Article Text

Extended report
A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study
  1. R A Furie1,
  2. G Leon2,
  3. M Thomas3,
  4. M A Petri4,
  5. A D Chu5,
  6. C Hislop5,
  7. R S Martin5,
  8. M A Scheinberg6
  9. for the PEARL-SC Study
  1. 1North Shore–Long Island Jewish Health System, Great Neck, New York, USA
  2. 2Rheumatology Gynecology & Reproduction Institute, Lima, Peru
  3. 3Health and Research Centre, Trivandrum, Kerala, India
  4. 4Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  5. 5Anthera Pharmaceuticals, Hayward, California, USA
  6. 6Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil
  1. Correspondence to Dr Renee Martin, Anthera Pharmaceuticals, Inc. 25801 Industrial Blvd, Suite B., Hayward, CA 94545, USA; rmartin{at}


Objective To evaluate the efficacy and safety of subcutaneous blisibimod, an inhibitor of B cell activating factor, in patients with systemic lupus erythematosus (SLE) in a dose-ranging Phase 2b clinical trial.

Methods 547 patients with SLE with anti-double stranded DNA or antinuclear antibodies and Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline were randomised to receive placebo or blisibimod at one of 3 dose levels. The primary end point, measured at Week 24, was the SLE Responder Index-5 (SRI-5, meeting established SRI criteria but with ≥5 point improvement in SELENA-SLEDAI).

Results Although SRI-5 response rates were not significantly improved in the pooled blisibimod groups compared with placebo, they were higher in subjects randomised to the highest dose of blisibimod (200 mg once-weekly (QW)) compared with pooled placebo, from Week 16 to Week 24, reaching statistical significance at Week 20 (p=0.02). SRI response rates compared with placebo were higher still in subjects who attained SELENA-SLEDAI improvements of ≥8, and in a subgroup of patients with severe disease (SELENA-SLEDAI ≥10 and receiving corticosteroids at baseline). In subjects with protein:creatine ratios of 1–6 at baseline, significant reductions in proteinuria were observed with blisibimod. Significant (p<0.01) changes in anti-double stranded DNA antibodies, complement C3 and C4, and reductions in B cells were observed with blisibimod.

No imbalances in serious adverse events or infections (4/280 and 3/266), deaths (4/280 and 3/266) and malignancies (2/280 and 2/266) were reported for blisibimod compared with placebo.

Conclusions This study successfully identified a safe, effective and convenient dose, study population and end point for evaluation of blisibimod effect in Phase 3.

Trial registration number NCT01162681.

  • Systemic Lupus Erythematosus
  • B cells
  • Autoimmunity

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Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of unknown cause with diverse clinical manifestations that disproportionately affects women especially between the ages of 15 years and 45 years.1 ,2 Hallmarks of SLE are B cell hyperactivity and the production of circulating autoantibodies, for example, to nuclear antigens (ANA) as well as to double stranded DNA (anti-dsDNA). B cell activating factor (BAFF) is a critical survival factor for B cells and, acting via its three cognate receptors (BAFF-receptor, B cell maturation antigen, and transmembrane activator and calcium-modulating cyclophilin ligand interactor), is required for B cell differentiation and survival.3

Blisibimod (A-623, AMG 623) is a biological therapeutic agent composed of four high-affinity BAFF binding domains fused to the Fc domain of human IgG1. Blisibimod selectively inhibits soluble BAFF and membrane-bound BAFF.4 In vivo administration of blisibimod improved survival and disease activity in non-clinical models of autoimmune disease, including NZBxNZW lupus mice, and collagen-induced arthritis.4 In a Phase 1 clinical trial with blisibimod, significant decreases in B cell counts were observed following repeat dosing to patients with SLE.5

BAFF is upregulated in SLE, and peripheral BAFF concentrations have been shown to correlate with disease activity.6 The clinical benefits of BAFF inhibition were demonstrated in Phase 3 clinical trials with an anti-BAFF monoclonal antibody, belimumab.7 ,8 Post hoc analyses of the belimumab Phase 3 studies additionally identified superior responses to belimumab in patients with high disease activity at baseline.9 ,10

This report summarises the findings of a randomised, double-blind, placebo-controlled, Phase 2b study that evaluated the effects of 24-week treatment with blisibimod on disease activity in patients with moderate-to-severe SLE. The primary end point in this study was the SLE Responder Index (SRI-511), a composite endpoint in which responders are defined as meeting all of the following: (1) ≥5-point improvement in SELENA-SLEDAI12 (Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI)), (2) no new British Isles Lupus Assessment Group (BILAG 200413) A organ domain scores or no more than one new BILAG B score, and (3) no worsening in Physician's Global Assessment (PGA)(<0.3-point increase in PGA). Additional secondary analyses evaluated drug effect on alternate measures of disease activity, biomarkers and effects in patient subgroups with different baseline disease characteristics.

