| 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) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| 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 |
The primary objective of this study is to evaluate and compare the efficacy of 3 dose levels of PF-04236921 to placebo in subjects with active SLE using the SLE Responder Index
(SRI). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study include:
- Evaluate the safety, tolerability, and immunogenicity of PF-04236921.
- Evaluate and compare the clinical response to treatment and changes in disease activity using components of the SRI, modified SRI, and British Isles Lupus Assessment Group based Composite Lupus Assessment (BICLA).
- Characterize pharmacokinetics (PK) of PF-04236921 in subjects with SLE.
- Assess patient reported outcomes including: global assessment of disease activity by visual
analog scale (VAS), Medical Outcome Survey Short Form 36 (SF-36), European Quality
of Life 5 Dimensions Questionnaire (EQ-5D), and Functional Assessment of Chronic
Illness Therapy – Fatigue (FACIT-F).
- Assess efficacy biomarkers (eg, anti-ds DNA).
The exploratory objectives of the study are described within the protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent form document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male and/or female subjects between the ages of ≥18 and ≤75 years old at the time of signing of Informed Consent Form (ICF).
4. Have a clinical diagnosis of SLE according to the 1997 update on the 1982 revised American College of Rheumatology (ACR) criteria.
5. Have unequivocally positive anti-nuclear antibody (ANA) or anti-dsDNA test results by either:
• Positive test result from within the study screening period. Screening results must be based on the study’s central laboratory results. A positive ANA test is defined as an ANA titer ≥1:80 and/or a positive anti dsDNA (> the ULN for the central laboratory reported result) serum antibody.
OR
• One positive historical test result that in the opinion of the investigator and the sponsor is unequivocally due to SLE. Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer, ANA by ELISA) or anti-dsDNA (eg, anti dsDNA by Farr assay or ELISA) must include the date and type of the test, the testing laboratory name, numerical reference range, and a key that explains values provided as positive versus negative OR negative, equivocal/borderline, positive. Only unequivocally positive values as defined in the laboratory’s reference range are acceptable; borderline values will not be accepted.
6. Active disease at screening defined by both:
• SLEDAI-2K score of ≥6, and
• 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.
7. Subjects who are receiving treatment for their SLE activity are on stable doses of SLE treatment (alone or in combination) for at least 30 days prior to the Day 1 visit (first dose of study medication) as follows:
• Corticosteroids (prednisone or prednisone equivalent, up to 25 mg/day). For those patients on alternating day doses of corticosteroids, use the average of two daily doses to calculate the average daily steroid dose.
• Other immunosuppressive or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium), 6-mercaptopurine or thalidomide.
• Anti-malarials (eg, hydroxychloroquine, chloroquine, quinacrine).
NOTE:
• New SLE therapy must not be added within 60 days prior to Day 1; pre-existing SLE medications must be stable for at least 30 days prior to Day 1.
• Corticosteroids may be added as new medication or their doses adjusted only up to 30 days prior to Day 1.
8. All women of childbearing potential (WOCBP) must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result at baseline and prior to receiving each treatment.
• WOCBP are defined as women who are biologically capable of becoming pregnant, including women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
• Women of non childbearing (WONCBP) potential are defined as either females who are over the age of 60, females who are 45 to 60 years of age must be amenorrheic for at least 2 years PLUS have a serum FSH level within the laboratory’s reference range for postmenopausal, or females who are surgically sterile, such as after hysterectomy, bilateral oophorectomy, or tubal ligation (procedure performed ≥52 weeks before screening). This information must be documented in the subject’s source documents.
• WONCBP do not require a serum and urine pregnancy test.
