| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SYSTEMIC LUPUS ERYTHEMATOSUS, NOS |
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| MedDRA Classification |
| 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 for this study will be to assess the proportion of subjects with a new clinical flare of SLE during the 1 year double-blind treatment period, comparing abatacept with placebo on a background of tapering glucocorticosteroids.
Protocol Amendment 04 - Long Term extension:
The primary objective of this amendment is to assess the long-term safety and tolerability of abatacept in subjects with SLE (entry BILAG “A’ or “B” flare activity in pre-defined organ systems) who have completed the initial 12 month double-blind treatment period on a background of tapering glucocorticosteroids.
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| E.2.2 | Secondary objectives of the trial |
1) Assess the proportion of subjects with a new clinical flare of SLE within the initial 6
months of the double-blind treatment period.
2) Assess the total number of SLE flares a subject experienced during the double-blind
study period in the two treatment groups.
3) Evaluate the time to occurrence of a new clinical flare of SLE in the two treatment
groups.
4) Assess the proportion of subjects in each study arm who have no or minimal SLE
activity (ie, all scores are BILAG “C”,”D” or “E”) and while on a prednisone or
prednisone equivalent dose of ≤ 7.5 mg for at least 2 consecutive months.
5) Assess SLICC/ACR Damage Index at one year compared with baseline for the two
treatment groups.
6) Assess the safety of chronic use of abatacept.
7) Assess the immunogenicity of abatacept during chronic use.
Long Term Extension Amdt 4:
See Section 2.2 of Protocol Amendment 04
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Subjects must have SLE as defined by meeting 4 of the 11 classification criteria of the American College of Rheumatology for the classification of Systemic Lupus Erythematosus (Appendix 1), either sequentially or coincident. The 4 criteria need not be present at study entry, but have occurred at some time during the course of the disease.
2) Within 28 days of the screening visit, subjects must have at least one of the following flare manifestations of SLE, as defined by the BILAG criteria as modified for use in this study. The flare manifestation may represent the initial activity within that organ system or may be a recurrence of activity in an organ system previously affected. [the subject may be experiencing other BILAG “A” or “B” features of lupus as well (other than renal or central nervous system which are specifically excluded from entry), but features other than those specified below are not sufficient for entry into the study]:
a) Active mucocutaneous discoid lesions:
i) “A”: severe active facial and/or extensive discoid lesions (> 2/9 of body surface area), scarring or causing disability recorded as > 1.
ii) “B”: localized active discoid lesions (< 1/9 total body surface area), including lupus profundus recorded as > 1. The skin lesions must be actively inflamed; they cannot be solely chronic changes, e.g. scar with depigmentation. In order to satisfy inclusion rules, the currently active lesions cannot represent ongoing chronic and continuous activity - they must constitute a flare, either newly inflamed or previously inflamed but quiescent for at least 3 months.
b) Active polyarthritis:
i) “A”: severe polyarthritis as recorded as > 1 with loss of function (not responsive to steroids less than 10 mg per day, antimalarials, NSAIDs)
ii) “B”: Arthritis as recorded as > 1: active joint inflammation without loss of functional range of motion. At least 3 actively inflamed joints--swollen, tender, erythematous--not
isolated Jaccoud arthropathy although the presence of Jaccoud arthropathy in a subject with active inflammation will not preclude study entry. The inflamed joints cannot have been chronically and continuously inflamed- they must constitute a flare, either newly inflamed or previously inflamed but quiescent for at least 3 months.
Activity in an organ system that was either minimally or not active for at least 3
months:
i) now BILAG A in an organ system that was BILAG B, C, D, or E, OR
ii) now BILAG B in an organ system that was previously BILAG C, D, or E
c) Active serositis (pleuritis/pericarditis):
i) “A”: Symptomatic effusion recorded as > 1 plus two other criteria listed below > 1 or four of the following criteria listed below recorded as > 1: pleuropericardial pain; dyspnea; friction rub; chest x-ray revealing pleural or pericardial effusion; electrocardiogram changes of pericarditis; or cardiac arrhythmia including tachycardia > 100 beats per minute in the absence of fever.
ii) “B”: Two of the following criteria listed below each recorded as > 1: pleuropericardial pain; dyspnea; friction rub; chest x-ray revealing pleural or pericardial effusion; electrocardiogram changes of pericarditis; or cardiac arrhythmia including tachycardia > 100 beats per minute in the absence of fever.