Patients and methods

Study design

In this Phase 2 randomised, double-blind, placebo-controlled trial (NCT01162681), subjects who were seropositive for ANA (≥1:80 in immunofluorescence assay) or anti-dsDNA (≥30 IU/mL), and met at least four of the criteria for SLE defined by the American College of Rheumatology (ACR,14) were randomised 1:1:1:1:1:1 in parallel to receive subcutaneous blisibimod in one of three dose levels (100 mg once-weekly (QW), 200 mg QW or 200 mg every 4 weeks), or corresponding volume-matched and frequency-matched placebo. An interactive web response system assigned eligible subjects to the treatment groups using a double-blind schedule based on blocks permuted randomly by a statistician. Randomisation was stratified by baseline SELENA-SLEDAI score (6–9 vs ≥10) and race (African descent or indigenous American vs other). For subjects receiving corticosteroids at baseline, a gradual tapering in corticosteroid was encouraged from Week 12 onwards. Subjects received study drug for a minimum of 24 weeks and up to 52 weeks. Subjects who completed this study were invited to enrol in an open-label extension study (NCT01305746).

The primary end point, SRI-5, evaluated the proportion of responders in the pooled blisibimod groups compared with the pooled placebo groups. Subjects who required increases in background SLE medication, including steroid doses that exceeded the baseline dose by >25% or 5 mg prednisone (or equivalent), or the introduction of new medications, or withdrew from study for any reason were defined as treatment failures for the SRI variable.

Patients’ rights and well-being were ensured through compliance with the provisions of the Declaration of Helsinki, and governmental, state and local laws. Each site obtained ethics committee/institutional review board approval of the final study protocol. Informed consent was obtained from each patient prior to study screening. The trial started in July 2010, and the last patient completed the Week 24 visit in April 2012. The trial was funded by Anthera Pharmaceuticals.

Statistical analyses and sample size

Two interim analyses were conducted by an independent statistician to evaluate (A) the pharmacological assumptions of the trial through change in B cell counts after 24 subjects completed 16 weeks and (B) early stopping for overwhelming efficacy using the SRI-5 end point at Week 24 after enrolment of the 350th subject. No subjects, investigators or individuals directly involved in the trial were unblinded during the interim analyses or prior to database lock at the end of study.

The primary analysis of SRI-5 comparing pooled blisibimod groups with pooled placebo groups at 24 weeks was conducted using linear contrasts of a logistic regression model of SRI response rates. The SRI-5 analysis used the Lan-DeMets method for group sequential trials with levels of significance for the interim and final analyses of 0.01087 and 0.04664, respectively. The evaluation of sample size and power was informed by the Phase 3 clinical trials with belimumab where SRI-5 responder rates of 38.9% and 24.9% were observed in SLE subjects treated with belimumab (10 mg/kg intravenous) or placebo, respectively.15 Assuming similar responder rates, and a target enrolment of 240 subjects per group, the estimated power to detect a treatment effect with two-sided α of 0.04664 was 90.5%.

Secondary end points were evaluated without correction for multiplicity. Prospectively defined evaluations were undertaken to determine the effect of blisibimod using modified versions of the SRI in which subjects were required to achieve greater improvements in SELENA-SLEDAI of ≥6 (SRI-6), ≥7 (SRI-7), ≥8 (SRI-8) in order to be considered responders. The effect of treatment on SLE flares was evaluated using the SLE flare index12 ,16 and analysed using a Cox proportional hazards regression model with covariates as used in the logistic regression model for the primary end point. Subjects who did not experience a flare were censored for that time point in the analysis. Reduction of prednisone dose among subjects taking >7.5 mg/day prednisone or equivalent at baseline was assessed using the logistic regression model used for the primary end point. Continuous variables including proteinuria (from protein:creatine ratios from spot urine), complement C3 and C4, anti-dsDNA and B cells, the absolute and per cent change from baseline were evaluated using an analysis of covariance (ANCOVA) model.


The study was conducted in Argentina, Brazil, Chile, Colombia, Hong Kong, India, Mexico, Peru, the Philippines, Taiwan and USA. The study enrolled 547 adults (≥18 years) with seropositive SLE (positive for either or both ANA or anti-dsDNA) who fulfilled at least four of the criteria for SLE defined by ACR (1997), and had a SELENA-SLEDAI score ≥6. All subjects were required to have been treated for SLE for at least 2 months, and to have been on a stable treatment regimen for at least 30 days prior to enrolment.

Patients were excluded from the study if they had severe lupus nephritis, central nervous system (CNS) lupus or severe vasculitis. Additional exclusion criteria were: infection with HIV or hepatitis B or C, or tuberculosis; malignancy in the last 5 years; treatment within protocol-specified periods prior to enrolment with B cell targeted drug or investigational products, cyclophosphamide or other alkylating agent, transfusion, intravenous immunoglobulin, plasmapheresis, plasma exchange, high-dose corticosteroid, anti-TNFα, ciclosporin or live vaccines.


Patient demographics and disposition

Eight hundred and sixty-seven subjects were screened, and 547 enrolled in the study (figure 1). One subject received no study medication and was excluded from analysis. The remaining subjects were followed through a minimum of 24 weeks or until withdrawal from the study. The most common reasons for withdrawal were adverse events and withdrawal of consent. No dose-related trends were noted in subject withdrawals. Retention of subjects through the completion of the study was relatively high (81%), and withdrawal rates were balanced between blisibimod (18.4%) and placebo arms (19.6%). Thirteen subjects (2.4%) were withdrawn from study due to structural failure (cracking) of vials of investigational product. At the end of study, after the last patient enrolled completed 24 weeks of study drug therapy, 382 subjects enrolled in the companion open-label extension study. Over 10% of the subjects enrolled in the PEARL -SC study were not able to enrol in the extension study owing to delayed approvals for study conduct in some institutions.

Figure 1

Disposition of subjects. Definitions of abbreviations in this figure—Admin Decision: Administrative decision by Investigator or Sponsor; Protocol Viol.: Protocol violation; Non-compliance: Subject non-compliance; Prohibited meds: Use of prohibited medication; Study on hold: Study on hold as per sponsor decision. Study was halted from 16 November 2010 to 27 December 2010 due to structural failure of vials of investigational product.

Patient demographics, baseline disease characteristics and SLE medications were similar across all treatment groups (table 1), with the exception of immunosuppressive use which was somewhat higher in the placebo subjects (52.3% of placebo subjects and 38.2% of blisibimod subjects). At randomisation, background medication predominantly consisted of monotherapy or combination therapy with oral corticosteroids, antimalarials and/or immunosuppressants. Based on accepted clustering of SELENA-SLEDAI organ domains,17 common manifestations at baseline were mucocutaneous (91%), immunological (low complement or increased DNA binding) (77%) and musculoskeletal (75%). Renal involvement was observed in 14% of the subjects.

Table 1

Demographics and baseline disease characteristics

SRI responder rates

The interim efficacy analysis failed to meet the criteria for stopping the study early for overwhelming efficacy (ie, p<0.01087), and the study continued towards completion. Efficacy analyses were conducted at the end of the study on the modified intent to treat (mITT) population, comprised of all subjects who received at least one dose of study drug. As there were no significant differences between the SRI-5 responder rates among the three placebo regimens, data from these three groups was pooled. The primary efficacy end point, the SRI-5 improvement in the pooled blisibimod groups compared with the pooled placebo groups at Week 24, was not met (table 2). However, the proportion of responders in the highest blisibimod dose group, 200 mg QW, was greater than the pooled placebo groups and the regimen-matched placebo group from Week 12 to Week 36 (table 2). Significantly more SRI-5 responders were observed at Week 20 in subjects randomised to this blisibimod dose compared with placebo (p=0.02).