9. Women of childbearing potential, as well as sexually active males agree that when sexually active to use highly effective contraceptive methods and abide by the timeframes noted in the Contraception section of the Lifestyle Guidelines. |
|
| E.4 | Principal exclusion criteria |
1. Any prior history of treatment with PF-04236921, or anti-IL-6 agent.
2. Have received any of the following within 364 days of Day 1: A biologic investigational agent other than those noted below (eg, abatacept or interferon alpha inhibitors). (Investigational agent is defined as any drug not approved for sale in the country in which it is being used) ;Have required 3 or more courses of systemic corticosteroids for concomitant conditions (eg, asthma, Crohn’s disease, ulcerative colitis, systemic vasculitis, atopic dermatitis) within 364 days of Day 1 (Topical or inhaled steroids are permitted).
3. Received IV or oral cyclophosphamide within 180 days of Day 1.
4. Have received any of the following within 90 days of Day 1: Anti-TNF therapy (eg, adalimumab, etanercept, infliximab); Interleukin-1 receptor antagonist (anakinra); Intravenous immunoglobulin (IVIG); High dose corticosteroids (>100 mg/day prednisone or equivalent) or pulse IV doses; Plasmapheresis.
5. Have received any of the following within 60 days of Day 1: Any intramuscular, or intravenous steroid injection; Any new immunosuppressive/immunomodulatory agent, or anti-malarial agent. New inhaled and/or new topical immunosuppressive agents (eg, eye drops, topical creams) are allowed.
6. Have received any of the following within 30 days of Day 1: A live vaccine; Any new or change in dose of a corticosteroid, any change in dose of a immunosuppressive / immunomodulatory or anti malarial agent; Any intraarticular steroid injection;
7. Has been treated with any B-cell depleting agents such as rituximab (or other CD20+ directed therapies), epratuzumab, anti-CD52 [alemtuzumab], or TACI Ig, within the last 12 months unless it is determined that the B cell counts have normalized prior to their screening visit (eg, B cell counts are at least as high as the patient’s last value prior to receiving the B cell depleting agent). Subjects that have been treated with TACI Ig must have also normalized their plasma cells and serum immunoglobulin levels (returned to pre treatment levels).
8. Has been treated with belimumab or any anti-Blyss (or anti BAFF) agent within the past 180 days.
9. Have severe lupus kidney disease (defined by proteinuria ≥6 g/24 hour or equivalent using spot urine protein to creatinine ratio, or serum creatinine ≥2.0 mg/dL), or have active nephritis (eg, BILAG A renal disease), or have required hemodialysis or high-dose corticosteroid (>100 mg/day prednisone or equivalent) within 90 days of Day 1.
10. 10. Have 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. Patients with BILAG B level neurologic disease, or with manageable chorea, are not excluded as long as they meet all other qualifying criteria for the study.
11. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
12. Any major illness/condition or evidence of an unstable condition (eg, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic disorder, or infectious illness) that in the investigator’s judgment, will substantially increase the risk to the subject if he or she participates in the study.
13. Has a history of thromboses (venous or arterial) or other vascular complications within the last 6 months due to antiphopholipid syndrome or anticardiolipin antibodies; Note: Any subject being treated for recurrent antiphospholipid syndrome or anticardiolipin antibodies must be adequately anticoagulated according to current guidelines; An appropiate level of vigilance for the recurrence of thromboembolic events in these subjects should be maintained.
14. Pregnant or breastfeeding women or women planning to become pregnant during study period.
15. Known active or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, granulomatous disease on chest x-ray, and herpes zoster) that in the investigator’s judgment, will substantially increase the risk to the subject if he or she participates in the study.
16. Known history of human immunodeficiency (HIV) based on documented history with positive serological test, or positive HIV serological test at screening. (Note: a documented negative HIV test within 12 months of screening is acceptable and does not need to be repeated).
17. Positive test for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBcAb; also called anti-HBc), and/or hepatitis C antibody (HCVAb).
For a full list of exclusion criteria please refer to the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the study is the proportion of subjects achieving the SLE Responder Index (SRI) at Week 24. The components of the SRI are the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K), the British Isles Lupus Assessment Group (BILAG) 2004, and the Physician’s Global Assessment (PhGA). In order to be classified as a responder, subjects must not meet the definition of a treatment failure (as per Section 5.6) and must meet all of the following compared with baseline:
•≥4 point reduction in the SLEDAI 2K score, and
•No new BILAG A organ domain score or 2 new BILAG B organ domain scores, and
•No worsening (<0.3 point increase) in PhGA score.
