E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Lupus Erythematosus (SLE) |
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E.1.1.1 | Medical condition in easily understood language |
Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease |
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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 | 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 |
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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. |
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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. |
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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 male and 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 monontherapy is not permitted. 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 . See Appendix 13 for allowable stable doses.
• Have active disease defined as:
o SLEDAI 2K score of ≥8 points at screening, and “Clinical” SLEDAI 2K score of ≥4 points at both screening and randomization
NOTE: "Clinical" SLEDAI 2K score (See Appendix 11) is the SLEDAI 2K score without the inclusion of points attributable to any urine or laboratory results including immunologic measures. For inclusion in the study, the Clinical SLEDAI-2K calculation for entry will exclude points for a) Lupus Headache, b) skin disease involving Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Erythema scores less than 2 and c) arthritis scores must involve a minimum of 3 joints with tenderness, swelling, or effusion (ie rather than 2).
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 qualifying screening Mucocutaneous B due to BILAG #6, mild skin eruption, must have a CLASI erythema activity score of >=2. A qualifying screening Musculoskeletal B due to #42, moderate arthritis, must show >=3 swollen, tender joints and a qualifying Musculoskeletal A score due to #41, severe arthritis, must show >=6 tender, swollen joints on the screening joint count. (see Appendix 12).
Note: Data from the SLICC, SLEDAI and BILAG evaluations will be reviewed by the Sponsor and/or the Sponsor-selected independent reviewer(s). For participants to receive their first administration of study agent, approval must be received by the Sponsor and/or Sponsor-selected independent reviewers.
See section 5.1 of the Protocol for a full list of Inclusion Criteria |
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E.4 | Principal exclusion criteria |
• Have active renal lupus as defined by the following: spot urine protein/creatinine ratio >3.0 mg/mg (proteinuria >3.0 g/24 hours may also be used if available) or have BILAG A renal disease, or have required hemodialysis or active urinary sediment with red blood cell cast(s), or histological evidence (if available) of diffuse proliferative glomerulonephritis within the 12 weeks prior to screening.
o 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, 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 (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 consider treated and cured, a note from the oncologist, or specialist following the participant for recurrence should be available in the source document. 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 a ischemic cerebrovascular event (stroke, TIA) within the past 12 months unless these were caused by known antiphospholipid syndrome and the patients 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 patients 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. 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.
See section 5.2 of the Protocol for a full list of Exclusion Criteria |
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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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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) SLE Flare Index (SELENA SLEDAI 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 and sustained for 12 weeks at 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 (AE’s)
• Incidence of serious AE’s (SAEs) and AE’s 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, independent adjudication committees will be responsible for the ongoing review and adjudication 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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Individual timepoints are included in each secondary endpoint bullet point above. |
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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 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Australia |
Belgium |
Bulgaria |
Canada |
China |
Colombia |
Czech Republic |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Japan |
Korea, Republic of |
Mexico |
Poland |
Portugal |
Romania |
Serbia |
Spain |
Taiwan |
Ukraine |
United Kingdom |
United States |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 17 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |