Clinical trial NCT01858792: A Pooled Analysis of the HGS1006-C1056 (BLISS-52) and HGS1006-C1057 (BLISS-76) Studies
Official title: Efficacy and Safety of Belimumab in a Subgroup of Systemic Lupus Erythematosus (SLE) Patients With Higher Disease Activity (Anti-dsDNA Positive and Low Complement): A Pooled Analysis of the HGS1006-C1056 (BLISS-52) and HGS1006-C1057 (BLISS-76) Studies
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Lupus Erythematosus, Discoid
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2013-05-21
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Subjects who were anti-dsDNA positive and had low C3 and/or C4 at baseline (Low C+anti-dsDNA Population) Subjects with baseline SELENA SLEDAI score \>= 10 (SS \>=10 Population)

Brief summary: Efficacy and Safety of Belimumab in a Subgroup of Systemic Lupus Erythematosus (SLE) Patients with Higher Disease Activity (anti-dsDNA positive and low complement): A Pooled Analysis of the HGS1006-C1056 (BLISS-52) and HGS1006-C1057 (BLISS-76) Studies

Detailed description: Studies C1056 and C1057 followed very similar protocols, were of nearly identical design, had common inclusion and exclusion criteria, and were conducted over the same time period. Nevertheless, given the heterogeneous presentation of SLE disease and the fact that the Phase III program was run globally, variation in the patient population, both within the studies (e.g., between different centres) and between the studies (analogous to differences between centres within the same study) should be expected.

Since it has been established that the conduct of the studies was effectively the same, it then must be determined whether the relative treatment effect is different in one study compared with the other study when evaluating whether two studies are similar enough to pool. Each of these Phase III studies achieved statistical significance for belimumab 10 mg/kg on the pre-specified primary endpoint of SRI response at Week 52; therefore, these nearly identical studies provide independent replication of results. While pooling is not necessary to establish the effectiveness of belimumab, it was considered appropriate in order to evaluate treatment effects in the high disease activity subgroup of interest, given that the individual studies were not designed to provide sufficient power to demonstrate effectiveness within subgroups. Thus, statistical evaluation pooling the studies and testing for a treatment-by-study interaction was undertaken. A significant treatment-by-study interaction would indicate that the relative treatment differences were statistically different in the two studies and pooling would not be justified. Conversely, the lack of a treatment-by-study interaction would indicate the studies resulted in a similar treatment response and pooling would be justified.

When the two Phase III studies were pooled for the SRI analysis, the treatment-by-study interaction was \>0.5. Likewise, for the target population of high disease activity, the treatment-by-study interaction was \>0.7 suggesting that the high disease activity subgroup may be more homogenous and therefore have a more similar treatment effect between the studies than the population as a whole.

Given these considerations, it is reasonable and valid to pool the two studies and allows better precision for evaluation of subgroups.

Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of SLE by ACR criteria.
* Active SLE disease.
* Autoantibody-positive.
* On stable SLE treatment regimen.

Exclusion Criteria:

* Pregnant or nursing
* Have received treatment with any B cell targeted therapy.
* Have received treatment with a biological investigational agent in the past year.
* Have received IV cyclophosphamide within 180 days of Day 0.
* Have severe lupus kidney disease.
* Have active central nervous system (CNS) lupus.
* Have required management of acute or chronic infections within the past 60 days.
* Have current drug or alcohol abuse or dependence.
* Have a historically positive test or test positive at screening for HIV, hepatitis B, or hepatitis C.

Primary outcomes:
measure: SLE (systemic lupus erythematosus) Response Index (SRI) at Week 52
timeFrame: Response rate by visit through Week 52 for the pooled studies and through Week 76 for Study C1056
Secondary outcomes:
measure: The response rate by visit modified to exclude anti-dsDNA and complement items in the determination of a 4-point reduction in SELENA SLEDAI (Safety of Oestrogen in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index).
timeFrame: By visit up to Week 52 for pooled studies.
measure: The percent of subjects with no new BILAG A (British Isles Lupus Assessment Group) organ domain score or 2 new BILAG B organ domain scores
timeFrame: By visit up to Week 52 for pooled studies
measure: Percent of subjects with greater than 4 point reduction from baseline in SELENA SLEDAI (Safety of Oestrogen in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index)
timeFrame: By visit up to Week 52
measure: Mean change in PGA (Physician's Global Assessment)
timeFrame: At Week 24, and by visit up to week 52 (population a only).
measure: All Flares and Severe Flares will be assessed for population a
timeFrame: In periods of Weeks 0-52 and weeks 24-52
measure: All BILAG A (British Isles Lupus Assessment Group) Flares will be assessed for population a
timeFrame: In periods of Weeks 0-52 and Weeks 24-52
measure: Percent of Subjects with Daily Prednisone Dose Reduced to ≤ 7.5 mg/day from > 7.5 mg/day at Baseline by Visit
timeFrame: For pooled studies through Week 52
measure: Mean change in SF-36 (Short Form 36 Health Survey questionnaire) domains (population a only), Physical Component Summary (PCS) and Mental Component Summary MCS (population a only)
timeFrame: By visit up to Week 52
measure: Mean change in FACIT (Functional Assessment of Chronic Illness Therapy) Fatigue Scale score
timeFrame: By visit up to Week 52
measure: EQ-5D (EuroQol five dimension self-reported health state questionnaire) individual item score (mobility, self-care, usual activities, pain/discomfort, anxiety/depression)
timeFrame: Change from baseline by visit up to Week 52
measure: Improvement in each SELENA SLEDAI (Safety of Oestrogen in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index) organ domain
timeFrame: At week 52
measure: Percent of subjects with no worsening in PGA (Physician's Global Assessment)
timeFrame: By visit up to Week 52
measure: Percent of Subjects with Daily Prednisone Dose Increased to > 7.5 mg/day from ≤7.5 mg/day at Baseline by Visit
timeFrame: For pooled studies through Week 52.
measure: Percent of Subjects with Daily Prednisone Dose Reduced by ≥25% and to ≤ 7.5 mg/day from > 7.5 mg/day at Baseline by Visit
timeFrame: For pooled studies through Week 52
measure: Time to first SELENA SLEDAI (Safety of Oestrogen in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index) organ improvement by organ domain, among subjects with involvement at baseline
timeFrame: Over Weeks 0-52
measure: Time to first BILAG organ improvement by organ domain, among subjects with involvement at baseline
timeFrame: Over Weeks 0-52
measure: EQ-5D (EuroQol five dimension self-reported health state questionnaire) index score using value set for the UK
timeFrame: Change from baseline by visit up to Week 52
measure: EQ-5D (EuroQol five dimension self-reported health state questionnaire) visual analogue scale (VAS) score using value set for the UK
timeFrame: Change from baseline by visit up to Week 52
measure: The response rate calculated without allowable and prohibited medication rules applied (population a only).
timeFrame: By visit up to Week 52
Other outcomes:
Locations:
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: van Vollenhoven RF, Petri MA, Cervera R, Roth DA, Ji BN, Kleoudis CS, Zhong ZJ, Freimuth W. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012 Aug;71(8):1343-9. doi: 10.1136/annrheumdis-2011-200937. Epub 2012 Feb 15.