• Sophie Dupuis-Girod, Alexis Ambrun, Evelyne Decullier, Anne-Emmanuelle Fargeton, Adeline Roux, Valentine Bréant, Bettina Colombet, Sophie Rivière, César Cartier, Pascal Lacombe, Thierry Chinet, Sandra Blivet, Jean-Hugues Blondel, Brigitte Gilbert-Dussardier, Xavier Dufour, Justin Michel, Jean-Robert Harle, Patrick Dessi, and Frédéric Faure.
• Hospices Civils de Lyon, Hôpital Femme-Mère-Enfants, Service de Génétique et centre de référence sur la maladie de Rendu-Osler, Bron, France2Université de Lyon, Faculté de médecine, Université Lyon 1, Lyon, France.
• JAMA. 2016 Sep 6; 316 (9): 934-42.

BackgroundEpistaxis 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.ObjectiveTo 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 ParticipantsRandomized, 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.InterventionsEighty 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 MeasuresMean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment.ResultsOf 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 RelevanceIn 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 Registrationclinicaltrials.gov Identifier: NCT02106520.

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