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Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.
JAMA 2018; 320(20):2108-2121JAMA

Abstract

Importance

Current treatments for long-term prophylaxis in hereditary angioedema have limitations.

Objective

To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks.

Design, Setting, and Participants

Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized.

Interventions

Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.

Main Outcome and Measures

Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period.

Results

Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab).

Conclusions and Relevance

Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy.

Trial Registration

EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

Authors+Show Affiliations

Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.Division of Rheumatology, Allergy & Immunology, University of California, San Diego.Department of Internal Medicine/Allergy Section Cincinnati, University of Cincinnati College of Medicine, Cincinnati, Ohio.Department of Biomedical and Clinical Sciences, Luigi Sacco, University of Milan, ASST Fatebenefratelli Sacco, Milan, Italy.Barts Health NHS Trust, London, United Kingdom.Division of Rheumatology, Allergy & Immunology, University of California, San Diego.Icahn School of Medicine at Mount Sinai, New York, New York.Clinical Research Center of Alabama, Birmingham.Department of Dermatology and Allergy, Dermatological Allergology, Charité-Universitätsmedizin Berlin, Berlin, Germany.Haemophilia Centre Rhine Main, Mörfelden-Walldorf, Germany.Rheumatology Allergy and Immunology, NYU Winthrop Hospital, Mineola, New York.Department of Biomedical and Clinical Sciences, Luigi Sacco, University of Milan, ASST Fatebenefratelli Sacco, Milan, Italy.Institute for Asthma and Allergy, Chevy Chase, Maryland.Department of Medicine and Pediatrics, Pennsylvania State University, Allergy, Asthma, and Immunology, Hershey.Allergy and Asthma Clinical Research, Walnut Creek, California.Clinical Research of Charlotte, Charlotte, North Carolina.Immunology Department, Midwest Immunology Clinic, Plymouth, Minnesota.Ottawa Allergy Research Corporation and University of Ottawa Medical School, Ottawa, Ontario, Canada.Allergy Asthma Research Associates Research Center, Dallas, Texas.Medical Research of Arizona, Scottsdale.Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Virginia Commonwealth University, Richmond.Triumpharma, Amman, Jordan.Asthma and Allergy Associates PC, Colorado Springs, Colorado.University of Puerto Rico School of Medicine, San Juan.Division of Allergy, Clinical Immunology & Rheumatology, University of Kansas Medical Center, Kansas City.Allergy Associates of Utah, Murray.AIRE Medical of Los Angeles, University of California, Los Angeles.Division of Allergy and Immunology, Washington University, St Louis, Missouri.Centre de Recherche Appliqué en Allergie de Québec, Quebec, Canada.Toledo Institute of Clinical Research, Toledo, Ohio.Department of Dermatology, University Medicine Mainz, Mainz, Germany.Shire, Lexington, Massachusetts.Shire, Lexington, Massachusetts.Shire, Lexington, Massachusetts.Department of Dermatology and Allergy, Dermatological Allergology, Charité-Universitätsmedizin Berlin, Berlin, Germany.No affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

30480729

Citation

Banerji, Aleena, et al. "Effect of Lanadelumab Compared With Placebo On Prevention of Hereditary Angioedema Attacks: a Randomized Clinical Trial." JAMA, vol. 320, no. 20, 2018, pp. 2108-2121.
Banerji A, Riedl MA, Bernstein JA, et al. Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial. JAMA. 2018;320(20):2108-2121.
Banerji, A., Riedl, M. A., Bernstein, J. A., Cicardi, M., Longhurst, H. J., Zuraw, B. L., ... Maurer, M. (2018). Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial. JAMA, 320(20), pp. 2108-2121. doi:10.1001/jama.2018.16773.
Banerji A, et al. Effect of Lanadelumab Compared With Placebo On Prevention of Hereditary Angioedema Attacks: a Randomized Clinical Trial. JAMA. 2018 11 27;320(20):2108-2121. PubMed PMID: 30480729.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial. AU - Banerji,Aleena, AU - Riedl,Marc A, AU - Bernstein,Jonathan A, AU - Cicardi,Marco, AU - Longhurst,Hilary J, AU - Zuraw,Bruce L, AU - Busse,Paula J, AU - Anderson,John, AU - Magerl,Markus, AU - Martinez-Saguer,Inmaculada, AU - Davis-Lorton,Mark, AU - Zanichelli,Andrea, AU - Li,H Henry, AU - Craig,Timothy, AU - Jacobs,Joshua, AU - Johnston,Douglas T, AU - Shapiro,Ralph, AU - Yang,William H, AU - Lumry,William R, AU - Manning,Michael E, AU - Schwartz,Lawrence B, AU - Shennak,Mustafa, AU - Soteres,Daniel, AU - Zaragoza-Urdaz,Rafael H, AU - Gierer,Selina, AU - Smith,Andrew M, AU - Tachdjian,Raffi, AU - Wedner,H James, AU - Hebert,Jacques, AU - Rehman,Syed M, AU - Staubach,Petra, AU - Schranz,Jennifer, AU - Baptista,Jovanna, AU - Nothaft,Wolfram, AU - Maurer,Marcus, AU - ,, PY - 2018/11/28/entrez PY - 2018/11/28/pubmed PY - 2018/12/29/medline SP - 2108 EP - 2121 JF - JAMA JO - JAMA VL - 320 IS - 20 N2 - Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/30480729/Effect_of_Lanadelumab_Compared_With_Placebo_on_Prevention_of_Hereditary_Angioedema_Attacks:_A_Randomized_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2018.16773 DB - PRIME DP - Unbound Medicine ER -