A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of BMS-188667 (Abatacept) or Placebo on a Background of Mycophenolate Mofetil (MMF) and Corticosteroids in Subjects with Active Class III or IV Lupus Nephritis
This is a randomized, double-blind, placebo controlled multi-national, multi-center trial in adults [GreaterThanorequalTo] 18 years old with active Class iii or iV lupus glomerulonephritis. The objective is to determine if abatacept is superior to placebo for induction of complete response of Ln, when added to a common background of mycophenolate mofetil (MMF) and corticosteroids.
Subjects will be randomized in a 1:1 fashion to either placebo or to abatacept at 30 mg/kg administered iV on Days 1, 15, 29, and 57, followed by a weight-tiered fixed dose approximating 10 mg/kg administered every 28 days throughout the 104-week double-blind treatment period.
on Day 729, subjects who are continuing to derive benefit from the study treatment,will have the opportunity to enter an optional 52-week long-term extension (LTe) period where they will continue to receive the same double-blind treatment previously assigned, at the same dose. on Day 897, at the investigator's discretion, subjects may be offered to switch to receive abatacept 125 mg / placebo via subcutaneous injection (SC).
all subjects will also receive therapy with MMF, corticosteroids, stable doses of anti-malarial agents, anti-proteinuric agents (angiotensin converting enzyme inhibitor [aCei] and angiotensin receptor blocker [aRBs] and anti-hypertensive regimens, salt restriction, and statins.
From Day 729 to day 897, MMF, daily oral corticosteroids and aCei/aRBs can be adjusted at the investigator's discretion.
Safety will be assessed throughout the study. The primary endpoint will be assessed at Day 365, based on an analysis performed when all subject have completed 52 weeks of treatment, or have discontinued prematurely.
Subjects will remain on blinded treatment for an additional 52 weeks to assess improvement or maintenance of response, and long term safety.
Subjects will be followed for 6 months after the last dose of study drug. in addition, subjects who discontinue treatment prematurely will be contacted at Study Day 365 and Day 729 to assess status of Ln.
Study endpoints, including the primary efficacy endpoint will be assessed at an analysis conducted after all subjects have completed 52 weeks of double-blind treatment, or have discontinued prematurely.
The primary efficacy endpoint is the proportion of subjects in complete renal response of lupus glomerulonephritis at Day 365.
Secondary efficacy endpoint(s)
* Proportion of subjects with ranked outcome of complete renal response, partial renal response and no response at Day 365
* Proportion of subjects in complete renal response of lupus glomerulonephritis at Day 729
* Proportion of subjects with ranked outcome of complete renal response, partial renal response and no response at Day 729
* Time to achieving first complete renal response during the double-blind period
* Time to achieving first partial renal response during the double-blind period
* Proportion of subjects meeting each of the components of PR and CR (uPCR[Less Than] 0.5, uPCR reduced by 50% and meeting target, eGFR normal or no less than 85% of baseline, corticosteroid dose no greater than 10 mg/day prednisone or prednisone equivalent) of response over time during the double-blind
* Mean change from baseline in disease activity as measured by BiLaG 2004 over time during the double-blind period
* Time to and proportion of subjects with sustained change to lower level of response, ie, CR to PR or nR, PR to nR (sustained response is defined as response present at 2 consecutive visits) during the double-blind period
* Time to first lupus treatment failure and proportion of subjects in lupus treatment failures overall, and after achievement of CR or PR during the double-blind period
Subjects who complete the LTe Day 1094 and who are clinically stable will have the option to continue into the Maintenance Phase extension (MPe).
1) Signed Written Informed Consent
2) Target Population
a) SLE as defined by meeting at least 4 of the 11 classification criteria of the American College of Rheumatology for the classification of Systemic Lupus Erythematosus, either sequentially or coincidentally. The 4 criteria need not be present at the time of study entry
b) Urine protein creatinine ratio (UPCR) >= 1 at Screening
c) Biopsy within 12 months prior to screening visit indicating active proliferative lupus glomerulonephritis ISN/RPS 2003 classification Class III or IV [excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 Classification Class III or IV (excluding IIIc, IVd). NOTE: If no prior biopsy was done for the subject at the time of the screening visit yet, the procedure can be performed during the screening period as a study procedure only after the subject meets all other inclusion and
d) Evidence of active disease within 3 months of Screening, based on at least one of the following:
i) Renal Flare (defined in section 126.96.36.199)
ii) UPCR > 3 at Screening
iii) Active urine sediment, defined as at least one of the following:
* >= 5 red blood cells (RBC) per high power field (hpf)
* >= 5 white blood cells (WBC) per hpf
* presence of cellular casts
iv) Biopsy within 3 months prior to screening visit indicating active proliferative lupus glomerulonephritis ISN/RPS 2003 classification Class III or IV [excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 Classification Class III or IV (excluding IIIc, IVd) (see Appendix 2). NOTE: If no prior biopsy was done for the subject at the time of the screening visit yet, the procedure can be performed during the screening period as a study procedure.
v) Subjects may be re-screened for urinary sediment and/or proteinuria ONCE within 2 weeks of the original screening visit.
e) Serum creatinine <= 3 mg/dL (ie, <= 265 micromol/L). Subjects not meeting this criterion but meeting all other inclusion and exclusion criteria may be re-screened for serum creatinine ONCE within 2 weeks of the original screening visit.
f) This study allows the re-enrollment of subjects who have been discontinued as pre-treatment failures (ie, subject has not been randomized / has not been treated). If re-enrolled, the subject must be re-consented and all screening procedures re-assessed with the exception of the chest x-ray, ECG and TB screen.
3) Age and Reproductive Status
a) Men and women, at least 18 years of age.
b) Women of childbearing potential (WOCBP) must use method(s) of contraception based on the tables in Appendix 8. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half lives.
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
d) Women must not be breastfeeding
e) Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours,
contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half lives.
f) Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile; see Section 3.3.3 for the definition of WOCBP) and azoospermic men do not require contraception
4) Disease Activity and Concomitant Medication
a) Eligibility of subjects for entry into the study is based on their current renal disease activity which may represent:
i) The first manifestation of SLE
ii) The first renal manifestation of SLE
iii) Recent worsening of glomerulonephritis that had been diagnosed previously
iv) Persistence of renal disease despite current therapies, including MMF and/or corticosteroids. MMF can have been used for no more than 3 months for the current flare of LN.
5) Inclusion criteria for the Long-Term Extension period
a) Signed Written Informed Consent
b) Subjects who complete 104 weeks of double-blind treatment and have achieved a complete or partial renal response at Day 701 (based on lab results from Day 701 or 722, if needed) as defined in Sections 188.8.131.52 and 184.108.40.206.
Inclusion criteria for the Maintenance Phase Extension
a) Subjects who complete the LTE and who, in the judgment of the investigator, are clinically stable and do not warrant use of alternative therapy to manage active LN
b) Signed Informed Consent before receiving additional study treatment beyond Day 1065