STUDY TO EVALUATE THE EFFICACY AND SAFETY OF PF 04236921 IN SUBJECTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

• Register: EUCTR
• Last refreshed on: 19 May 2014
• Main ID: EUCTR2011-000420-15-HU
• Date of registration: 15/12/2011
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc.235 East 42nd Street, New York, NY 10017
• Public title: STUDY TO EVALUATE THE EFFICACY AND SAFETY OF PF 04236921 IN SUBJECTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
• Scientific title: 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) - Butterfly
• Date of first enrolment: 08/02/2012
• Target sample size: 180
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-000420-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: dose-ranging If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 4

Countries of recruitment

Argentina, Chile, Colombia, Germany, Hungary, India, Israel, Korea, Republic of, Lithuania, Mexico, Moldova, Republic of, Peru, Poland, Romania, Taiwan, United States

Contacts

• Name: Clinical Trials.gov Call Centre
• Affiliation: Pfizer Inc

• Name: Clinical Trials.gov Call Centre
• Affiliation: Pfizer Inc

Key inclusion & exclusion criteria

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 antidsDNA
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 re
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. 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 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 parti

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
MedDRA version: 15.1 Level: PT Classification code 10042945 Term: Systemic lupus erythematosus System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: Not applicable
Product Code: PF-04236921
Pharmaceutical Form: Powder for injection
INN or Proposed INN: Not applicable
Current Sponsor code: PF-04236921
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 106-
Pharmaceutical form of the placebo: Powder for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

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.

Main Objective: 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).

Secondary Objective: 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.

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

Secondary Outcome(s)

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

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, antidsDNA,
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.

Secondary ID(s)

2011-000420-15-DE

B0151006

Source(s) of Monetary Support

Pfizer Inc