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Original Investigation |

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

Sophie Dupuis-Girod, PhD1,2; Alexis Ambrun, MD3; Evelyne Decullier, PhD4,5; Anne-Emmanuelle Fargeton, MSc1,2; Adeline Roux, MSc4; Valentine Bréant, PharmD6; Bettina Colombet, PharmD6; Sophie Rivière, MD7; César Cartier, MD8; Pascal Lacombe, PhD9; Thierry Chinet, PhD10; Sandra Blivet, MD10; Jean-Hugues Blondel, MD11; Brigitte Gilbert-Dussardier, PhD12; Xavier Dufour, PhD13; Justin Michel, MD14; Jean-Robert Harle, PhD14; Patrick Dessi, MD15; Frédéric Faure, PhD16
[+] 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.
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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

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Figure 1.
Participant Flow in a Randomized Trial Comparing Bevacizumab Nasal Spray vs Placebo for Epistaxis Among Patients With Hemorrhagic Hereditary Telangiectasia

aOne patient received 50 mg instead of 25 mg at the first treatment, followed by 25 mg at the second treatment and 25 mg at the third treatment because of an administration error, and 1 patient received only 1 of the 3 treatments planned.

bOne patient received 25 mg instead of 50 mg at the first treatment, followed by 50 mg at the second treatment and 50 mg at the third treatment because of an administration error.

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Figure 2.
Mean Monthly Epistaxis Duration Before and After Treatment

Error bars indicate 95% CIs.

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Figure 3.
Secondary Outcome Criteria Before and After Treatment in Each Group

Error bars indicate 95% CIs. SF-36 indicates Short Form Health Survey quality-of-life questionnaire.

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