tube test only if the central laboratory is unable to perform the test or cannot determine the results to be positive or negative and the Pfizer Medical Monitor approves it, on a case-by-case basis; A chest radiograph taken within the 3 months prior to screening without changes suggestive of active TB infection; No history of either untreated or inadequately treated latent or active TB infection. If a patient has previously received an adequate course of therapy for either latent (9 months of isoniazid in a locale where rates of primary multi drug resistant TB infection are <5% or an acceptable alternative regimen) or active (acceptable multi drug regimen) TB infection, neither a PPD test nor a QuantiFERON Gold®TM test need be obtained, but a chest radiograph must still be obtained if not done so within the prior 3 months. A patient who is currently being treated for latent TB infection can only be enrolled with confirmation of current incidence rates of multi drug resistant TB infection, documentation of an adequate treatment regimen, and prior approval of the Sponsor. In Ireland, patients currently being treated for either latent or active TB infection cannot be enrolled. 6. The patient has discontinued disallowed concomitant medications for the required time prior to the first dose of study drug, as defined in Appendix 1, and is taking only those concomitant medications in doses and frequency allowed by the protocol. 7. If the patient is a sexually active woman of childbearing potential, she must test negative for pregnancy prior to enrollment in this study. Sexually active women of childbearing potential are required to use adequate contraceptive methods during participation in this study. Men who are on background therapy and whose partners are women of childbearing potential will be required to follow the local label requirements for their background medications (including background DMARDs). Further description of the requirements and a list of contraceptives considered effective and acceptable for use in this study will be found in Lifestyle Guidelines 8. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
For the substudy (Cohort 1):
The eligible patients for Cohort 1 are the patients who have already enrolled and are ongoing in the main A3921024 study;
Any patient from the ongoing main A3921024 study may participate. It is mandatory for patients from Croatia, Denmark, Germany, Spain, Sweden,
Ireland, and the UK to participate in Cohort 1 of the substudy.
All patients must provide informed consent to participate in the lymphocyte substudy.
For the substudy (Cohort 2):
The eligible patients for Cohort 2 are the patients who have already enrolled and are ongoing in the main A3921024 study or patients from Cohort 1;
Patients who have at least a 40% decrease ALCs from baseline (pre-tofacitinib treatment from the qualifying study) and an ALC of ≤ 1000 cells/mm3 at last visit prior to the study entry;
Provide informed consent to participate in the lymphocyte substudy
For the substudy (Cohort 3):
Patients entering Cohort 3 must meet the A3921024 main study eligibility criteria. The exception is the A3921237 patients will only be required to have at least 2 weeks post-varicella vaccination before enrolling in the A3921024 study.
All patients must provide informed consent.
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|
| E.4 | Principal exclusion criteria |
For patients who do not rollover into this study within 14 days of their last visit of qualifying study(1-5): 1.Evidence of hematopoietic disorders or evidence of hemoglobin levels or hematocrit as defined in protocol 2.An absolute WBC count of <3.0 x 10^9/L <3000/mm3), absolute neutrophil count of <1.2 x 10^9/L (<1200/mm3), or absolute lymphocyte count of <0.5 x 10^9/L (<500/mm3) at screening visit or within 3 months prior to baseline. For patients in Czech Republic, Denmark, Germany, Spain, Sweden, Ireland, and the UK, absolute lymphocyte count <0.75 x 10^9/L (<750/mm3) at screening visit or within 3 months prior to baseline. 3. Thrombocytopenia as defined in protocol. 4.Estimated creatinine clearance as defined in protocol. 5.Total bilirubin, AST or ALT more than 1.5 times ULN at screening visit. For all patients: 6.Pregnant or lactating women. 7.Current or recent history of uncontrolled clinically significant renal,hepatic,hematological, gastro-intestinal,endocrine,pulmonary,cardiac, or neurological disease. 8.History of any other rheumatic autoimmune disease other than Sjogren’s syndrome. 9.History of an infected joint prosthesis at any time,with the prosthesis still in situ.10.History of any lympho-proliferative disorder such as EBV related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease. 11.History of recurrent (more than 1 episode) herpes zoster or disseminated(a single episode)herpes zoster or disseminated (a single episode)herpes simplex. 12.Patients with any infection requiring hospitalization, parenteral antimicrobial therapy or judged to be opportunistic by investigator within the 6 mths prior to the first dose of study drug. 13.Any other condition which would make patient unsuitable for inclusion.14.Participation in studies of investigational compounds as defined in protocol. Exposure to investigational biologics should be discussed with Pfizer Medical Monitor. 15.Any prior treatment with non B cell-specific lymphocyte depleting agents / therapies. See protocol for rituximab. 16. Intramuscular or intravenous corticosteroids in 4 wks preceding baseline. If an intra-articular injection is performed in the course of a qualifying study <4 wks before baseline visit of this study, the injected joint will be considered to have its pre-injection status from the qualifying study for full length of this protocol. 17.Patients who have been vaccinated with live or attenuated vaccines within 6 weeks prior to the first dose of study drug or is to be vaccinated with these vaccines at any time during treatment or within 6 weeks following discontinuation of study drug. 18.Patients with any condition possibly affecting oral drug absorption, eg, gastrectomy, clinically significant diabetic gastroenteropathy or certain types of bariatric surgery such as gastric bypass. Bariatric procedures such as gastric banding that simply divide stomach into separate chambers are NOT exclusionary. 19.History of alcohol or substance abuse, unless in full remission for >6 months prior to first dose of study drug. 20.Screening 12 lead electrocardiogram that demonstrates clinically relevant abnormalities that may affect patient safety. 21.Patients with a first degree relative with a hereditary immunodeficiency. 22. Patients with a malignancy or with 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. 23. Recent (within 1 month prior to first dose of study drug) significant trauma or major surgery. 24.Patients requiring prohibited concomitant medications. Patients receiving non prohibited concomitant medications must be on a stable regimen which is defined as not starting a new drug or changing dosage within 7days or 5 half lives (whichever is longer) prior to the baseline visit. 25. Patients known to be infected with HIV or Hepatitis B or C vrus. 26.Other severe acute or chronic medical or psychiatric condition or lab abnormality that may increase 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 patient inappropriate for entry into this study.
For the substudy (Cohort 2):
Patients from Croatia, Denmark, Germany, Spain, Sweden, Ireland, and the UK are excluded from Cohort 2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoints will be standard laboratory safety data (chemistry, hematology, etc.) and adverse event (AE) reports.
Primary endpoints of the substudy:
As described in Section 2 of Appendix 11 of A3921024 protocol. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Month 1, 2, 3, 6, 9 and 12 months and various intervals thereafter (see protocol).
For substudy: Timepoints for substudy visits should be scheduled to coincide with the study visit from the main A3921024 study, although unplanned visits may be used if needed. The schedule of activities should be the same as that from the main A3921024 study with additional procedures for Cohorts 1, 2 & 3 as described in Section 6 of Appendix 11 to protocol.
Blood samples for lymphocyte subset count will be collected as detailed Section 6 of Appendix 11 to protocol. |
|
| E.5.2 | Secondary end point(s) |
1) percent of patients with ACR 20, 50 and 70 responses at each timepoint (1, 2, 3 months and every 3 months thereafter); analyzed for the full study group and stratified by participation in different qualifying studies and by CP-690,550 dose.
2) HAQ-DI score at each timepoint
3) Disease Activity Score (DAS 28-3 C-Reactive Protein (CRP) and DAS 28-4 (ESR) at each timepoint). Also incidence of Disease Activity Score <2.6 and <3.2.
Secondary endpoints of the substudy:
As described in Section 2 of Appendix 11 of A3921024 protocol. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Various timepoints (see description in section E.5.2).
For substudy:
Timepoints for substudy visits should be scheduled to coincide with the study visit from the main A3921024 study, although unplanned visits may be used if needed. The schedule of activities should be the same as that from the main A3921024 study with additional procedures for Cohorts 1 and 2 as described in Section 6 of Appendix 11 to protocol.
Blood samples for lymphocyte subset count will be collected as follows:
Cohort 1 (all patients): at entry visit then at 3, 6, 12, 18 & 24 months.
Cohort 1 (patients in Germany, Spain, Sweden, Ireland & UK): at entry visit then at 3, 6, 9, 12, 15, 18, 21 & 24 months.
For Cohort 2: at entry visit, week 4 (month 1) then at 3, 6, 9 &12 months. |
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| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 120 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Bosnia and Herzegovina |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Colombia |
| Costa Rica |
| Croatia |
| Czech Republic |
| Denmark |
| Dominican Republic |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Ireland |
| Italy |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Netherlands |
| New Zealand |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
| Venezuela, Bolivarian Republic of |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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