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. 2021 Oct 19;10(10):CD012929.
doi: 10.1002/14651858.CD012929.pub2.

Anti-interleukin-13 and anti-interleukin-4 agents versus placebo, anti-interleukin-5 or anti-immunoglobulin-E agents, for people with asthma

Andrew Gallagher  1 , Michaela Edwards  2 , Parameswaran Nair  3 , Stewart Drew  4 , Aashish Vyas  5 , Rashmi Sharma  6 , Paul A Marsden  5   7   8 , Ran Wang  9   8 , David Jw Evans  10
Affiliations

Anti-interleukin-13 and anti-interleukin-4 agents versus placebo, anti-interleukin-5 or anti-immunoglobulin-E agents, for people with asthma

Andrew Gallagher et al. Cochrane Database Syst Rev. .

Abstract

Background: Targeting the immunoglobulin E pathway and the interleukin-5 pathway with specific monoclonal antibodies directed against the cytokines or their receptors is effective in patients with severe asthma. However, there are patients who have suboptimal responses to these biologics. Since interleukin-4 and interleukin-13, signalling through the interleukin-4 receptor, have multiple effects on the biology of asthma, therapies targeting interleukin-4 and -13 (both individually and combined) have been developed.

Objectives: To assess the efficacy and safety of anti-interleukin-13 or anti-interleukin-4 agents, compared with placebo, anti-immunoglobulin E agents, or anti-interleukin-5 agents, for the treatment of children, adolescents, or adults with asthma.

Search methods: We identified studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist for the Group and through searches of the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The search was carried out on the 16 October 2020.

Selection criteria: We included parallel-group randomised controlled trials that compared anti-interleukin-13 or -4 agents (or agents that target both interleukin-13 and interleukin-4) with placebo in adolescents and adults (aged 16 years or older) or children (younger than 16 years), with a diagnosis of asthma; participants could receive their usual short- or long-acting medications (e.g. inhaled corticosteroids (ICS), long-acting beta adrenoceptor agonists (LABA), long-acting muscarinic antagonists (LAMA), and/or leukotriene receptor antagonists) provided that they were not part of the randomised treatment.

Data collection and analysis: We used standard methods expected by Cochrane.

Main results: We identified and included 41 RCTs. Of these, 29 studies contributed data to the quantitative analyses, randomly assigning 10,604 people with asthma to receive an anti-interleukin-13 (intervention) or anti-interleukin-4 agent (intervention), or placebo (comparator). No relevant studies were identified where the comparator was an anti-immunoglobulin agent or an anti-interleukin-5 agent. Studies had a duration of between 2 and 52 (median 16) weeks. The mean age of participants across the included studies ranged from 22 to 55 years. Only five studies permitted enrolment of children and adolescents, accounting for less than 5% of the total participants contributing data to the present review. The majority of participants had moderate or severe uncontrolled asthma. Concomitant ICS use was permitted or required in the majority (21 of 29) of the included studies. The use of maintenance systemic corticosteroids was not permitted in 19 studies and was permitted or required in five studies (information not reported in five studies). Regarding the most commonly assessed anti-interleukin-13/-4 agents, four studies evaluated dupilumab (300 mg once every week (Q1W), 200 mg once every two weeks (Q2W), 300 mg Q2W, 200 mg once every four weeks (Q4W), 300 mg Q4W, each administered by subcutaneous (SC) injection); eight studies evaluated lebrikizumab (37.5 mg Q4W, 125 mg Q4W, 250 mg Q4W each administered by SC injection); and nine studies (3259 participants) evaluated tralokinumab (75 mg Q1W, 150 mg Q1W, 300 mg Q1W, 150 mg Q2W, 300 mg Q2W, 600 mg Q2W, 300 mg Q4W, each administered by SC injection; 1/5/10 mg/kg administered by intravenous (IV) injection); all anti-interleukin-13 or-4 agents were compared with placebo. The risk of bias was generally considered to be low or unclear (insufficient detail provided); nine studies were considered to be at high risk for attrition bias and three studies were considered to be at high risk for reporting bias. The following results relate to the primary outcomes. The rate of exacerbations requiring hospitalisation or emergency department (ED) visit was probably lower in participants receiving tralokinumab versus placebo (rate ratio 0.68, 95% CI 0.47 to 0.98; moderate-certainty evidence; data available for tralokinumab (anti-interleukin-13) only). In participants receiving an anti-interleukin-13/-4 agent, the mean improvement versus placebo in adjusted asthma quality of life questionnaire score was 0.18 units (95% CI 0.12 to 0.24; high-certainty evidence); however, this finding was deemed not to be a clinically relevant improvement. There was likely little or no difference between groups in the proportion of patients who reported all-cause serious adverse events (anti-interleukin-13/-4 agents versus placebo, OR 0.91, 95% CI 0.76 to 1.09; moderate-certainty evidence). In terms of secondary outcomes, there may be little or no difference between groups in the proportion of patients who experienced exacerbations requiring oral corticosteroids (anti-interleukin-13/-4 agents versus placebo, rate ratio 0.98, 95% CI 0.72 to 1.32; low-certainty evidence). Anti-interleukin-13/-4 agents probably improve asthma control based on asthma control questionnaire score (anti-interleukin-13/-4 agents versus placebo, mean difference -0.19; 95% CI -0.24 to -0.14); however, the magnitude of this result was deemed not to be a clinically relevant improvement. The proportion of patients experiencing any adverse event was greater in those receiving anti-interleukin-13/-4 agents compared with those receiving placebo (OR 1.16, 95% CI 1.04 to 1.30; high-certainty evidence); the most commonly reported adverse events in participants treated with anti-interleukin-13/-4 agents were upper respiratory tract infection, nasopharyngitis, headache and injection site reaction. The pooled results for the exploratory outcome, the rate of exacerbations requiring oral corticosteroids (OCS) or hospitalisation or emergency department visit, may be lower in participants receiving anti-interleukin-13/-4 agents versus placebo (rate ratio 0.71, 95% CI 0.65 to 0.77; low-certainty evidence). Results were generally consistent across subgroups for different classes of agent (anti-interleukin-13 or anti-interleukin-4), durations of study and severity of disease. Subgroup analysis based on category of T helper 2 (TH2) inflammation suggested greater efficacy in patients with higher levels of inflammatory biomarkers (blood eosinophils, exhaled nitric oxide and serum periostin).

