E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Active Class III or IV lupus glomerulonephritis |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025140 |
E.1.2 | Term | Lupus nephritis |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 |
The primary objective of this study is to compare the proportion of subjects with Complete Renal Response (CR) of lupus glomerulonephritis (as defined in Section 5.4.1.1 of the study protocol) at Day 365 following 1 year treatment with abatacept or placebo administered on a background of MMF and corticosteroids. |
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E.2.2 | Secondary objectives of the trial |
Assess
1) proportion of subj. with CR of lupus glomerulonephritis at Day 729 following 2 years treatment with abatacept or Pbo, on background MMF and corticosteroids
2) proportion of subj. achieving the ranked outcomes of CR, Partial Renal Response (PR) or No Response (NR) at Day 365 & Day 729 following 2 years treatment with abatacept or Pbo, on background MMF plus corticosteroids
3) time to 1st achievement of CR, and time to 1st achievement of CR and/or PR between the abatacept and Pbo arms (a) in all subj., (b) in subj. who achieved CR and/or PR at Day 365, and (c) in subj. who achieved CR and who achieve CR and/or PR at Day 729
4) components of response over time incl. proportion of subj. who meet each component of the criteria and the values of UPCR and eGFR over time
5) abatacept safety and immunogenicity
6) change in overall disease activity from Day 1 through Day 365 and Day 729, and from Day 365 through Day 729
7) durability of CR & PR achieved during treatment period |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
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.
b) Urine protein creatinine ratio (UPCR) ≥ 1.0 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).
d) Evidence of active disease within 3 months of Screening, based on at least one of the following:
i) Renal Flare
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.
e) Serum creatinine ≤ 3 mg/dL (ie, ≤ 265 micromol/L). |
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E.4 | Principal exclusion criteria |
a) Subjects with drug-induced SLE, as opposed to idiopathic SLE.
b) Subjects with autoimmune disease other than SLE as their main diagnosis (eg; RA, MS).
c) Current symptoms of severe, progressive, or uncontrolled non-SLE related renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease, or other concomitant medical conditions that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study.
d) Active CNS lupus (BILAG A or B) with the exception of fatigue or mild stable cognitive dysfunction (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).
e) Subjects who are diagnosed as end-stage renal disease.
f) Subjects with persistent non-lupus related pyuria or hematuria (eg, hemorrhagic cystitis).
g) Subjects with a degree of tubulo-interstitial changes that suggests a significant and irreversible decrease in renal function
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects achieving Complete Response of renal disease following 52 weeks of treatment, where complete response is a composite endpoint based on renal function, proteinuria, urine sediment, and corticosteroid dose. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Proportion of subjects with ranked outcome of complete renal response, partial renal response and no response
• Proportion of subjects in complete renal response of lupus glomerulonephritis
• Proportion of subjects with ranked outcome of complete renal response, partial renal response and no response
• Time to achieving first complete renal response
• Time to achieving first partial renal response
• Proportion of subjects meeting each of the components of PR and CR (UPCR< 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
• Mean change from baseline in disease activity as measured by BILAG 2004:
• 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).
• Time to first lupus treatment failure and proportion of subjects in lupus treatment failures overall, and after achievement of CR or PR.
• Time to first overall treatment failure and proportion of subjects in lupus treatment failure overall, and after achievement of CR or PR
Safety Endpoints
• All adverse events (AEs/SAEs)
• AEs of interest (infections, malignancies, autoimmune disorders, and infusional reactions)
• Vital signs
• Laboratory test abnormalities
Immunogenicity Endpoint
• Proportion of subjects with abatacept induced antibody response
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-At Day 365
-At Day 729
-At Day 729
-At Day 365
-At Day 365
-At Day 365
-At Day 365
-At Day 365
-At Day 365
-At Day 365
-At Day 365 and 729
-At Day 365 and Day 729
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarkers; Outcomes Research Assessments; Immunogenicity Assessments |
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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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 | No |
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 |
Argentina |
Australia |
Brazil |
Canada |
Chile |
China |
Colombia |
Czech Republic |
Hong Kong |
India |
Italy |
Japan |
Korea, Republic of |
Mexico |
Peru |
Romania |
Russian Federation |
Taiwan |
United States |
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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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |