A Pooled Analysis of the HGS1006-C1056 (BLISS-52) and HGS1006-C1057 (BLISS-76) Studies

Lupus Erythematosus, Discoid Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01858792
• Other study ID #: 115030
• Status: Completed
• Phase: N/A
• First received: December 19, 2012
• Last updated: May 16, 2013
• Start date: May 2011
• Est. completion date: June 2011

Study information

• Verified date: May 2013
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Paul-Ehrlich InstituteAustria: Agency for Health and Food SafetyFrance: Ministry of HealthSlovenia: Ministry of Health Agency for Medicinal ProductsUnited States: Food and Drug AdministrationBelgium: Belgian Federal Agency for Medicinal and Health ProductsPoland: Ministry of HealthItaly: Ministry of HealthSweden: Medical Products AgencyNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Czech Republic: State Institute for Drug Control
• Study type: Observational

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

N/A

Related Conditions & MeSH terms

• Lupus Erythematosus, Discoid
• Lupus Erythematosus, Systemic

Intervention

Drug:
• Belimumab 1 mg/kg
Belimumab 1 mg/kg IV plus standard therapy; belimumab 1 mg/kg administered on Days 0, 14, 28, and every 28 days thereafter through 72 weeks.
• Belimumab 10 mg/kg
Belimumab 10 mg/kg IV plus standard therapy; belimumab 10 mg/kg administered on Days 0, 14, 28, and every 28 days thereafter through 72 weeks.

Other:
• Placebo
Placebo IV plus standard therapy; placebo administered on Days 0, 14, 28, and every 28 days thereafter through 72 weeks.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Human Genome Sciences Inc., a GSK Company	GlaxoSmithKline

References & Publications (1)

R.F. van Vollenhoven,1 M.A. Petri,2 R. Cervera,3 D. Roth,4 B. Ji,5 C. Kleoudis,6 Z. John Zhong,7 W. Freimuth,7 for the BLISS-52 and BLISS-76 Study Groups. Response of Systemic Lupus Erythematosus Patients With High Disease Activity to Belimumab Treatment in the BLISS Trials . [Ann Rheum Dis]. 2012;71(8):1343-9.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	SLE (systemic lupus erythematosus) Response Index (SRI) at Week 52	Composite endpoint resulting from the combination of three well-established tools for evaluating SLE disease activity which include an objective measure of the reduction in global disease activity for efficacy and two measures to ensure that the improvement in disease activity (score) is not offset by worsening of the subject's condition overall.	Response rate by visit through Week 52 for the pooled studies and through Week 76 for Study C1056	No
Secondary	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).		By visit up to Week 52 for pooled studies.	No
Secondary	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		By visit up to Week 52 for pooled studies	No
Secondary	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)		By visit up to Week 52	No
Secondary	Mean change in PGA (Physician's Global Assessment)		At Week 24, and by visit up to week 52 (population a only).	No
Secondary	All Flares and Severe Flares will be assessed for population a	Number of subjects experiencing a flare/severe flare (Weeks 0-52 and Weeks 24-52). Time to 1st flare/severe flare (Weeks 0-52 and Weeks 24-52.) Flares/Severe flares per subject year (Weeks 0-52).	In periods of Weeks 0-52 and weeks 24-52	No
Secondary	All BILAG A (British Isles Lupus Assessment Group) Flares will be assessed for population a	Number of subjects experiencing a BILAG A flare (Weeks 0-52 and Weeks 24-52). Time to 1st BILAG A flare (Weeks 0-52 and Weeks 24-52). BILAG A flares per subject year (Weeks 0-52).	In periods of Weeks 0-52 and Weeks 24-52	No
Secondary	Percent of Subjects with Daily Prednisone Dose Reduced to = 7.5 mg/day from > 7.5 mg/day at Baseline by Visit		For pooled studies through Week 52	No
Secondary	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)		By visit up to Week 52	No
Secondary	Mean change in FACIT (Functional Assessment of Chronic Illness Therapy) Fatigue Scale score		By visit up to Week 52	No
Secondary	EQ-5D (EuroQol five dimension self-reported health state questionnaire) individual item score (mobility, self-care, usual activities, pain/discomfort, anxiety/depression)		Change from baseline by visit up to Week 52	No
Secondary	Improvement in each SELENA SLEDAI (Safety of Oestrogen in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index) organ domain		At week 52	No
Secondary	Percent of subjects with no worsening in PGA (Physician's Global Assessment)		By visit up to Week 52	No
Secondary	Percent of Subjects with Daily Prednisone Dose Increased to > 7.5 mg/day from =7.5 mg/day at Baseline by Visit		For pooled studies through Week 52.	No
Secondary	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		For pooled studies through Week 52	No
Secondary	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		Over Weeks 0-52	No
Secondary	Time to first BILAG organ improvement by organ domain, among subjects with involvement at baseline		Over Weeks 0-52	No
Secondary	EQ-5D (EuroQol five dimension self-reported health state questionnaire) index score using value set for the UK		Change from baseline by visit up to Week 52	No
Secondary	EQ-5D (EuroQol five dimension self-reported health state questionnaire) visual analogue scale (VAS) score using value set for the UK		Change from baseline by visit up to Week 52	No
Secondary	The response rate calculated without allowable and prohibited medication rules applied (population a only).		By visit up to Week 52	No