Authors' conclusions: Based on the totality of the evidence, compared with placebo, anti-interleukin-13/-4 agents are probably associated with a reduction in exacerbations requiring hospitalisation or ED visit, at the cost of increased adverse events, in patients with asthma. No clinically relevant improvements in health-related quality of life or asthma control were identified. Therefore, anti-interleukin-13 or anti-interleukin-4 agents may be appropriate for adults with moderate-to-severe uncontrolled asthma who have not responded to other treatments. These conclusions are generally supported by moderate or high-certainty evidence based on studies with an observation period of up to one year.

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Conflict of interest statement

Andrew Gallagher: None known.

Michaela Edwards: None known.

Parameswaran Nair: In the past 2 years, has received research grants from Roche, Teva, Sanofi, AZ, Novartis, and BI, and has provided consultation and received honoraria from Roche, Teva, Sanofi, AZ, Novartis, Theravance, Knopp.

Drew Stuart: None known.

Aashish Vyas: None known.

Rashmi Sharma: None known.

Paul A Marsden: Has received lecture fees and conference accommodation and fees from industry and a resarch grant from Merck unrelated to the current review.

Ran Wang: None known.

David JW Evans: Provides freelance medical writing services to medical communications agencies.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Forest plot of comparison: 1 Anti‐interleukin‐13 or ‐4 agents with placebo, outcome: 1.1 Exacerbation requiring hospitalisation or ED visit.
5
5
Forest plot of comparison: 1 Anti‐interleukin‐13 or ‐4 agents with placebo, outcome: 1.2 Health‐related quality of life (adjusted mean diff versus placebo). A change of 0.5 is considered the minimum clinically significant difference (MCID).
1.1
1.1. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 1: Exacerbation requiring hospitalisation or ED visit
1.2
1.2. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)
1.3
1.3. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 3: Serious adverse events
1.4
1.4. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 4: Exacerbation requiring OCS (rate ratio)
1.5
1.5. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 5: Exacerbation requiring OCS (dichotomous)
1.6
1.6. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 6: Change from baseline in pre‐bronchodilator FEV1
1.7
1.7. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 7: Change from baseline in ACQ score
1.8
1.8. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 8: Adverse events
1.9
1.9. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 9: Change from baseline in FENO, ppb
1.10
1.10. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 10: Change from baseline in blood eosinophils, cells x 10*9/L
1.11
1.11. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 11: Change from baseline in periostin, ng/mL
1.12
1.12. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 12: Percentage reduction from baseline in OCS use
1.13
1.13. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 13: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)
1.14
1.14. Analysis
Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 14: Exacerbation requiring hospitalisation/ED/OCS (relative risk)
2.1
2.1. Analysis
Comparison 2: Subanalysis: agents directly targeting IL‐13, Outcome 1: Exacerbation requiring hospitalisation or ED visit
2.2
2.2. Analysis
Comparison 2: Subanalysis: agents directly targeting IL‐13, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)
2.3
2.3. Analysis
Comparison 2: Subanalysis: agents directly targeting IL‐13, Outcome 3: Serious adverse events
2.4
2.4. Analysis
Comparison 2: Subanalysis: agents directly targeting IL‐13, Outcome 4: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)
3.1
3.1. Analysis
Comparison 3: Subanalysis: agents directly targeting IL‐4R, Outcome 1: Health‐related quality of life (adjusted mean diff versus placebo)
3.2
3.2. Analysis
Comparison 3: Subanalysis: agents directly targeting IL‐4R, Outcome 2: Serious adverse events
3.3
3.3. Analysis
Comparison 3: Subanalysis: agents directly targeting IL‐4R, Outcome 3: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)
4.1
4.1. Analysis
Comparison 4: Subanalysis: study duration <= 6 months, Outcome 1: Health‐related quality of life (adjusted mean diff versus placebo)
4.2
4.2. Analysis
Comparison 4: Subanalysis: study duration <= 6 months, Outcome 2: Serious adverse events
4.3
4.3. Analysis
Comparison 4: Subanalysis: study duration <= 6 months, Outcome 3: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)
5.1
5.1. Analysis
Comparison 5: Subanalysis: study duration > 6 months, Outcome 1: Exacerbation requiring hospitalisation or ED visit
5.2
5.2. Analysis
Comparison 5: Subanalysis: study duration > 6 months, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)
5.3
5.3. Analysis
Comparison 5: Subanalysis: study duration > 6 months, Outcome 3: Serious adverse events
5.4
5.4. Analysis
Comparison 5: Subanalysis: study duration > 6 months, Outcome 4: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)
6.1
6.1. Analysis
Comparison 6: Subanalysis: asthma severity mild‐to‐moderate, Outcome 1: Health‐related quality of life (adjusted mean diff versus placebo)
6.2
6.2. Analysis
Comparison 6: Subanalysis: asthma severity mild‐to‐moderate, Outcome 2: Serious adverse events
7.1
7.1. Analysis
Comparison 7: Subanalysis: asthma severity severe, Outcome 1: Exacerbation requiring hospitalisation or ED visit
7.2
7.2. Analysis
Comparison 7: Subanalysis: asthma severity severe, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)
7.3
7.3. Analysis
Comparison 7: Subanalysis: asthma severity severe, Outcome 3: Serious adverse events
7.4
7.4. Analysis
Comparison 7: Subanalysis: asthma severity severe, Outcome 4: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)
8.1
8.1. Analysis
Comparison 8: Subanalysis: no concomitant ICS, Outcome 1: Health‐related quality of life (adjusted mean diff versus placebo)
8.2
8.2. Analysis
Comparison 8: Subanalysis: no concomitant ICS, Outcome 2: Serious adverse events
9.1
9.1. Analysis
Comparison 9: Subanalysis: concomitant ICS, Outcome 1: Exacerbation requiring hospitalisation or ED visit
9.2
9.2. Analysis
Comparison 9: Subanalysis: concomitant ICS, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)
9.3
9.3. Analysis
Comparison 9: Subanalysis: concomitant ICS, Outcome 3: Serious adverse events
9.4
9.4. Analysis
Comparison 9: Subanalysis: concomitant ICS, Outcome 4: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)
10.1
10.1. Analysis
Comparison 10: Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS, Outcome 1: Blood eosinophils high (> 300 cells/uL)
10.2
10.2. Analysis
Comparison 10: Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS, Outcome 2: Blood eosinophils low (< 300 cells/uL)
10.3
10.3. Analysis
Comparison 10: Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS, Outcome 3: Blood eosinophils low (> 150 < 300 cells/uL)
10.4
10.4. Analysis
Comparison 10: Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS, Outcome 4: Blood eosinophils low (< 150 cells/uL)
11.1
11.1. Analysis
Comparison 11: Subanalysis by FENO: exacerbations requiring hospitalisation/ED/OCS, Outcome 1: FENO high (≥ 50 ppb)
11.2
11.2. Analysis
Comparison 11: Subanalysis by FENO: exacerbations requiring hospitalisation/ED/OCS, Outcome 2: FENO medium (≥ 25 to < 50 ppb)
11.3
11.3. Analysis
Comparison 11: Subanalysis by FENO: exacerbations requiring hospitalisation/ED/OCS, Outcome 3: FENO low (< 25 ppb)
12.1
12.1. Analysis
Comparison 12: Subanalysis by periostin level: exacerbations requiring hospitalisation/ED/OCS, Outcome 1: Periostin high (≥ 50 ng/mL)
12.2
12.2. Analysis
Comparison 12: Subanalysis by periostin level: exacerbations requiring hospitalisation/ED/OCS, Outcome 2: Periostin low (< 50 ng/mL)
13.1
13.1. Analysis
Comparison 13: Sensitvity analysis ‐ random‐effects, Outcome 1: Exacerbation requiring hospitalisation or ED visit
13.2
13.2. Analysis
Comparison 13: Sensitvity analysis ‐ random‐effects, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)
13.3
13.3. Analysis
Comparison 13: Sensitvity analysis ‐ random‐effects, Outcome 3: Serious adverse events
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Castro 2018 {published data only}
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Hanania 2011 {published data only}
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Hanania 2015a {published data only}
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Hanania 2015b {published data only}
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    1. NCT01545453. A study of lebrikizumab in patients with uncontrolled asthma who are on inhaled corticosteroids and a second controller medication (VERSE). clinicaltrials.gov/show/NCT01545453 (6 March 2012).
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    1. Hanania N, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro PL, et al. LAVOLTA I and II: results of 2 phase III studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma. European Respiratory Journal 2016;48(Suppl 60):OA1975. - PubMed
    1. Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respiratory Medicine 2016;4(10):781-96. - PubMed
    1. Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, et al. LAVOLTA I and II: design and baseline characteristics of two phase III, randomized, double-blind, placebo-controlled studies to assess the efficacy and safety of lebrikizumab in adult patients with uncontrolled asthma. American Journal of Respiratory and Critical Care Medicine 2016;193:A1318. - PubMed
    1. NCT01867125. A study of lebrikizumab in participants with uncontrolled asthma who are on inhaled corticosteroids and a second controller medication [A phase III, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma who are on inhaled corticosteroids and a second controller medication]. clinicaltrials.gov/show/NCT01867125 (first received 3 June 2013).