Table 2

SRI responder rates in the mITT population and in the ‘severe’ SLE subgroup

Similar trends were observed using modified SRI responses, SRI-6. SRI-7 and SRI-8, with the highest responder rates occurring with 200 mg QW blisibimod. The average numbers of subjects at risk in the SRI-7 and SRI-8 analyses were 77 and 76 per treatment arm, and significant improvements were observed with 200 mg QW blisibimod compared with regimen-matched placebo (p=0.003 and p=0.001, respectively, table 2, figure 2A,B). Although the number of subjects meeting the SRI-7 and SRI-8 criteria was lower than with the SRI-5 end point, the differences between treatment and placebo responder rates (ΔSRI) was higher. The increase in ΔSRI between SRI-5 and SRI-8 can be attributed to the decrease in placebo response with increasing SELENA-SLEDAI threshold from 5 points to 8 points.

Figure 2

Effects of blisibimod on measures of systemic lupus erythematosus (SLE) disease activity (A) and (B) Proportions subjects who achieve the SLE Responder Index-5 (SRI-5), and SRI-8 end point in the modified intent to treat (mITT) population through Week 24. (C) Proportions subjects in the ‘severe’ SLE subgroup (Safety of Estrogens in Lupus Erythematosus National Assessment - SLE Disease Activity Index (SELENA-SLEDAI) ≥10 and receiving steroid at baseline) who achieve the SRI-8. At all time points through Week 24, SRI responder rates with blisibimod were compared with pooled placebo (*p<0.05) and regimen-matched placebo (#p<0.05, ##p<0.01, ###p<0.001). Effects of blisibimod on severe SLE flare are shown in figures (D) Kaplan Meier curve showing the probability of no severe SLE flare, and (E) Time to first severe SLE flare. Severe SLE flare is defined using the SELENA-SLEDAI SLE Flare Index as having a >12-point increase in SELANA-SLEDAI, or increase in prednisone of >0.5 mg/kg/day (or equivalent), or use of new cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate or hospitalisation for SLE, or an increase to >2.5 in Physician's Global Assessment. (F) Effects of blisibimod on the proportion of subjects who achieved a reduction in background corticosteroid dose to ≤7.5 mg/day prednisone (or equivalent) compared with baseline.

SRI analyses were conducted in a subgroup of patients (N=278) with high baseline disease activity, defined as SELENA-SLEDAI ≥10, and receiving systemic corticosteroid. Henceforth, this subgroup will be referred to as ‘severe’ SLE. As with the mITT population, significant improvements in SRI-7 and SRI-8 responder rates were observed with blisibimod compared with regimen-matched placebo (p=0.002 and p<0.001, table 2), with higher ΔSRIs than observed in the mITT population.

Effects on SLE Flare, SELENA-SLEDAI, BILAG, PGA, corticosteroid use and urinary protein

Based on the SLE Flare Index, favourable trends in the cumulative probability of severe flare, and time to first severe flare, were observed at the highest dose of blisibimod (200 mg QW, Cox proportional hazard p=0.22, figure 2D–E). While the proportion of subjects achieving a ≥5-point improvement in SELENA-SLEDAI was similar among subjects randomised to blisibimod (37.5% across all arms) compared with placebo (36.8%), more profound improvements were observed at the highest blisibimod dose (43.5%). The percentage of subjects with no new BILAG 1A or 2B manifestations, which was high throughout the study (74.7% in the pooled placebo group), was generally higher in the 200 mg QW blisibimod group (78.3%). Similarly, high proportions of subjects randomised to placebo or 200 mg QW blisibimod had no worsening of the PGA (72.9% and 76.1%, respectively).

At the time of enrolment, 88.8% of subjects were taking oral corticosteroids. Efforts to taper below the baseline dose were encouraged after Week 12 at the physician's discretion. Among subjects receiving >7.5 mg/day of prednisone or equivalent at enrolment (N=327), a modest increase in the proportion of subjects achieving a daily prednisone dose ≤7.5 mg was observed in subjects receiving 200 mg QW blisibimod compared with placebo from Week 16 to Week 24 (11.9% and 9.5% for pooled blisibimod and pooled placebo, respectively, at Week 24, figure 2F).

