| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| IMMUNOSUPPRESSION FOR DISEASE, NOS |
|
| 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 |
|
| 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 study is to compare the time to achieving confirmed
protocol-defined complete renal response of lupus glomerulonephritis (defined in
Section 3.3.1.1) during this 12 month double-blind study of two abatacept regimens
versus placebo on a background of MMF plus glucocorticosteroids using the classical
Cox proportional hazards model.
*Open-Label (OL) Extension Phase:
Assess the long-term clinical safety and tolerability of abatacept treatment during the
Open-Label Extension Phase. |
|
| E.2.2 | Secondary objectives of the trial |
*DB:
1) Compare the proportion of subjects achieving confirmed complete renal response of
lupus glomerulonephritis at 12 months between the abatacept and placebo regimens.
2) Assess the time to achieving Renal Improvement (Section 3.3.1.2); or together the
criteria Complete Renal Response (Section 3.3.1.1) and Renal Improvement (Section
3.3.1.2) between the abatacept and placebo regimens.
3) Assess the proportion of subjects achieving Renal Improvement (Section 3.3.1.2) or
together the criteria Complete Renal Response (Section 3.3.1.1) and Renal
Improvement (Section 3.3.1.2) between the abatacept and 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, and corticosteroid use. |
|
| 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 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
Class III c, IVd). NOTE: If the biopsy was performed > 3 months but ≤ 12 months
prior to screening visit, at least 1 of the following 3 serologies (performed locally)
must be abnormal prior to screening visit:
Complement (C3 or C4) level below normal range
OR
Anti-dsDNA > upper limit of normal range
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
Subjects not meeting all the criteria but meeting all other inclusion and exclusion
criteria may be re-screened for urinary sediment ONCE within 2 weeks of the original
screening visit in consultation with the BMS Medical Monitor.
NOTE: Subjects prior to consenting who were treated with systemic
glucocorticosteroid treatment (at least 30 mg or 0.5 mg/kg of prednisone-equivalent
or intravenous pulse, as per local standards) during the current episode of lupus
nephritis AND had documented abnormal (> ULN) urinary sediment (as per local
laboratory) during the current episode of lupus nephritis AND have persisting
proteinuria (urinary protein/creatinine ratio ≥ 50 mg/mmol) present at screening visit,
will be considered to have met this inclusion criterion.
5) Serum creatinine ≤ 3 mg/dL (i.e., ≤ 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 in consultation with the BMS Medical
Monitor).
6) Men and women, at least 16 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.
|
|
| 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 that require definitive
therapy according to local guidelines or the Consensus Guidelines and have not been
properly treated (refer to Protocol Section 7.3.2.4).
14) Subjects with a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers mst be removed prior to randomization (Day 1 treatment). Subjects with carcinoma n situ, treated with definitive surgical intervention, are allowed.
15) Subjects with any serious bacterial infection within the last 3 months, unless treated nd resolved with antibiotics, or any chronic bacterial infection (such as chronic
pyelonephritis, osteomyelitis and bronchiectasis).
16) Subjects at risk for tuberculosis. Specifically, subjects with:
a) Current clinical, radiographic or laboratory evidence of active TB.
b) A history of active TB within the last 3 years even if it was treated.
c) A history of active TB greater than 3 years ago unless there is documentation that
the prior anti-TB treatment was appropriate in duration and type.
d) Latent TB which has not been successfully treated.
17) Subjects with herpes zoster that resolved less than 2 months prior to screening visit.
18) Subjects with evidence (as assessed by the Investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of Human Immunodeficiency Virus (HIV) infection.
19) Subjects who are renal transplant recipients or candidates.
20) Subjects who are diagnosed as end-stage renal disease.
21) Subjects with persistent non-lupus related pyuria.
22) Subjects with 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 and 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 ELEVATION 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 less than 1 month prior to randomization [Day 1]).
Refer to Protocol Section 5.2 for additional Exclusion Criteria.
|
|
| 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. |
|
| 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 |
|
| 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 |
|
| 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 | 2 |
| 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 |
|
| 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
|
|
| 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 |
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