Hanania 2016b {published data only}
    1. Hanania N, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro PL, et al. LAVOLTA I and II: results of 2 phase III studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma. European Respiratory Journal 2016;48(Suppl 60):OA1975. - PubMed
    1. Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respiratory Medicine 2016;4(10):781-96. - PubMed
    1. Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, et al. LAVOLTA I and II: design and baseline characteristics of two phase III, randomized, double-blind, placebo-controlled studies to assess the efficacy and safety of lebrikizumab in adult patients with uncontrolled asthma. American Journal of Respiratory and Critical Care Medicine 2016;193:A1318. - PubMed
    1. NCT01867125. A study of lebrikizumab in participants with uncontrolled asthma who are on inhaled corticosteroids and a second controller medication. clinicaltrials.gov/show/NCT01867125 (first received 3 June 2013).
Hodsman 2013 {published data only}
    1. Hodsman P, Ashman C, Cahn A, De Boever E, Locantore N, Serone A, et al. A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal antibody in healthy subjects and mild asthmatics. British Journal of Clinical Pharmacology 2013;75(1):118-28. - PMC - PubMed
Korenblat 2018 {published data only}
    1. Korenblat P, Kerwin E, Leshchenko I, Yen K, Holweg CTJ, Anzures-Cabrera J, et al. Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids. Respiratory Medicine 2018;134:143-9. - PubMed
    1. Yen K, Holweg CJ, Anzures-Cabrera J, Martin C, Olsson J, Matthews JG. STRETTO: design and baseline characteristics of a phase III, double-blind, placebo-controlled study to assess the efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma. American Journal of Respiratory and Critical Care Medicine 2016;193:A1316.
NCT00425061 {published data only}
    1. NCT00425061. Study evaluating the effect of IMA-638 in subjects with persistent asthma [Randomized, double-blind, placebo-controlled, parallel group, phase 2 study conducted sequentially with 3 doses of Ima-638 administered sc]. clinicaltrials.gov/show/NCT00425061 (first received 22 January 2007).
NCT00640016 {published data only}
    1. NCT00640016. A study to assess the efficacy, safety, and tolerability of CAT-354 in subjects with asthma [A double-blind, placebo-controlled, parallel-group study to assess the efficacy, safety, and tolerability of CAT-354]. clinicaltrials.gov/show/NCT00640016 (first received 20 March 2008).
Noonan 2013 {published data only}
    1. Noonan M, Korenblat P, Mosesova S, Scheerens H, Arron JR, Zheng Y, et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. Journal of Allergy and Clinical Immunology 2013;132(3):567-74.e12. - PubMed
Pannetieri 2018A {published data only}
    1. Carlsson M, Braddock M, Li Y, Wang J, Xu W, White N, et al. Evaluation of antibody properties and clinically relevant immunogenicity, anaphylaxis, and hypersensitivity reactions in two phase III trials of tralokinumab in severe, uncontrolled asthma. Drug Safety 2019;426:769-84. - PMC - PubMed
    1. EudraCT 2013-005615-27. A phase 3 study to evaluate the efficacy and safety of tralokinumab in adults and adolescents with asthma that is not controlled. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 24 Sep 2014).
    1. NCT02161757. A phase 3 study to evaluate the efficacy and safety of tralokinumab in adults and adolescents with uncontrolled asthma (STRATOS1) [A phase 3 study to evaluate the efficacy and safety of tralokinumab in adults and adolescents with asthma inadequately controlled on inhaled corticosteroid plus long-acting β2-agonist.]. clinicaltrials.gov/show/NCT02161757 (first received 12 June 2014).
    1. Panettieri RA Jr, Sjöbring U, Péterffy A, Wessman P, Bowen K, Piper E, et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respiratory Medicine 2018;6:511-25. - PubMed
Pannetieri 2018B {published data only}
    1. NCT02194699. A phase 3 study to evaluate the efficacy and safety of tralokinumab in adults and adolescents with uncontrolled asthma (STRATOS2) [A phase 3 study to evaluate the efficacy and safety of tralokinumab in adults and adolescents with asthma inadequately controlled on inhaled corticosteroid plus long-acting β2-agonist]. clinicaltrials.gov/show/NCT02194699 (first received 18 July 2014).
    1. Panettieri RA Jr, Sjöbring U, Péterffy A, Wessman P, Bowen K, Piper E, et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respiratory Medicine 2018;6:511-25. - PubMed
Piper 2013 {published data only}
    1. Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. European Respiratory Journal 2013;41(2):330-8. - PMC - PubMed
    1. Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. Phase 2 randomized, double-blind, placebo-controlled study of tralokinumab, an anti-IL-13 monoclonal antibody, in moderate to severe asthma. European Respiratory Journal 2011;38(55):608s [3425]. - PMC - PubMed
    1. Piper E, She D, Molfino NA. Subgroup analysis of a phase 2A randomized, double-blind, placebo-controlled study of tralokinumab, an anti-IL-13 monoclonal antibody, in moderate to severe asthma. American Journal of Respiratory and Critical Care Medicine 2012;185:A2759.
Rabe 2018 {published data only}
    1. Castro M, Maspero J, Sher L, Rabe K, Casale T, Rice M, et al. Dupilumab reduces oral corticosteroid use and severe exacerbations and improves lung function in patients with oral corticosteroid-dependent severe asthma with and without comorbid allergic rhinitis in the phase 3 LIBERTY ASTHMA VENTURE study. Journal of Allergy and Clinical Immunology 2020;145:AB173.
    1. Castro M, Rabe KF, Brusselle G, Rice MS, Rowe P, Deniz Y, et al. Dupilumab effect on asthma control and health-related quality of life in patients with oral corticosteroid-dependent severe asthma with comorbid chronic rhinosinusitis with and without nasal polyps. European Journal of Allergy and Clinical Immunology 2019;74:27.
    1. EudraCT 2015-001573-40. Evaluation of dupilumab in patients with severe steroid dependent asthma. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 4 November 2015).
    1. Hanania N, Castro M, Mirapeix C, Bateman E, Rice M, Djandji M, et al. Dupilumab reduces severe exacerbations in patients with oral corticosteroid-dependent severe asthma with and without early improvements in lung function. Chest 2019;156:A929-32.
    1. Maspero JF, Rabe KF, Castro M, Rice MS, Rowe P, Deniz Y, et al. Dupilumab improves health-related quality of life in patients with oral corticosteroid dependent, severe asthma with comorbid chronic rhinosinusitis with and without nasal polyps. European Journal of Allergy and Clinical Immunology 2019;74:35-6.
Russell 2018 {published data only}
    1. EudraCT 2015-000857-19. A phase 2 study to evaluate the effect of tralokinumab in adults with asthma inadequately controlled on inhaled corticosteroid [A multicentre, randomized, double-blind, parallel group, placebo-controlled, 12-week, phase 2 study to evaluate the effect of tralokinumab on airway inflammation in adults with asthma inadequately controlled on inhaled corticosteroid (MESOS)]. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 6 August 2015).
    1. NCT02449473. Study to evaluate efficacy & safety of tralokinumab in subjects with asthma inadequately controlled on corticosteroids (MESOS) [A multicentre, randomized, double-blind, parallel group, placebo controlled, 12-week, ph 2 study to evaluate the effect of tralokinumab on airway inflammation in adults with asthma inadequately controlled on inhaled corticosteroid (MESOS)]. clinicaltrials.gov/show/NCT02449473 (first received 20 May 2015).
    1. Russell RJ, Chachi L, FitzGerald JM, Backer V, Olivenstein R, Titlestad IL, et al. Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Respiratory Medicine 2018;6(7):499-510. - PubMed
    1. Russell RJ, Fitzgerald JM, Backer V, Wang M, Braddock M, Nordenmark LH, et al. Effect of tralokinumab upon eosinophilic airway inflammation in participants with moderate to severe, uncontrolled asthma (MESOS) study. American Journal of Respiratory and Critical Care Medicine 2018;197:A7714.
Scheerens 2014 {published data only}
    1. Scheerens H, Arron JR, Su Z, Zheng Y, Putnam W, Erickson RW, et al. Predictive and pharmacodynamic biomarkers of interleukin-13 blockade: effect of lebrikizumab on late phase asthmatic response to allergen challenge [abstract]. Journal of Allergy and Clinical Immunology 2011;127(2 Suppl 1):AB164.
    1. Scheerens H, Arron JR, Zheng Y, Putnam WS, Erickson RW, Choy DF, et al. The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge. Clinical and Experimental Allergy 2014;44(1):38-46. - PMC - PubMed
Singh 2010 {published data only}
    1. Bhowmick B, Singh D, Molfino N, Cranmer H, Birrell C, Faggioni R, et al. A double blind placebo controlled study to assess the pharmacokinetics safety and tolerability of multiple ascending intravenous doses of CAT 354 a recombinant human anti-IL 13 antibody, in subjects with moderate asthma. In: European Respiratory Society 18th Annual Congress; 2008 Oct 3-7; Berlin. 2008:3021.
    1. Singh D, Kane B, Molfino NA, Faggioni R, Roskos L, Woodcock A. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma. BioMed Central Pulmonary Medicine 2010;10:3. [DOI: 10.1186/1471-2466-10-3] - DOI - PMC - PubMed
Tripp 2017 {published data only}
    1. Tripp CS, Cuff C, Campbell AL, Hendrickson BA, Voss J, Melim T, et al. RPC4046, a novel anti-interleukin-13 antibody, blocks IL-13 binding to IL-13 alpha1 and alpha2 receptors: a randomized, double-blind, placebo-controlled, dose-escalation first-in-human study. Advances in Therapy 2017;34(6):1364-81. - PMC - PubMed
Wenzel 2007a {published data only}
    1. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007;370(9596):1422-31. - PubMed
    1. Wilbraham D, Fuller R. AER 001 effects on antigen challenge in atopic asthmatic subjects [abstract]. European Respiratory Journal 2006;28(Suppl 50):114s [746].
Wenzel 2007b {published data only}
    1. NCT00535431. Effects of AER 001 administered by nebulization on antigen challenge in atopic asthmatics. clinicaltrials.gov/show/NCT00535431 (first received 26 September 2007).
    1. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007;370(9596):1422-31. - PubMed
    1. Wilbraham D, Burmeister Getz E, Longphre M, Wenzel S, Fuller R. Inhaled IL-4/IL-13 antagonist decreases response to antigen challenge in atopic asthmatic subjects. European Respiratory Journal 2016;30(Suppl 51):490s [2959].
    1. Wilbraham D, Fuller R. AER 001 effects on antigen challenge in atopic asthmatic subjects. European Respiratory Journal 2006;28(Suppl 50):114s [746].
Wenzel 2010 {published data only}
    1. EudraCT 2007-006545-41. A phase iib study to investigate the treatment-sparing effects of Aerovant™ (aer 001 inhalation powder) in asthma patients not fully controlled on current therapy - aerovant. clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-00... (first received 20 March 2009).
    1. NCT00801853. A study of the treatment-sparing effects of AEROVANT™ AER 001 inhalation powder in asthma patients, AEROTRIAL [A phase IIb study to investigate the treatment-sparing effects of AEROVANT™ AER 001 inhalation powder in asthma patients not fully controlled on current therapy]. clinicaltrials.gov/show/NCT00801853 (first received 4 December 2008).
    1. Otulana BA, Wenzel SE, Ind PW, Bowden A, Puthukkeril S, Tomkinson A, et al. A phase 2b study of inhaled pitrakinra, an IL-4/IL-13 antagonist, successfully identified responder subpopulations of patients with uncontrolled asthma [abstract]. American Journal of Respiratory and Critical Care Medicine 2011;183:A6179.
    1. Wenzel SE, Ind PW, Otulana BA, Bleecker ER, Kuna P, Yen YP. Inhaled pitrakinra, an IL-4/IL-13 antagonist, reduced exacerbations in patients with eosinophilic asthma [abstract]. In: European Respiratory Society 20th Annual Congress; 2010 Sep 18-22; Barcelona. 2010:P3980.
Wenzel 2013 {published data only}
    1. Castro M, Teper A, Wang L, Pirozzi G, Radin A, Graham N, et al. Responder analysis for FEV1 improvement with dupilumab in patients with persistent asthma and elevated eosinophil levels. American Journal of Respiratory and Critical Care Medicine 2014;189:A1321.
    1. NCT01312961. Efficacy, safety, and tolerability of dupilumab in patients with persistent moderate to severe eosinophilic asthma [Randomized, double-blind, placebo-controlled, parallel group study to assess the efficacy, safety, and tolerability of SAR231893/REGN668 administered subcutaneously once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma who are partially controlled/uncontrolled by inhaled corticosteroid plus long-acting beta2 agonist therapy]. clinicaltrials.gov/show/NCT01312961 (first received 11 March 2011).
    1. Swanson B, Ming J, Ren H, Wang L, Wenzel S, Beck L, et al. Dupilumab suppresses Th2 inflammation in adult asthma and atopic dermatitis. World Allergy Organization Journal 2013;7(Suppl 1):P13.
    1. Swanson BN, Wang L, Ming J, Hamilton JD, Teper A, Dicioccio T, et al. Exhaled nitric oxide (FENO) and t-helper 2 cell biomarkers: can they predict treatment response to dupilumab, an il-4ra antibody, in an eosinophilic asthma population? Journal of Allergy and Clinical Immunology 2014;133(2 Suppl):AB85.
    1. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. New England Journal of Medicine 2013;368(26):2455-66. - PubMed
Wenzel 2016 {published data only}
    1. Bernstein J, Ford L, Jayawardena S, Maroni J, Rowe P, Amin N, et al. Dupilumab reduces exacerbations and improves lung function in uncontrolled persistent asthma patients across baseline exacerbations. Annals of Allergy, Asthma and Immunology 2017;119(5 Suppl 1):S50.
    1. Bourdin A, Papi AA, Corren J, Virchow JC, Rice MS, Deniz Y, et al. Dupilumab is effective in type 2-high asthma patients receiving high-dose inhaled corticosteroids at baseline. Allergy 2020;76(1):269-80. [DOI: 10.1111/all.14611] - DOI - PMC - PubMed
    1. Castro M, Swanson BN, Jayawardena S, Hamilton JD, Amin N, Pirozzi G, et al. Exacerbation risk and type 2 inflammation in placebo patients during a phase 2b study of dupilumab in patients with uncontrolled persistent asthma. Journal of Allergy and Clinical Immunology 2018;141(2 Suppl 1):AB112.
    1. Castro M, Wenzel SE, Corren J, Maspero J, Zhang B, Pirozzi G, et al. Dupilumab improves lung function inclusive of small airways in patients with uncontrolled persistent asthma: results from a Phase 2b clinical trial. American Journal of Respiratory and Critical Care Medicine 2016;193:A6489.
    1. Chanez P, Corren J, Castro M, Fabbri L, Joish VN, Evans RE, et al. Dupilumab improves patient-reported outcomes in uncontrolled persistent asthma: results from a Phase 2b clinical trial. American Journal of Respiratory and Critical Care Medicine 2016;193:A6491.

References to studies excluded from this review

Bachert 2016 {published data only}
    1. Bachert C, Hellings P, Mullol J, Hamilos D, Naclerio R, Joish VN, et al. Dupilumab improves patient-reported outcomes in chronic sinusitis with nasal polyps patients with comorbid asthma: results from a phase 2a trial. European Respiratory Journal 2016;48(Suppl 60):OA251.
Bachert 2019 {published data only}
    1. Bachert C, Desrosiers M, Mullol J, Maspero JF, Wagenmann M, Niemann I, et al. Baseline characteristics of patients with chronic rhinosinusitis with nasal polyps (with and without asthma) enrolled in SINUS-52, a randomized, double-blind, phase 3 study of dupilumab. Laryngorhinotologie 2019;98:S176.
Banfield 2008 {published data only}
    1. Banfield C, Vincent M, Kakkar T, Chia M, Thien F, Cheah T, et al. Multiple dose study of AMG 317 in adults with asthma: pharmacokinetics and safety [abstract]. In: European Respiratory Society 18th Annual Congress; 2008 Oct 3-7; Berlin. 2008:3022.
Djukanovic 2004 {published data only}
    1. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. American Journal of Respiratory and Critical Care Medicine 2004;170(6):583-93. - PubMed
NCT00339872 {published data only}
    1. NCT00339872. Study evaluating IMA-638 in asthma [Randomized, double-blind, placebo-controlled, sequential-group, ascending single dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of IMA-638 administered subcutaneously and intravenously to subjects with asthma]. clinicaltrials.gov/show/NCT00339872 (first received 21 June 2006).
NCT00638989 {published data only}
    1. NCT00638989. A study to assess bioavailability and pharmacokinetics of CAT- 354 [An open-label, parallel-group, bioavailability study to assess the pharmacokinetics of CAT-354 following subcutaneous and intravenous administration]. clinicaltrials.gov/show/NCT00638989 (first received 19 March 2008).
NCT00785668 {published data only}
    1. NCT00785668. A phase 1 safety and pharmacokinetics study of AER 001 administered as a dry powder in asthmatic subjects. clinicaltrials.gov/show/NCT00785668 (first received 5 November 2008).
NCT01592396 {published data only}
    1. NCT01592396. A phase 1, open-label study to investigate the pharmacokinetics of tralokinumab (CAT-354) in adolescents with asthma. clinicaltrials.gov/show/NCT01592396 (first received 7 May 2012).
NCT01875003 {published data only}
    1. EudraCT 2012-000180-25. A study of lebrikizumab in adolescent patients with uncontrolled asthma who are on inhaled corticosteroids and a second controller medication [A phase III, randomized, double-blind, placebo-controlled study to assess the efficacy, safety, and tolerability of lebrikizumab in adolescent patients with uncontrolled asthma who are on inhaled corticosteroids and a second controller medication]. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 9 September 2013).
    1. NCT01875003. A study of lebrikizumab in adolescent participants with uncontrolled asthma who are on inhaled corticosteroids and a second controller medication. clinicaltrials.gov/show/NCT01875003 (first received 11 June 2013).
NCT02085473 {published data only}
    1. NCT02085473. A phase 1 study to evaluate the pharmacokinetics and tolerability of tralokinumab when delivered at different flow rates to healthy volunteers [A phase 1 study to evaluate the pharmacokinetics and tolerability of a single subcutaneous dose of tralokinumab when delivered as a 2 mL injection at different flow rates to healthy volunteers]. clinicaltrials.gov/show/NCT02085473 (first received 12 March 2014).
NCT02099656 {published data only}
    1. Austin CD, Gonzalez Edick M, Ferrando RE, Solon M, Baca M, Mesh K, et al. A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER). Clinical and Experimental Allergy 2020;50(12):1342-51. [DOI: 10.1111/cea.13731] - DOI - PMC - PubMed
    1. NCT02099656. A study evaluating the effects of lebrikizumab on airway eosinophilic inflammation in participants with uncontrolled asthma [A phase II, randomized, double-blind, placebo-controlled bronchoscopy study to evaluate the effects of lebrikizumab on airway eosinophilic inflammation in patients with uncontrolled asthma on inhaled corticosteroids and a second controller medication]. clinicaltrials.gov/show/NCT02099656 (first received 31 March 2014).
NCT02134028 {published data only}
    1. EudraCT 2013-003856-19. Long-term safety evaluation of dupilumab in patients with asthma [Open label extension study to evaluate the long-term safety and tolerability of dupilumab in patients with asthma who participated in previous dupilumab asthma clinical study]. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 28 May 2014).
    1. NCT02134028. Long-term safety evaluation of dupilumab in patients with asthma (LIBERTY ASTHMA TRAVERSE) [Open-label extension study to evaluate the long-term safety and tolerability of dupilumab in patients with asthma who participated in a previous dupilumab asthma clinical study]. clinicaltrials.gov/show/NCT02134028 (first received 8 May 2014).
NCT02546869 {published data only}
    1. NCT02546869. A single-arm study to evaluate administration of lebrikizumab by participants or caregivers in the home setting. clinicaltrials.gov/show/NCT02546869 (first received 11 September 2015).
NCT02902809 {published data only}
    1. NCT02902809. A study to evaluate the safety of tralokinumab in adults and adolescents with uncontrolled asthma [A 52-week, open-label, multicentre study to evaluate the safety of tralokinumab in Japanese adults and adolescents with asthma inadequately controlled on inhaled corticosteroid plus long-acting β2-agonist]. clinicaltrials.gov/show/NCT02902809 (first received 16 September 2016).
Nsouli 2018 {published data only}
    1. Nsouli S. Efficacy of subcutaneous dupilumab a human anti-interleukin-4 receptor alpha monoclonal antibody for moderate-to-severe uncontrolled asthmatics. Annals of Allergy, Asthma and Immunology 2018;121(5 Suppl):S40-1.
Oh 2009 {published data only}
    1. Oh CK, Faggioni R, Jin F, Roskos LK, Wang B, Birrell C, et al. An open-label, single-dose bioavailability study of the pharmacokinetics of CAT-354 after subcutaneous and intravenous administration in healthy males. British Journal of Clinical Pharmacology 2010;69:645-55. - PMC - PubMed
    1. Oh CK, Fraggioni R, Roskos L, Dialino-Felix A, Smith H, Wilson R, et al. An open-label, parallel-group, bioavailability study to assess the pharmacokinetics of CAT-354 following subcutaneous and intravenous administration in healthy subjects [abstract]. In: American Thoracic Society International Conference; 2009 May 15-20 San Diego. 2009:A2813 [Poster #J81].
Parsey 2004 {published data only}
    1. Parsey M, Moveck R, Allison M, Pearlman D, Marbury T, Furfine E, et al. A phase I study of IL-4/13 trap in patients with clinically stable, mild to moderate asthma [abstract]. In: American Thoracic Society 100th International Conference; 2004 May 21-26; Orlando. 2004:D81.
Weinstein 2017 {published data only}
    1. Weinstein S, Staudinger H, Guillonneau S, Taniou C, Eckert L, Joish V, et al. Dupilumab improves lung function and reduces severe exacerbations in uncontrolled persistent asthma patients with ongoing allergic rhinitis. European Respiratory Journal 2017;50(Suppl 61):PA3550.

