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Oral corticosteroid-sparing study (SIRIUS)

Mepolizumab and oral corticosteroid dose: Steroid Reduction with Mepolizumab Study (SIRIUS)

Bel EH, et al. N Engl J Med 2014;371:1189–97.1

SIRIUS was a randomised, double-blind trial investigating the corticosteroid-sparing effect of s.c. mepolizumab (100 mg) compared with placebo, given every 4 weeks for 20 weeks. The study included 135 patients, aged 16–74 years, with severe asthma who were maintained on OCS (5–25 mg/day) for a minimum of 6 months prior to the study.

Unlike the DREAM and MENSA studies there was no separate requirement in the SIRIUS study for a history of exacerbations, as this population was maintained on daily OCS.

Patients treated with mepolizumab were able to achieve greater reductions in daily OCS dose, while maintaining asthma control, compared with patients treated with placebo. The odds ratio was statistically significant. A larger proportion of patients treated with mepolizumab was able to achieve 50% reductions and reductions to <5 mg in daily OCS dose compared with those treated with placebo.
*This is an unlicensed dose/route of administration.

  • Patient eligibility

    Selected inclusion criteria

    Selected exclusion criteria

    • Documented requirement for regular treatment with:
      • Maintenance systemic corticosteroids (5–35 mg/day prednisone or equivalent)
        and
      • High-dose ICS and additional controller(s)
    • Blood eosinophils:
      • Eosinophil level ≥300 cells/µL that was related to asthma within the 12 months prior to Visit 3
        or
      • Eosinophil level ≥150 cells/µL between Visit 1 and Visit 3
    • Present smoking or >10 pack-year smoking history
    • Concurrent respiratory disease, eosinophilic disease or other substantial uncontrolled morbidity
    • Parasitic infection in the previous 6 months
    • Possibility of pregnancy
    • History of poor treatment adherence
    • Recent treatment with omalizumab or another biologic for inflammatory disease
    • Previous participation in any mepolizumab study

    ICS, inhaled corticosteroids.

  • Endpoints

    Primary endpoint: percent reduction of OCS dose during Weeks 20–24 compared with baseline dose, whilst maintaining asthma control, categorised as follows:

    • 90 to 100%
    • 75 to <90%
    • 50 to <75%
    • >0 to <50%
    • No decrease in OCS, lack of asthma control during Weeks 20–24, or withdrawal from treatment

    Secondary endpoints: during Weeks 20–24, whilst maintaining asthma control:

    • Proportion of patients who achieved a reduction of 50% or greater in their daily OCS dose, compared with baseline dose
    • Proportion of patients who achieved a reduction of OCS dose to ≤5.0 mg
    • Proportion of patients who achieved a total reduction of OCS dose
    • Median percentage reduction in baseline in daily OCS dose

    Additional measurements: annualised rates of asthma exacerbations; FEV1; ACQ-5 and SGRQ scores; safety

  • Efficacy

    Effect of mepolizumab on oral corticosteroid dose

    Primary and secondary outcomes

    Outcome

    Placebo
    (n=66)

    Mepolizumab 100 mg s.c.
    (n=69)

    Odds ratio
    (95% CI)*

    p value

    Reduction in oral glucocorticoid dose at 20–24 weeks: primary outcome – n (%)

     

     

    2.39 (1.25–4.56)

    0.008

    90 to 100%

    7 (11)

    16 (23)

     

     

    75 to <90%

    5 (8)

    12 (17)

     

     

    50 to <75%

    10 (15)

    9 (13)

     

     

    >0 to <50%

    7 (11)

    7 (10)

     

     

    No decrease in oral glucocorticoid dose, a lack of asthma control, or withdrawal from treatment

    37 (56)

    25 (36)

     

     

    Secondary outcomes

    Patients with daily OCS dose reduction of ≥50% – n (%)

    22 (33%)

    37 (54%)

    2.26 (1.10–4.65)

    0.03

    Patients with daily OCS dose reduction to ≤5.0 mg – n (%)

    21 (32%)

    37 (54%)

    2.45 (1.12–5.37)

    0.02

    Patients with 100% OCS dose reduction – n (%)

    5 (8%)

