| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Lupus Erythematosus (SLE) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042945 |
| E.1.2 | Term | Systemic lupus erythematosus |
| 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 evaluate the efficacy of 3 once daily (QD) dose levels of PF-06700841 compared to placebo in participants with active SLE. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess time to first severe flare in PF-06700841 treated participants relative to placebo.
- To assess attainment of low disease activity state of 3 QD dose levels of PF-06700841 compared to placebo in participants with active SLE.
- To compare the corticosteroid use (prednisone or equivalent) in PF-06700841 treated participants relative to placebo.
- To evaluate the efficacy of PF-06700841 compared to placebo in participants with active SLE and with sustained reduction of oral corticosteroids.
- To evaluate the Cutaneous Lupus Erythematosus Disease Area and Severity Index activity (CLASI-A) score in the subset of participants with baseline CLASI-A score ≥10 in PF-06700841 treated participants relative to placebo.
- To evaluate the effect on fatigue of PF-06700841 treated participants relative to placebo.
Please refer to protocol B7931028 section 3 for a full list of secondary objectives. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female participants between the ages of 18 (or the minimum country specific age of consent if >18) and 75 years, inclusive, at the time of signing the informed consent document (ICD). o Refer to Appendix 4 for reproductive and contraceptive criteria for female participants.
• Have a clinical diagnosis of SLE according to the 1997 update on the 1982 revised American College of Rheumatology (ACR) Criteria for the Classification of SLE see Appendix 8 OR meet at least 4 of the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria see Appendix 9, including at least 1 clinical criterion and 1 immunologic criterion, at least 6 months prior to dosing of study agent.
• Have serologically positive SLE at the screening visit based on 1 of the following test results from the central laboratory during the screening period: o ANA titer ≥1:80, or o Positive anti dsDNA.
Note: The ANA and/or anti double stranded DNA (anti-dsDNA) measurement may be repeated once at the central laboratory within approximately 2 weeks of the initial value, and the value resulting from repeat testing may be accepted for enrollment eligibility if it meets the eligibility criterion.
• All participants must be currently receiving EITHER a stable dose of an immunosuppressant [methotrexate (MTX), azathioprine(AZA)/6- mercaptopurine (6-MP), leflunomide, mizoribine, mycophenolate/mycophenolic acid(MMF)] with or without antimalarials and/or corticosteroids, OR anti-malarials(hydroxychloroquine or chloroquine) in combination with corticosteroids. Antimalarial or steroid monotherapy is not permitted. If receiving antimalarials in combination with corticosteroids, the minimum dose of corticosteroids permitted as part of this combination is 5 mg prednisone daily or an equivalent dose and steroids must have been started at least 8 weeks prior to Day 1. Participants may not be receiving combinations of 2 or more immunosuppressants.
Note: Stable dose is defined as no new therapy or change in standard of care therapies as above within 12 weeks of Day 1 for immunosuppressives or within 2 weeks of Day 1 for corticosteroids, however brief fluctuations in therapy for toxicity are permitted (eg, holding a dose (≤7 days) or temporary reduction in corticosteroids of less than 3 mg/day. See Appendix 13 for allowable stable doses.
Have active disease defined as:
SLEDAI-2K score of ≥8 points at screening and at randomization and "Clinical" SLEDAI-2K score of ≥6 points at both screening and at randomization.
NOTE: "Clinical" SLEDAI-2K score (See Appendix 11) the SLEDAI-2K score without the inclusion of points attributable to any urine or laboratory results including immunologic measures (a For inclusion in the study, the Clinical SLEDAI-2K calculation for entry will exclude points for: 1.Lupus Headache b) Skin disease involving Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Erythema scores <2, c) Arthritis scores must involve a minimum of 3 joints both swollen and tender, d) .Mucosal ulcers which may have occurred within the previous 30 days but are not noted on exam and CLASI at the time of screening. b.On the day of randomization, a minimum of 3 joints that are both swollen and tender is required if SLEDAI Arthritis is marked PRESENT. The site should check the joint exam prior to randomization to ensure there are ≥3 joints that are both tender and swollen to avoid a protocol deviation. c.For SCREENING and ONSTUDY visits, SLEDAI arthritis SHOULD be scored per the glossary definitions if there are ≥ 2 joints with both swelling and tenderness noted on the joint assessment. However, the 4 points due to arthritis will not be counted towards the total and clinical SLEDAI-2K scores required for eligibility unless ≥3 joints are both swollen and tender are present. The adjudicators will review the joint exam to determine if there are enough swollen and tender joints present at screening to meet eligibility. Similarly, the SLEDAI rash, alopecia and mucosal ulcers SHOULD be scored if present as per usual SLEDAI glossary, at all visits (even if the CLASI score is not ≥ 2). The adjudicators will review the CLASI at screening to determine if the patient has enough mucocutaneous disease activity for eligibility.
AND
o BILAG Level A disease in ≥1 organ system (except renal or central nervous system [CNS]) or BILAG B disease in ≥2 organ systems if no level A disease is present at screening. At least one A or one B level body system grade must be in the Mucocutaneous or Musculoskeletal systems.
a and b. For eligibility at screening and at randomization, please See Section 5.1. c. For SCREENING and ONSTUDY visits and BILAG moderate arthritis please See Section 5.1.
