E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
IMMUNOSUPPRESSION FOR DISEASE, NOS |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025139 |
E.1.2 | Term | Lupus erythematosus systemic |
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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 |
*Double-Blind (DB) Period: The primary objective of this adaptive design study is to compare a single abatacept regimen versus placebo on a background of MMF plus glucocorticosteroids using the posterior probability of superiority over placebo in the time to achieving protocol-defined complete renal response of lupus glomerulonephritis (defined in Protocol Section 3.3.1.1) during this 12 month double-blind study.
*Open-Label (OL) Extension Phase: Assess the long-term clinical safety and tolerability of abatacept treatment during the Open-Label Extension Phase. |
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E.2.2 | Secondary objectives of the trial |
*DB: Compare: 1)time to achieving protocol-defined complete renal response of lupus glomerulonephritis (Protocol Section 3.3.1.1) during this 12 month DB study of an abatacept regimen vs placebo on a background of MMF + glucocorticosteroids using the classical Cox proportional hazards model 2)proportion of subjects achieving complete renal response of lupus glomerulonephritis during the 12 months between abatacept & placebo regimens 3)proportion of subjects with a complete renal response who maintain complete renal response for at least 3 months between abatacept & placebo regimens 4)time to achieving Renal Improvement (Protocol Section 3.3.1.2); or together the criteria Complete Renal Response & Renal Improvement between abatacept & placebo regimens
Refer to protocol section 2.2 for additional DB phase Sec. Objectives
*OL: Assess durability of efficacy (e.g. complete renal response, renal improvement, SLICC/ACR Damage Index), immunogenicity & corticosteroid use |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed written informed consent 2) 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 (Protocol Appendix 1), either sequentially or coincidentally. The 4 criteria need not be present at the time of study entry. 3) Biopsy within 6 months of enrollment (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)]. If renal function has deteriorated, biopsy may have been no more than 3 months prior to enrollment (screening visit). 4) Active renal disease at the screening visit, as defined by: urinary protein/creatinine ratio ≥ 50 mg/mmol AND an active urinary sediment as defined by at least one of the following 3 criteria: a) > 5 RBC/hpf OR b) > 8 WBC/hpf (with no evidence of a urinary tract infection) OR c) cylindruria 5) Serum creatinine ≤ 3 mg/dL. (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 in consultation with the BMS Medical Monitor). 6) Men and women, at least 18 years of age. 7) Eligibility of subjects for entry into the study is based on their current renal disease activity which may represent: a) The first manifestation of their SLE. b) The first renal manifestation of SLE. c) Recent worsening of glomerulonephritis that had been diagnosed previously. d) Persistence of renal disease despite current therapies, including MMF and/or glucocorticosteroids, as long as the medications used are permitted by protocol.
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E.4 | Principal exclusion criteria |
1)WOCBP unwilling or unable to use an acceptable method to avoid pregnancy for entire study period & up to 10 weeks after study 2)WOCBP using a prohibited contraceptive method (there are none) 3)pregnant or breastfeeding women 4)Women with positive pregnancy test on enrollment or prior to study drug administration 5)Males unwilling or unable to follow recommendations for use of contraception specified by the manufacturer of any protocol-permitted disease sparing medication (biologic or non-biologic) being used during study 6)Subjects with a rise of serum creatinine of ≥ 1 mg/dL within 1 month prior to screening visit 7)Subjects with drug-induced SLE, as opposed to idiopathic SLE. 8)Subjects with severe, unstable &/or progressive CNS lupus (screening MRI or other imaging of the brain is not required to rule-out CNS disease in subjects who have no clinical features suggesting active CNS disease) 9)Subjects with autoimmune disease other than SLE as their main diagnosis (e.g.; RA, MS) 10)Current symptoms of severe, progressive, or uncontrolled non-SLE related renal, hepatic, hematological, gastrointestinal, pulmonary, cardiovascular, neurological, endocrine, or cerebral disease. Concomitant medical conditions that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study 11)Concomitant illness that in the opinion of the investigator, is likely to require additional high dose oral glucocorticosteroid therapy (i.e. > 45 mg per day) during study, (e.g.; asthma) 12)Female subjects who have had breast cancer screening study suspicious for malignancy, & in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations 13)Female subjects who have evidence of cervical dysplasia unless treated with definitive therapy 14)history of cancer within last 5 years (other than non-melanoma skin cell (NMSC) cancers cured by local resection). Existing NMSC cancers must be removed prior to randomization (Day 1 treatment). Subjects with carcinoma in situ, treated with definitive surgical intervention, are allowed 15)any serious bacterial infection within last 3 months, unless treated & resolved with antibiotics, or any chronic bacterial infection (such as chronic pyelonephritis, osteomyelitis & bronchiectasis) 16)Subjects at risk for tuberculosis. Specifically subjects with: a)Current clinical, radiographic or laboratory evidence of active TB b)history of active TB within last 3 years even if treated c)history of active TB > 3 years ago unless there is documentation that the prior anti-TB treatment was appropriate in duration & type d)Latent TB which has not been successfully treated 17)Subjects with herpes zoster that resolved < 2 months prior to screening visit 18)Subjects with evidence (as assessed by the Investigator) of active or latent bacterial or viral infections at time of potential enrollment, including subjects with evidence of HIV infection 19)renal transplant recipients or candidates 20)Subjects who are diagnosed as end-stage renal disease 21)persistent non-lupus related pyuria 22)a degree of tubulo-interstitial changes that suggest an irreversible decrease in renal function 23) Subjects currently on hydroxychloroquine or chloroquine with evidence of retinopathy within 6 months of screening visit. If local standards for routine ophthalmologic follow-up suggest such formal examinations are needed subjects who have had no ophthalmologic evaluation & will not have this examination done will be excluded 24)Hepatitis-B surface antigen-positive subjects 25)Hepatitis C antibody-positive subjects who are also RIBA-positive or PCR-positive 26)Subjects with serum ALT or AST > 3 times upper limit of normal UNLESS IN THE JUDGMENT OF THE INVESTIGATOR THE EVALATION IS EXPLICITLY RELATED TO SLE 27)Any other laboratory test results that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study 28) Subjects who have at any time in the past received treatment with CTLA4Ig or abatacept 29) Subjects taking anti-proteinuric agents (e.g. angiotensin II receptor blockers, ACE inhibitors) for < 1 month prior to randomization [Day 1]) 30) Subjects not discontinuing disease modifying and/or steroid sparing medications (i.e. azathioprine, leflunomide, methotrexate), cyclosporine (or any other calcineurin inhibitor) or any other agents for the treatment of SLE or proteinuria at or before the Screening Visit. 31) Subjects who have received treatment with any investigational drug within 28 days or less than 5 terminal half lives of elimination (whichever is longer) of randomization (Day 1). (In Ireland, subjects who have received treatment with any investigational drug (including placebo) within 16 weeks (4 months) of randomization).
Refer to Protocol Section 5.2 for additional Exclusion Criteria.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the time to complete renal response as defined by this protocol. The proportion of subjects experiencing a complete renal response or renal improvement during the 12 months will be secondary endpoints. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Health related Quality of Life: The Short Form-36 Questionnaire |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open Label extension after double blind study period |
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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.8.3 |
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 | 13 |
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 | Information not present in EudraCT |
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 |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |