A Phase IIB, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept in Combination Therapy with Glucocorticosteroids vs. Placebo plus Glucocorticosteroids in the Treatment of Active Systemic Lupus Erythematosus and the Prevention of Subsequent Lupus Flares. Revised Protocol 03: Incorporates Amendments 2, 3 & 5 (v1.0, Date 22-Jun-2007). Protocol Amendment 1 - Site Specific. And Protocol Amendment 04: Long Term Extension (v 3.0, dated 30-Aug-2006).

• Register: EUCTR
• Last refreshed on: 1 May 2012
• Main ID: EUCTR2004-004051-19-DE
• Date of registration: 22/03/2005
• Prospective Registration: Yes
• Primary sponsor: Bristol-Myers Squibb International Corporation
• Public title: A Phase IIB, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept in Combination Therapy with Glucocorticosteroids vs. Placebo plus Glucocorticosteroids in the Treatment of Active Systemic Lupus Erythematosus and the Prevention of Subsequent Lupus Flares. Revised Protocol 03: Incorporates Amendments 2, 3 & 5 (v1.0, Date 22-Jun-2007). Protocol Amendment 1 - Site Specific. And Protocol Amendment 04: Long Term Extension (v 3.0, dated 30-Aug-2006).
• Scientific title: A Phase IIB, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept in Combination Therapy with Glucocorticosteroids vs. Placebo plus Glucocorticosteroids in the Treatment of Active Systemic Lupus Erythematosus and the Prevention of Subsequent Lupus Flares. Revised Protocol 03: Incorporates Amendments 2, 3 & 5 (v1.0, Date 22-Jun-2007). Protocol Amendment 1 - Site Specific. And Protocol Amendment 04: Long Term Extension (v 3.0, dated 30-Aug-2006).
• Date of first enrolment: 13/05/2005
• Target sample size: 250
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2004-004051-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Germany, Italy, Sweden, United Kingdom

Key inclusion & exclusion criteria

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.

Are the tri
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 o

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

SYSTEMIC LUPUS ERYTHEMATOSUS, NOS

Intervention(s)

Product Name: Abatacept
Product Code: BMS-188667
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Abatacept
CAS Number: 332348-12-6
Current Sponsor code: BMS-188667
Other descriptive name: CTLA4Ig
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Secondary Objective: 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

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.

Main Objective: 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.

Secondary ID(s)

IM101-042