For full list of Inclusion Criteria please see Protocol Section 5.1. |
|
| E.4 | Principal exclusion criteria |
• Active, severe lupus nephritis (World Health Organization Class III, IV) that requires or may require treatment with cytotoxic agents or high-dose CS are excluded. Participants with prior, controlled, renal disease that has been treated with an ACE or ARB inhibitor and immunosuppressive therapy (cyclophosphamide or mycophenolate mofetil) with serum creatinine ≤ 2× upper limit of normal (ULN) and either residual proteinuria up to ≤3 g/day or a urine protein/creatinine ratio (UPCR) of ≤3 mg/mg or339 mg/mmol are allowed if prior treatment has been demonstrated. Control of renal disease must be documented with at least 2 measurements of proteinuria or UPCR over the past 6 months. Participants with pure Type V membranous nephropathy must be biopsy confirmed if immunosuppressive therapy was not administered. Pfizer clinical and adjudicators will make the final decision regarding this exclusion criteria. If at all possible, biopsy results confirming the diagnosis should be available in the participant chart.
Note: The lab measurements related to lupus nephritis may be repeated once within approximately 2 weeks of the initial values, and the values resulting from repeat testing may be accepted for enrollment eligibility if they meet the eligibility criteria.
• Have severe active central nervous system (CNS) lupus (eg, BILAG A neurological disease and/or active, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia or dementia related to SLE, active psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) requiring therapeutic intervention within 60 days of Day 1. Participants with BILAG B level neurologic disease are not excluded as long as they meet all other qualifying criteria for the study.
• Have cancer or a history of cancer within 5 years of screening (other than adequately resected cutaneous basal cell, squamous cell carcinoma, or carcinoma in situ of the uterine cervix with no evidence of recurrence within the previous 3 years). If a participant is followed for a history of cancer that is considered to be treated and cured, a note from the oncologist, or specialist following the participant for recurrence noting they are aware of and agree with potential participation should be available in the source document. Potential participants who have an unacceptably high risk of tumor recurrence may be rejected by the Sponsor or their delegate. Additionally, the participant is required to comply with recommended follow up testing with their specialist of record while participating in the study.
• The following is exclusionary;
- Any history of thrombosis (venous or arterial) or cerebrovascular ischemic event (stroke or transient ischemic attack [TIA]) within the last 6 months.
- A history of an ischemic cerebrovascular event (stroke, TIA) within the past 12 months unless these were caused by known antiphospholipid syndrome and the participant has been adequately anticoagulated (and will continue on anticoagulation per guidelines) according to current guidelines for at least 6 months without a recurrence of any thrombotic event.
• Any history of a pulmonary embolus, unless these were caused by known antiphospholipid syndrome and the participant has been adequately anticoagulated (and will continue on anticoagulation per guidelines) according to current guidelines for at least 6 months without a recurrence of any thrombotic event.
Note: Any participant being treated for antiphospholipid syndrome or anticardiolipin antibodies must be adequately anticoagulated according to current local guidelines. Women with a history of antiphospholipid syndrome with prior obstetrical loss but with no prior thrombosis do not require anticoagulation for eligibility. Sites should make every effort to obtain a medical history of at least 3 years duration to document that there have been no thrombotic events or an obstetrical history of repeat fetal losses. In the absence of this medical history information, a hematology consult may be required if antiphospholipid screening tests are positive.
• Active bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, allergic aspergillosis or cavitary lung lesions or granulomatous disease on chest x-ray). History of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to TB and atypical mycobacterial disease, granulomatous disease on chest x-ray) that would substantially increase the risk to the participant if he or she participates in the study.
For full list of Exclusion Criteria please see Protocol Section 5.2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of participants achieving the Systemic Lupus Erythematosus Responder Index (SRI) change of 4 (SRI 4) at Week 52. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Time to first severe flare as measured by the modified Safety of Estrogen in Lupus: National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (mS-SFI).
• Proportion of participants achieving the Lupus Low Disease Activity State (LLDAS) at Week 52.
• Proportion of participants achieving a reduction in prednisone (or equivalent) dose to ≤ 7.5 mg/day at week 52 and sustained for 12 weeks prior to Week 52, in the subset of participants on prednisone >7.5 mg/day (or equivalent) at baseline.
• Proportion of participants achieving SRI-4 response with dose of prednisone (or equivalent) reduced to ≤7.5 mg/day and sustained for 12 weeks at Week 24 and Week 52, in the subset of participants with prednisone dose >7.5 mg/day (or equivalent) at baseline.
• Proportion of Participants with Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI-A) Total Activity Score ≥10 at Baseline with ≥50% Reduction in CLASI-A Total Activity Score
• Change from baseline in the total scores of Functional Assessment of Chronic Illness Therapy Fatigue (FACIT F) at Week 52.
• Change from baseline in the individual domain scores of the Lupus Quality of Life (LupusQoL) at Week 52.
• Incidence of treatment-emergent adverse events (AEs)
• Incidence of serious AEs (SAEs) and AEs leading to discontinuation.
• The incidence of clinically significant abnormalities in vital signs and ECGs.
• The incidence of clinically significant abnormalities in clinical laboratory values.
Separate blinded adjudication committees consisting of independent external experts who will be responsible for the ongoing review of the following efficacy and safety endpoints: 1) BILAG, SLEDAI and associated data; 2) Severe Flare; 3) Cardiovascular and thromboembolic events; 4) Malignancy; and 5) Opportunistic infections. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Individual timepoints are included in each secondary endpoint bullet point above. |
|
| 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 | 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 | 4 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 |
| Canada |
| China |
| Colombia |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Mexico |
| Taiwan |
| United States |
| France |
| Poland |
| Bulgaria |
| Netherlands |
| Romania |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Belgium |
| Hungary |
| Portugal |
| Serbia |
| Ukraine |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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