• Something wrong with this record ?

Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials

NA. Hanania, P. Korenblat, KR. Chapman, ED. Bateman, P. Kopecky, P. Paggiaro, A. Yokoyama, J. Olsson, S. Gray, CT. Holweg, M. Eisner, C. Asare, SK. Fischer, K. Peng, WS. Putnam, JG. Matthews,

. 2016 ; 4 (10) : 781-796. [pub] 20160905

Language English Country Great Britain

Document type Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc18017049

BACKGROUND: In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication. METHODS: Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40-80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice-web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061. FINDINGS: 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34-0·69], p<0·0001) and in the 125 mg dose group (RR 0·70 [0·51-0·95], p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 [95% CI 0·54-1·01], p=0·0609; 125 mg: RR 0·74 [0·54-1·02], p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% [1125 of 1432 patients] for both lebrikizumab doses vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group. INTERPRETATION: Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out. FUNDING: F Hoffmann-La Roche.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc18017049
003      
CZ-PrNML
005      
20180515103310.0
007      
ta
008      
180515s2016 xxk f 000 0|eng||
009      
AR
024    7_
$a 10.1016/S2213-2600(16)30265-X $2 doi
035    __
$a (PubMed)27616196
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxk
100    1_
$a Hanania, Nicola A $u Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address: hanania@bcm.edu.
245    10
$a Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials / $c NA. Hanania, P. Korenblat, KR. Chapman, ED. Bateman, P. Kopecky, P. Paggiaro, A. Yokoyama, J. Olsson, S. Gray, CT. Holweg, M. Eisner, C. Asare, SK. Fischer, K. Peng, WS. Putnam, JG. Matthews,
520    9_
$a BACKGROUND: In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication. METHODS: Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40-80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice-web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061. FINDINGS: 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34-0·69], p<0·0001) and in the 125 mg dose group (RR 0·70 [0·51-0·95], p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 [95% CI 0·54-1·01], p=0·0609; 125 mg: RR 0·74 [0·54-1·02], p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% [1125 of 1432 patients] for both lebrikizumab doses vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group. INTERPRETATION: Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out. FUNDING: F Hoffmann-La Roche.
650    _2
$a dospělí $7 D000328
650    _2
$a senioři $7 D000368
650    _2
$a antiastmatika $x aplikace a dávkování $7 D018927
650    _2
$a monoklonální protilátky $x aplikace a dávkování $7 D000911
650    _2
$a bronchiální astma $x krev $x farmakoterapie $7 D001249
650    _2
$a biologické markery $x krev $7 D015415
650    _2
$a molekuly buněčné adheze $x krev $7 D015815
650    _2
$a progrese nemoci $7 D018450
650    _2
$a dvojitá slepá metoda $7 D004311
650    _2
$a eozinofily $x účinky léků $7 D004804
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a lidé $7 D006801
650    _2
$a počet leukocytů $7 D007958
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a lidé středního věku $7 D008875
650    _2
$a výsledek terapie $7 D016896
655    _2
$a klinické zkoušky, fáze III $7 D017428
655    _2
$a časopisecké články $7 D016428
655    _2
$a multicentrická studie $7 D016448
655    _2
$a randomizované kontrolované studie $7 D016449
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Korenblat, Phillip $u The Clinical Research Center LLC, St Louis, MI, USA.
700    1_
$a Chapman, Kenneth R $u Asthma and Airway Centre, University Health Network, University of Toronto, Toronto, ON, Canada; Division of Respiratory Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada.
700    1_
$a Bateman, Eric D $u Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
700    1_
$a Kopecky, Petr $u MediTrial s.r.o, Pulmonary Outpatient Clinic, Jindrichuv Hradec, Czech Republic.
700    1_
$a Paggiaro, Pierluigi $u Department of Surgery, Medicine, Molecular Biology and Critical Care, University of Pisa, Pisa, Italy.
700    1_
$a Yokoyama, Akihito $u Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan.
700    1_
$a Olsson, Julie $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
700    1_
$a Gray, Sarah $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
700    1_
$a Holweg, Cecile T J $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
700    1_
$a Eisner, Mark $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
700    1_
$a Asare, Charles $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
700    1_
$a Fischer, Saloumeh K $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
700    1_
$a Peng, Kun $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
700    1_
$a Putnam, Wendy S $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
700    1_
$a Matthews, John G $u Genentech (a member of the Roche Group), South San Francisco, CA, USA.
773    0_
$w MED00188827 $t The Lancet. Respiratory medicine $x 2213-2619 $g Roč. 4, č. 10 (2016), s. 781-796
856    41
$u https://pubmed.ncbi.nlm.nih.gov/27616196 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20180515 $b ABA008
991    __
$a 20180515103443 $b ABA008
999    __
$a ok $b bmc $g 1300673 $s 1013889
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2016 $b 4 $c 10 $d 781-796 $e 20160905 $i 2213-2619 $m The Lancet Respiratory medicine $n Lancet Respir Med $x MED00188827
LZP    __
$a Pubmed-20180515

Find record

Citation metrics

Archiving options