Although commonly used in some practices, echocardiographic confirmation of the presence of pericardial disease is not considered a BILAG criterion and therefore cannot be substituted for any of the criteria noted above.
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| E.4 | Principal exclusion criteria |
1) Women who are pregnant or breast-feeding.
2) Women with a positive pregnancy test on enrollment or prior to study drug administration.
3) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 10 weeks after the last infusion of study medication.
4) Contraception for male subjects treated with any protocol-permitted non-biologic steroid sparing agent during the study should follow the recommendation of that steroid sparing agent’s manufacturer for method to be used. Males unwilling or unable to follow these recommendations will be excluded.
5) Treatment of current SLE flare with corticosteroids for more than 14 days prior to randomization, or treatment of the flare at any time with a dose 30 mg (prednisone or prednisone equivalent) per day.
6) Active anti-phospholipid antibody syndrome, (i.e. recent untreated thromboses, cerebral or pulmonary emboli, pregnancy loss, pleurisy due to thromboembolic phenomena) as the sole or primary feature of their SLE or SLE-like syndrome should be excluded. However, subjects currently controlled with anti-coagulation therapy, who have no disease activity may be included in the study.
7) Subjects with drug-induced SLE, rather than “idiopathic” SLE.
8) Subjects with other autoimmune disease as a main diagnosis other than SLE (e.g.; RA, MS).
9) Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, non-SLE pulmonary, non-SLE cardiac, neurological, or cerebral disease; pulmonary and/or cardiac manifestations of SLE shall not constitute an exclusion to study entry. Concomitant medical conditions that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study.
10) Concomitant illness that in the opinion of the investigator, is likely to require additional systemic glucocorticosteroid therapy during the study, (e.g.; asthma) is exculsionary.
11) Female subjects with a breast cancer screening that is suspicious for malignancy and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations.
12) Subjects with a history of cancer within the last five years (other than nonmelanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers must be removed prior to randomization (Day 1 treatment). Carcinoma in situ, treated with definitive surgical intervention, is allowed.
13) Subjects who have a history of clinically significant drug or alcohol abuse. Subjects currently taking methotrexate who admit to consumption of more than an average of 1 alcoholic drink per day.
14) Subjects with any serious bacterial infection (such as pneumonia, renal infection and sinusitis), unless treated and resolved with antibiotics or chronic bacterial infection (such as pyelonephritis, osteomyelitis and lung infection with bronchiectasis) in the previous 3 months.
15) The following subjects will not be allowed in this study:
-Subjects with current clinical or laboratory evidence of active or latent tuberculosis (TB).
-Subjects with a history of active TB treated within the last 3 years.
16) Subjects with herpes zoster that resolved less than 2 months prior to enrollment.
17) 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.
18) Subjects currently on hydroxychloroquine or chloroquine with evidence of retinopathy within 6 months of enrollment or who have had no ophthalmologic evaluation within one year of enrollment and will not have this examination done.
19) Subjects who have at any time received treatment with CTLA4Ig or abatacept.
20) Subjects who have received treatment with any investigational drug within 28 days (or less than 5 terminal half lives of elimination) of the Day 1 dose.
21) Subjects who have at any time received treatment with rituximab.
22) Subjects who have received treatment with cyclophosphamide within the 1 year prior to enrollment. Any subject who has received prior cyclophosphamide and now has non menstrual hematuria will be excluded from the study.
23) Subjects who have received treatment with cyclosporine, another calcineurin inhibitor or other immunosuppressive medication (oral or topical) within 3 months of enrollment.
24) Subjects who have received treatment with gamma globulin within 4 months of enrollment.
Please refer to the section 5.2. of the protocol for additional exclusion criteria. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy measure is the occurrence of SLE disease flare during the 12 month treatment period. The occurrence of flare will be summarized as the proportion of subjects in each of the two treatment arms to experience one or more flares. The treatment difference will be provided along with its 95% confidence interval. In addition, the hazard ratio and its 95% confidence interval, adjusted for the randomization strata using Cochran-Mantel-Haenszel (CMH) methods, will be summarized. Subjects whose active manifestations of lupus at study entry do not remit within 8 weeks of randomization will also be counted as having experienced a lupus flare. |
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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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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