    10 (14%)

    1.67 (0.49–5.75)

    0.41

    Median daily OCS dose reduction from baseline – %§

    0%
    (–20.0 to 33.3)

    50%
    (20.0 to 75.0)

     

    0.007

    *Odds ratios are for the mepolizumab group as compared with the placebo group.
    Data for the primary outcome were analysed with the use of a proportional-odds model (ordered multinomial logistic regression), with terms for study group, region, duration of oral glucocorticoid use at baseline (<5 years vs ≥5 years), and baseline oral glucocorticoid dose during the optimisation phase.
    Data were analysed with the use of a binary logistic-regression model with terms for study group, region, duration of oral glucocorticoid use at baseline (<5 years vs ≥5 years), and baseline oral glucocorticoid dose during the optimisation phase.
    §The median difference and associated CIs were calculated with the use of the Hodges-Lehman estimation. p values were calculated with the use of a Wilcoxon rank-sum test. For patients who withdrew from the study before the maintenance phase, a value equal to the minimum percent reduction in oral glucocorticoid use for all patients was imputed for the analysis.
    CI, confidence interval; OCS, oral corticosteroids; s.c., subcutaneous.
    Adapted from Bel EH, et al. 2014.
    1

    Effect of mepolizumab on exacerbations

    Cumulative rate of clinically significant asthma exacerbations over 24 weeks

    Graph showing cumulative rate of significant asthma exacerbations over 24 weeks with mepolizumab versus placebo.

    Bel, et al. 2014.1
    From N Engl J Med, Bel EH et al, Oral Glucocoticoid-Sparing Effect of Mepolizumab in Eosinophilic asthma. 2014;371:7. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

    Effect of mepolizumab on quality of life

    Change in quality of life measures with mepolizumab

    Graph showing change in ACQ-5 and SGRQ over 24 weeks with mepolizumab or placebo.

    ACQ, Asthma Control Questionnaire; SGRQ, St Georges’ Respiratory Questionnaire.
    Bel, et al. 2014.
    1

    From N Engl J Med, Bel EH et al, Oral Glucocoticoid-Sparing Effect of Mepolizumab in Eosinophilic asthma. 2014;371:7. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

    Non-significant difference in FEV1

    Changes from baseline in pre-bronchodilator FEV1 percent of predicted value

    Graph showing changes from baseline in pre-bronchodilator FEV1 percent of predicted value with mepolizumab or placebo.

    Values are adjusted for covariates.
    FEV1, forced expiratory volume in 1 second; s.c., subcutaneous.
    Bel, et al. 2014.
    1

    From N Engl J Med, Bel EH et al, Oral Glucocoticoid-Sparing Effect of Mepolizumab in Eosinophilic asthma. 2014;371:7. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

  • Safety summary

    The most common drug-related adverse events reported in the SIRIUS study were nausea, headache and injection-site reaction. The incidence of these adverse events was comparable between the mepolizumab and placebo treatment groups.

    Twelve patients (18%) in the placebo group and one patient (1%) in the mepolizumab group experienced non-fatal serious adverse events during the study period. The most common non-fatal severe adverse event was asthma exacerbation (occurring in seven patients [11%] in the placebo group and pneumonia (occurring in three patients [5%] in the placebo group). Neither of these serious adverse events occurred in the mepolizumab group.

    SIRIUS study: Summary of adverse events and serious adverse events with mepolizumab

    Event

    Placebo
    (n=66)

    Mepolizumab
    (n=69)

    No. of patients (%)

    Adverse event

     

     

    Any

    61 (92)

    57 (83)

    Non-asthma

    60 (91)

    57 (83)

    Worsening of asthma

    8 (12)

    2 (3)

    Related to study drug*

    12 (18)

    21 (30)

    Leading to discontinuation of study drug or withdrawal from the study

    3 (5)

    3 (4)

    Serious adverse events

     

     

    During treatment

    12 (18)

    1 (1)

    Fatal

    1 (2)

    0

    *This determination was made by investigators who were unaware of study-group assignments.
    Adapted from Bel EH, et al. 2014.
    1

    Immunogenicity

    A total of 135 patients were evaluated for the presence of mepolizumab anti-drug antibodies. Six patients in the mepolizumab group tested positive during at least one post-baseline visit. No positive test occurred in the placebo group.