References to studies awaiting assessment

Euctr 2015‐001572‐22 {published data only}
    1. EudraCT 2015-001572-22. Evaluation of dupilumab's effects on airway inflammation in patients with asthma [An exploratory, randomized, double-blind, placebo-controlled study of the effects of dupilumab on airway inflammation of adults with persistent asthma]. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 1 December 2015).
NCT00024544 {published data only}
    1. NCT00024544. Pilot study in patients with symptomatic steroid-naive asthma [A phase I/II, randomized, double-blind, placebo-controlled, parallel-group pilot study of SB 240683 in patients with symptomatic steroid-naive asthma]. clinicaltrials.gov/ct2/show/NCT00024544 (first received 20 September 2001).
NCT01987492 {published data only}
    1. EudraCT2012-000190-24. A study of lebrikizumab in patients with severe asthma who depend on oral corticosteroids [A phase II, randomized, double-blind, placebo-controlled, multicenter trial to assess the oral corticosteroid–sparing effect of lebrikizumab in patients with severe corticosteroid-dependent asthma]. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 6 November 2013).
    1. NCT01987492. A study of lebrikizumab (RO5490255) in participants with severe oral corticosteroids (OCS) dependent asthma [A phase II, randomized, double-blind, placebo controlled, multicenter trial to assess the oral corticosteroid-sparing effect of lebrikizumab in patients with severe corticosteroid dependent asthma]. clinicaltrials.gov/show/NCT01987492 (first received 19 November 2013).
NCT02948959 {published data only}
    1. NCT02948959. Evaluation of dupilumab in children with uncontrolled asthma (VOYAGE) [Randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of dupilumab in children 6 to <12 years of age with uncontrolled persistent asthma]. clinicaltrials.gov/show/NCT02948959 (first received 31 October 2016).
NCT03112577 {published data only}
    1. NCT03112577. Study of REGN3500 and dupilumab in patients with asthma [A randomized, placebo-controlled, parallel panel study to assess the effects of REGN3500, dupilumab, and combination of REGN3500 plus dupilumab on markers of inflammation after bronchial allergen challenge in patients with allergic asthma]. clinicaltrials.gov/show/NCT03112577 (first received 13 April 2017).
NCT03387852 {published data only}
    1. NCT03387852. Evaluation of SAR440340 and AS combination therapy with dupilumab in moderate-to-severe asthma patients [A randomized, double-blind, placebo-controlled, parallel-group, 12-week proof-of-concept (PoC) study to assess the efficacy, safety, and tolerability of SAR440340 and the coadministration of SAR440340 and dupilumab in patients with moderate-to-severe asthma who are not well controlled on inhaled corticosteroid (ICS) plus long-acting β2 adrenergic agonist (LABA) therapy]. clinicaltrials.gov/show/NCT03387852 (first received 2 January 2018).

References to ongoing studies

NCT03782532 {published data only}
    1. NCT03782532. Efficacy and safety study of dupilumab in patients with persistent asthma [A randomized, double blind, placebo-controlled, parallel-group phase 3 study to evaluate the efficacy and safety of dupilumab in patients with persistent asthma]. clinicaltrials.gov/show/nct03782532 (first received 20 December 2018).

Additional references

Agache 2020
    1. Agache I, Rocha C, Beltran J, Song Y, Posso M, Sola, I, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: a systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy 2020;75(5):1043-57. - PubMed
Agache 2020b
    1. Agache I, Beltran J, Akdis C, Akdis M, Canelo-Aybar C, Canonica GW, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy 2020;75(5):1023-42. - PubMed
Austin 2020
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