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Original Investigation
September 6, 2016

Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic TelangectasiaA Randomized Clinical Trial

Author Affiliations
  • 1Hospices Civils de Lyon, Hôpital Femme-Mère-Enfants, Service de Génétique et centre de référence sur la maladie de Rendu-Osler, Bron, France
  • 2Université de Lyon, Faculté de médecine, Université Lyon 1, Lyon, France
  • 3Hospices Civils de Lyon, Hôpital de la Croix Rousse, Service d’ORL, Lyon, France
  • 4Hospices Civils de Lyon, pôle IMER, Lyon, France
  • 5Université Lyon 1, Lyon, France
  • 6Hospices Civils de Lyon, Pharmacie, Hôpital Louis Pradel, Bron, France
  • 7Service de Médecine Interne A, Centre Hospitalier Universitaire, Montpellier, France
  • 8Service d’ORL, Centre Hospitalier Universitaire, Montpellier, France
  • 9Hôpital Ambroise Paré, Service de Radiologie, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest, Boulogne, France
  • 10Hôpital Ambroise Paré, Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest, Boulogne, France
  • 11Hôpital Ambroise Paré, Service d’ORL, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest, Boulogne, France
  • 12Service de génétique médicale, CHU de Poitiers, Université de Poitiers, Poitiers, France
  • 13Service d’ORL, CHU La Milétrie, Poitiers, France
  • 14Hôpital de la conception, CHU de Marseille, Service de médecine interne, Marseille, France
  • 15Hôpital la Timone, CHU de Marseille, Service d’ORL, Marseille, France
  • 16Hospices Civils de Lyon, Hôpital E. Herriot, Service d’ORL, Lyon, France
JAMA. 2016;316(9):934-942. doi:10.1001/jama.2016.11387

Background  Epistaxis is the most frequent and disabling manifestation of hereditary hemorrhagic telangiectasia (HHT). The efficacy of intravenous bevacizumab (an anti–vascular endothelial growth factor monoclonal antibody) for epistaxis has been shown. However, the efficacy of intranasal bevacizumab has yet to be evaluated.

Objective  To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT.

Design, Setting, and Participants  Randomized, multicenter, placebo-controlled, phase 2/3 clinical trial with dose selection at an intermediate analysis and prespecified stopping rules (nonbinding stopping for futility). Patients aged 18 years or older with a diagnosis of HHT were recruited from 5 French centers from April 2014 to January 2015 with a 6-month follow-up after the end of treatment. Participants had a history of self-reported nosebleeds with a monthly duration of more than 20 minutes in at least the 3 months prior to inclusion corroborated by epistaxis grids completed during the same preinclusion period.

Interventions  Eighty consecutive HHT patients were randomized and treated in the phase 2 study, with 4 parallel groups in a 1:1:1:1 ratio. One group received placebo (n = 21); the other 3 received bevacizumab nasal spray. Each bevacizumab group received a different dose of the drug (25 mg [n = 20], 50 mg [n = 20], or 75 mg [n = 19] per treatment) in 3 doses 14 days apart for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, and 225 mg in each treatment group.

Main Outcomes and Measures  Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment.

Results  Of the 80 patients who were randomized (mean age, 60.47 [SD, 10.61] years; 37 women [46.25%]), 75 completed the study. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1-436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8-406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8-327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3-291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee.

Conclusions and Relevance  In patients with HHT, a bevacizumab nasal spray treatment of 3 administrations at 14-day intervals with doses of 25 mg, 50 mg, or 75 mg per spray, compared with a placebo, did not reduce monthly epistaxis duration in the 3 consecutive months immediately after the end of treatment.

Trial Registration  clinicaltrials.gov Identifier: NCT02106520