    One patient on mepolizumab tested positive for neutralising antibodies at Weeks 13 and 32.

  • Discussion

    At the end of the SIRIUS study, patients treated with mepolizumab had a significantly reduced maintenance OCS dose compared with those receiving placebo. This finding was of note as the patient population had already had their OCS dose optimised to the lowest required for asthma management prior to study treatment initiation.

    In addition to a clinically relevant OCS dose reduction, mepolizumab-treated patients also experienced improvements in exacerbations, asthma control and quality of life compared with the placebo group. These data build on previous studies showing corticosteroid-sparing effects of mepolizumab.2 However, SIRIUS also showed improvements in quality of life and asthma control that were not observed in other studies.

  • Study design and patient baseline characteristics

    SIRIUS was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial lasting 24 weeks.

    The study consisted of four phases:

    1. Optimisation: OCS dose adjusted weekly using a protocol-defined process based on asthma control and using the protocol-defined adjustment table. Once the optimised OCS dose was identified, it had to be maintained for 2 weeks prior to randomisation. The purpose of this phase was to determine the lowest dose of maintenance OCS for acceptable asthma control
    2. Induction phase: 4 weeks following the first dose of study treatment and prior to being assessed for steroid reduction
    3. Reduction phase: OCS dose was adjusted on a monthly basis using protocol-defined titration table. OCS dose reduction decisions were based on protocol-defined objective assessments of asthma (PEF, rescue medication use, etc.)
    4. Maintenance phase: the last 4 weeks of the study following the last dose of study treatment. The primary endpoint analysis was to determine asthma control whilst maintaining OCS dose

    SIRIUS study design

    SIRIUS study design.

    ICS, inhaled corticosteroids; OCS, oral corticosteroids; s.c., subcutaneous.
    Bel, et al. 2014.
    1
    From N Engl J Med, Bel EH et al, Oral Glucocoticoid-Sparing Effect of Mepolizumab in Eosinophilic asthma. 2014;371:7. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

    Baseline patient characteristics

    Characteristic

    Placebo
    (n=66)

    Mepolizumab
    (n=69)

    Mean age (range) – years

    50 (28–70)

    50 (16–74)

    Female sex – n (%)

    30 (45)

    44 (64)

    BMI*

    29.5 ± 6.0

    27.8 ± 5.9

    Former smoker – n (%)

    25 (38)

    28 (41)

    Duration of asthma – years

    20.1 ±14.4

    17.4 ± 11.8

    Median daily oral glucocorticoid dose – mg

     

     

    At screening

    15.0

    12.5

    During optimisation phase

    12.5

    10.0

    Duration of oral glucocorticoid use ≥5 years – n (%)

    31 (47)

    34 (49)

    FEV1 before bronchodilation

     

     

    Mean – litres

    2.00 ± 0.82

    1.90 ± 0.66

    % predicted value

    57.8 ± 18.5

    59.6 ± 17.0

    FEV1:FVC ratio before bronchodilation

    61 ± 11.7

    63 ± 12.4

    Percent FEV1 reversibility

    24.8 ± 18.1

    27.3 ± 17.4

    ACQ-5 score§

    2.0 ± 1.2

    2.2 ± 1.3

    SGRQ score

    45 ± 18

    50 ± 18

    Geometric mean IgE on loge scale – U/mL

    114 ± 1

    117. ± 1

    Geometric mean blood eosinophil count on loge scale – cells/µLǁ

    230 ± 1001

    250 ± 1245

    Severe exacerbations in previous year – n/patient

    2.9 ± 2.8

    3.3 ± 3.4

    Exacerbations in the previous year requiring hospitalisation – n (%)

    9 (14)

    14 (20)

    History of asthma-related intubation – n (%)

    3 (5)

    2 (3)