In a subgroup of subjects with baseline urinary protein:creatine ratio of 1–6 g/g (N=54), significantly greater reductions in proteinuria were observed with pooled blisibimod compared with pooled placebo from Week 8 to Week 24 (figure 3A). Mean reductions in protein:creatine ratio of 0.73 (−35.0%, p=0.045) and 0.24 (−5.1%) were observed at Week 24 for blisibimod and placebo, respectively.

Figure 3

Effects of blisibimod on systemic lupus erythematosus (SLE) biomarkers. (A) Significant decrease in mean per cent change in protein:creatine ratio (a ratio of 1 may be considered to be equivalent to 1 g/24 h proteinuria18). (B) and (C) Significant increases in complement cascade C3 and C4 were observed in patients in the blisibimod treatment arms compared with placebo. (D) and (E) Significant decreases in anti-double stranded DNA (anti-dsDNA) autoantibodies (mean absolute change and mean per cent change) and total B cell counts (CD19+CD20+) determined by flow cytometry were observed with blisibimod (all dosing regimens) compared with placebo (all dosing regimens). Data for pooled blisibimod (N=277) and pooled placebo (N=269) are presented. (F) Normalisation of SLE biomarkers at Week 24 in subjects who were positive for anti-dsDNA (>30 IU/mL), or had low C3 (<0.9 g/L) or C4 (<0.16 g/L) at baseline and became normal at the end of 24 weeks of study drug therapy. In panels A–E, data are plotted as means and SEMs, and pooled blisibimod response was compared with pooled placebo response at all time points through Week 24 (*p<0.05, **p<0.01, ***p<0.001).

Effects on biomarkers

Significant reductions in B cells were observed in the pooled blisibimod groups at the interim analysis, confirming the pharmacological assumptions of the study. At the end of the study, treatment with blisibimod was associated with statistically significant increases from baseline in serum concentrations of complement C3 and C4, and decreases from baseline in the per cent of CD19+CD20+ B cells and the concentration of anti-dsDNA autoantibodies in serum (figure 3B–E). There was a greater tendency towards normalisation of high anti-dsDNA to normal range (≤30 IU/mL), and normalisation of low C3 and low C4 to normal range (C3≥0.9 g/L and C4≥0.16 g/L, figure 3F). Immunoglobulins IgG and IgM were also decreased significantly in patients in the pooled blisibimod groups compared with placebo (p<0.01 by Week 16) without discernable change to infection risk or peripheral counts of white blood cells including monocytes, lymphocytes and neutrophils.


Blisibimod was generally safe and well tolerated at all dose levels (table 3). There were no meaningful differences between the numbers of subjects reporting adverse events or discontinuing due to adverse events in the placebo and blisibimod groups, including the highest blisibimod dose (200 mg QW). Fewer blisibimod-treated subjects reported serious adverse events compared with placebo (11.1 and 15.8%, respectively), and there were no differences between blisibimod and placebo in the number of subjects reporting severe infections, death or neoplasm. Injection site reactions were reported more frequently with blisibimod compared with placebo. Of the injection site reactions reported, injection site erythema was most common, occurring in 2/266 (0.8%) on placebo and 36/280 (12.9%) on blisibimod. No injection site reaction was reported as serious or severe in nature and no anaphylactic reactions were reported. Seven deaths were reported during this study. Three deaths (3/266, 1.1%) were reported in subjects randomised to placebo: cardiorespiratory arrest secondary to pneumonia, cardiac arrest and bronchopneumonia. Four deaths (4/280, 1.4%) were reported in subjects randomised to blisibimod: myocardial infarction, septic shock (two subjects) and respiratory failure. Four neoplasms (benign or malignant) were reported during the study: two placebo subjects with giant cell tumour of tendon sheath or Morton's neuroma, and two blisibimod subjects with skin papilloma or uterine leiomyoma.

Table 3

Treatment-emergent adverse events during blinded treatment with Blisibimod

An electrochemiluminescent assay was used to evaluate the presence of antidrug antibodies to blisibimod. However, since high rates of assay positivity were observed in blisibimod naïve subjects (prestudy and placebo), possibly due to matrix interference from SLE serum constituents, for example, rheumatoid factor, further refinement of the assay method is warranted.


