A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER, DOSE-RANGING STUDY TO EVALUATE THE EFFICACY AND SAFETY OF PF-04236921 IN SUBJECTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
This Phase 2, multicenter, randomized, parallel, dose ranging, double-blind, placebo controlled clinical trial will be conducted globally in subjects with active, generalized SLE.
After a 4-week screening period, eligible subjects will be randomized in a 1:1:1:1 ratio such that subjects will receive either one of three dose levels of PF-04236921 10, 50 or 200 mg [dosing stopped based upon sponsor decision], or placebo every 8 weeks, in a blinded fashion and stratified by baseline disease severity and anti-dsDNA status.
A decision was made to stop further dosing of subjects who were in the 200 mg treatment arm due to a review of the safety information. As of 16 April 2013, patients in the 200 mg treatment arm will be notified that they got the 200 mg dose and will be withdrawn from the study. Additional follow-up after withdrawal were added via telephone to check if patients are having any new symptoms approximately 2 weeks after each monthly Follow-Up Visit, followed by 2 additional telephone contacts approximately 4 weeks after each bimonthly Follow-Up visit. If they are having new symptoms, may be asked to come to the site for evaluation.
The study will consist of 2 parts:
1. 24 week treatment period.
2. 28 week follow up period (the duration of follow up following the last dose of PF-04236921 is 36 weeks).
Subjects will participate in this study for approximately 13 months (~56 weeks). This includes a 4-week screening period, a 24-week treatment period, and a 28-week follow-up period. Dosing of eligible subjects will occur within 28 days after successful completion of the screening process.
Subjects will receive investigational product on Day 1/Week 0, Week 8 and Week 16.
Subjects will be required to remain on a stable dose of their background medication/s (eg, immunosuppressives, antimalarials, etc) and follow the corticosteroid dosing guidelines during the treatment period of the study. During the treatment period, subjects who are withdrawn due to adverse events or worsening SLE will enter the follow up period.
Approximately 180 randomized subjects (45 subjects per treatment group) will participate in this study at approximately 100 sites worldwide.
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 (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 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 ([Less Than]0.3 point increase) in PhGA score.
Secondary endpoints of the study include:
* Proportion of patients achieving SRI at all scheduled timepoints except Week 24.
* 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 [Greater Than]25% from baseline and to [Less Than]7.5 mg/day during Weeks 12 through 24.
* Percent of patients with normalized serologic activity (subgroup patients with abnormal at baseline) including IgG, anti-dsDNA, C3 and C4.
* Mean change in patient global VAS, EQ-5D, SF-36 PCS, MCS and Vitality Score xall domains over time including SF-6D, FACIT.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into thestudy:
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) test results by either:
* Positive test result from within the study screening period. Screening results must be based on the study[Single Quote]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.
* 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[Single Quote]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
Anti-malarials (eg, hydroxychloroquine, chloroquine, quinacrine).
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[Single Quote]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[Single Quote]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 (Section 4.4).