    Plus–minus values are means (or geometric means) ±SD unless otherwise stated. There were no significant between-group differences at baseline with the exception of sex (p=0.04). Percentages may not total 100 because of rounding.
    *The BMI is the weight in kgs divided by the square of the height in metres.
    Doses are provided as prednisone equivalents.
    The FEV1:FVC ratio was calculated by dividing the FEV1 by the FVC and then multiplying by 100 to express the value as a percentage.
    §Scores on the ACQ-5 range from 0 to 6, with higher scores indicating worse control of asthma; a change of 0.5 points is the minimal clinically important difference.
    Scores on SGRQ range from 0 to 100, with higher scores indicating worse function; a change of 4 units is considered to be clinically relevant.
    ǁValues below the LLQ were replaced by 50% of the LLQ.
    ACQ, Asthma Control Questionnaire; BMI, body mass index; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IgE, immunoglobulin E; LLQ, lower limit of quantification; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire.
    Adapted from Bel EH, et al. 2014.
    1

This medical product is subject to additional monitoring.

References:

  1. Bel EH et al. N Engl J Med 2014; 371:1189–97.
  2. Nair P et al. N Engl J Med 2009;360:985–93.
    Nucala (Mepolizumab) Summary of product characteristics 2016

NUCALA (mepolizumab), 100 mg pulver till injektionsvätska, lösning, 100 mg injektionsvätska, lösning i förfylld spruta, 100 mg injektionsvätska, lösning i förfylld penna. Medel vid obstruktiva luftvägssjukdomar, övriga systemiska medel för obstruktiva lungsjukdomar
Rx (F), ATC kod: R03DX09.
Terapeutiska indikationer: Nucala är indicerat som tilläggsbehandling vid svår refraktär eosinofil astma hos vuxna patienter, ungdomar och barn från 6 års ålder. (För barn 6 till 11 år är endast Nucala 100 mg pulver till injektionsvätska godkänd). Dosering: Rekommenderad dos för mepolizumab hos vuxna och ungdomar från 12 års ålder är 100 mg administrerat subkutant en gång var fjärde vecka. Rekommenderad dos för mepolizumab hos barn från 6 till 11 år är 40 mg administrerat subkutant en gång var fjärde vecka. Nucala är avsett för långtidsbehandling. Behovet av fortsatt behandling ska omprövas minst en gång om året baserat på läkarens bedömning av sjukdomens svårighetsgrad och patientens kontroll över exacerbationer. Ytterligare information: I kliniska studier visades effekt hos följande subpopulation: aktuell standardbehandling som minst inkluderade högdosbehandling med inhalerade kortikosteroider (ICS) plus ytterligare en underhållsbehandling, två eller fler exacerbationer under de senaste 12 månaderna eller beroende av systemiska kortikosteroider samt blodeosinofilvärde minst 150 celler/μl vid behandlingsstart eller minst 300 celler/μl under de senaste 12 månaderna. Kontraindikationer: Överkänslighet mot den aktiva substansen eller mot något hjälpämne. Varningar och försiktighet: För att underlätta spårbarheten av biologiska läkemedel ska den administrerade produktens namn och batchnummer tydligt anges i patientjournalen. Mepolizumab ska inte användas för att behandla akuta astmaexacerbationer. Astmarelaterade biverkningar eller exacerbationer kan förekomma under behandling. Abrupt utsättning av kortikosteroider efter behandlingsstart med mepolizumab rekommenderas ej. Akuta och fördröjda systemiska reaktioner, inklusive överkänslighetsreaktioner (t.ex. anafylaxi, urtikaria, angioödem, hudutslag, bronkospasm, hypotoni), har förekommit efter administrering av mepolizumab. Patienter med befintliga maskinfektioner ska behandlas innan behandling med mepolizumab påbörjas. Om patienten blir infekterad under behandling med Nucala och inte svarar på maskmedel ska temporär utsättning av Nucala övervägas. 
Subventionsbegränsning: Subventioneras endast för patienter med svår eosinofil astma som är otillräckligt kontrollerade trots standardbehandling och antingen behandling med perorala kortikosteroider (OCS) i doser som ger ökad risk för biverkningar eller när OCS är kontraindicerat.

För fullständig förskrivningsinformation och pris, se www.fass.se. Datum för översyn av produktresumén: 2021-06-15. 
GlaxoSmithKline AB, Box 516, 169 29 Solna. Tel 08-638 93 00, www.se.gsk.com.