The results of the Phase 2 PEARL-SC study support the continuing development of blisibimod as a therapeutic for patients with SLE. Importantly, design features were identified that provide opportunities to increase the probability of success of clinical trials in patients with SLE. Prior studies established that treatment with a BAFF inhibitor improves disease activity in SLE,7 ,8 and that the greatest benefit appears to be in the most severely active patients.10 The PEARL-SC trial found that baseline disease severity and choice of end point are critical to evaluating the benefit of the medication. Specifically, in addition to identifying a safe, well-tolerated, efficacious and convenient dose of blisibimod (200 mg QW), this study established a patient population likely to benefit from blisibimod therapy (‘severe’ SLE: SELENA-SLEDAI ≥10 and receiving a corticosteroid), and an end point (SRI-8) that optimises the ability to discern clinical benefit over background therapy. In particular, although a trend towards SRI-5 improvement was observed with 200 mg QW blisibimod in the mITT population, the improvements over placebo were greater in subjects with ‘severe’ SLE (Week 24 ΔSRI-5=8.7% and 13.8%, respectively), and greater still when evaluated using the SRI-8 end point (Week 24 ΔSRI-8=17.4% and 31.1%, respectively). The use of higher thresholds of improvement in SELENA-SLEDAI score is consistent with the ACR-recommended measures of disease activity, which defines an improvement in the SELENA-SLEDAI score >7 points or a worsening of >8 points as clinically meaningful.19

Some limitations in the study design are acknowledged. Although double-blinded administration of study drug was maintained throughout the study, knowledge of subjects’ visit frequency (eg, every 1 week or 4 weeks) or dose volume (for 100 mg or 200 mg blisibimod or corresponding placebo regimens) may have biased scoring of disease activity or decisions relating to background therapy or safety assessment. The use of immunosuppressives was less frequent among subjects randomised to blisibimod compared with placebo, especially at the two lower dosing regimens where subjects theoretically may have had a treatment disadvantage. Sensitivity analyses to evaluate this imbalance have not been undertaken. Finally, there was no statistical correction for multiplicity for any secondary analyses in this study.

The observed pharmacodynamic effects of blisibimod in patients with SLE are similar to those reported for belimumab. The significant reductions in proteinuria and anti-dsDNA, and significant increases in C3 observed with blisibimod and belimumab, as well as the rapid and significant reductions in peripheral plasma cells reported with belimumab9 ,20 support a therapeutic benefit of BAFF inhibitors in renal manifestations of SLE.22 Other renal diseases with histologies that feature renal deposition of autoantibody-containing immune complexes, such as lupus nephritis and IgA nephropathy,23–25 may similarly benefit from blisibimod therapy. In addition, the findings of the PEARL-SC study, including the favourable safety observations, support further evaluation of blisibimod in patients with severe active SLE achieving substantial SRI improvements (eg, SRI-8). A focus on subjects with severe SLE is especially important as current treatment options for this patient subset include drugs with unacceptable toxicities.26 ,27


The authors acknowledge the contributions of the patients enrolled in this study as well as the PEARL-SC study team.

R A Furie,1 G Leon,2 M Thomas,3 M A Petri,4 A D Chu,5 C Hislop,5 R S Martin,5 M A Scheinberg6; for the PEARL-SC Study.


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Supplementary materials

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  • Handling editor Tore K Kvien

  • Contributors The data reported in this manuscript were generated by the Investigators in Latin America, Asia and the USA who participated in the PEARL-SC trial. RAF, MAP, ADC, CH, RSM were involved in the design, conduct and/or analysis of data. The guidance of GL, MT and MAS in addition to their roles as study investigators was critical to the generation and interpretation of the data.

  • Funding This sponsorship of this clinical trial by Anthera Pharmaceuticals included all funding and oversight of all clinical operations, laboratory analyses, data collection, statistical analyses, drug manufacturing and distribution to conduct and complete the trial.

  • Competing interests RAF and MAP are current or prior consultants for the sponsor, Anthera Pharmaceuticals. RAF and MAP, GL, MT, MAS were clinical investigators in this trial. ADC, CH and RSM are current or previous employees and shareholders in Anthera Pharmaceuticals.

  • Ethics approval Multiple EC/IRBs in Latin America, Asia, USA.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data for this study are housed at Anthera Pharmaceuticals (contact