The composite endpoint is designed to assure that if improvements occur, they are not accompanied by clinically-relevant worsening. The SRI requires demonstration of improvement in disease activity as measured by at least a 4-point reduction in SLEDAI 2K score as the first step in identifying a responder. Since the SLEDAI 2K 4-point improvement threshold is based on a published threshold for clinical meaningfulness, and because reduction in the score generally requires normalization of a manifestation, not just improvement, an SRI response is also considered clinically meaningful. Once achieving at least a 4-point reduction in SLEDAI 2K, a subject must also show no worsening of disease as measured by BILAG and PhGA to be considered a responder. If either tool shows worsening, the subject is not considered a responder, despite an improvement in the SLEDAI 2K. All 3 of the components are needed to be scored as a responder. In addition, no increases in concomitant SLE medications beyond protocol-specified thresholds are allowed, since such medication changes are indicative of worsening disease and the subject will be considered a treatment failure.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
BILAG: Screening, Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36 44, 52
SLEDAI 2K: Screening, Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 44, 52
Physician Global Assessment: screening, Week 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 44, 52
|
|
| E.5.2 | Secondary end point(s) |
• Proportion of patients achieving SRI at all scheduled timepoints except Week 24.
• Proportion of patients achieving modified SRI at all scheduled timepoints.
• Proportion of patients achieving BICLA response at all scheduled timepoints.
• Components and Disposition of SRI at Week 24.
• Safety and tolerability of PF 04236921 dose levels versus placebo: laboratory tests, AEs, infections, ECGs and vital signs. The incidence of AEs, withdrawals due to AEs, and serious adverse events (SAEs) will be reported.
• Percent of subjects who develop anti-drug antibodies (ADAs) and neutralizing antibodies (Nabs), if observed.
• Serum concentration of PF 04236921.
• Percentage of subjects whose corticosteroid dose has been reduced by both ≥25% from baseline and to ≤7.5 mg/day during Weeks 12 through 24.
• Percent of patients with normalized serologic activity (subgroup patients with abnormal at baseline) including IgG, immunglobulins, anti dsDNA, C3 and C4.
• Mean change in patient global VAS, EQ 5D, SF-36 PCS, MCS and Vitality Score –all domains over time including SF 6D, FACIT.
The exploratory endpoints are described within the protocol.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety labs: week 0, 2, 4, 6, 8, 12, 16, 20, 24, 28 32, 36, 44, 52
ECG: week 12, 24
Vitals: week 0, 2, 4, 6, 8, 12, 16, 20, 24, 28 32, 36, 44
AEs will be collected throughout the study
Serum Anti-PF-04236921: week 0, 8, 16, 24, 32, 44
Serum Pharmacokinetic: week 0, 2, 4, 6, 8, 12, 16, 20, 24, 28 32, 36, 44
SF-36: week 0, 4, 8, 12, 16, 20, 24, 32, 52
SF-6D: week 0, 4, 8, 12, 16, 20, 24, 32
EQ-5D: week 0, 4, 8, 12, 16, 20, 24, 32, 52
Facit-F: week 0, 4, 8, 12, 16, 20, 24, 32, 52
Patient global assessment of disease activity scores VAS: week 0, 2, 4, 6, 8, 12, 16, 20, 24, 28 32, 36, 44, 52
|
|
| 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 | No |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability, immunogenicity & pharmacodynamics |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Korea, Republic of |
| Lithuania |
| Moldova, Republic of |
| Israel |
| Mexico |
| Peru |
| Poland |
| Romania |
| Taiwan |
| United States |
| Germany |
| Argentina |
| Chile |
| Colombia |
| Hungary |
| India |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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