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



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.



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.



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.



Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment.



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.



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.



clinicaltrials.gov Identifier: NCT02106520.
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.
Sophie
S
Dupuis-Girod
Hospices Civils de Lyon, Hôpital de la Croix Rousse, Service d'ORL, Lyon, France.
Alexis
A
Ambrun
Hospices Civils de Lyon, pôle IMER, Lyon, France5Université Lyon 1, Lyon, France.
Evelyne
E
Decullier
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.
Anne-Emmanuelle
AE
Fargeton
Hospices Civils de Lyon, pôle IMER, Lyon, France.
Adeline
A
Roux
Hospices Civils de Lyon, Pharmacie, Hôpital Louis Pradel, Bron, France.
Valentine
V
Bréant
Hospices Civils de Lyon, Pharmacie, Hôpital Louis Pradel, Bron, France.
Bettina
B
Colombet
Service de Médecine Interne A, Centre Hospitalier Universitaire, Montpellier, France.
Sophie
S
Rivière
Service d'ORL, Centre Hospitalier Universitaire, Montpellier, France.
César
C
Cartier
Hôpital Ambroise Paré, Service de Radiologie, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest, Boulogne, France.
Pascal
P
Lacombe
Hôpital Ambroise Paré, Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest, Boulogne, France.
Thierry
T
Chinet
Hôpital Ambroise Paré, Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest, Boulogne, France.
Sandra
S
Blivet
Hôpital Ambroise Paré, Service d'ORL, Assistance Publique-Hôpitaux de Paris, Université Paris Ile-de-France Ouest, Boulogne, France.
Jean-Hugues
JH
Blondel
Service de génétique médicale, CHU de Poitiers, Université de Poitiers, Poitiers, France.
Brigitte
B
Gilbert-Dussardier
Service d'ORL, CHU La Milétrie, Poitiers, France.
Xavier
X
Dufour
Hôpital de la conception, CHU de Marseille, Service de médecine interne, Marseille, France.
Justin
J
Michel
Hôpital de la conception, CHU de Marseille, Service de médecine interne, Marseille, France.
Jean-Robert
JR
Harle
Hôpital la Timone, CHU de Marseille, Service d'ORL, Marseille, France.
Patrick
P
Dessi
Hospices Civils de Lyon, Hôpital E. Herriot, Service d'ORL, Lyon, France.
Frédéric
F
Faure
D000068258:Bevacizumab; D004844:Epistaxis; D006801:Humans; D059085:Nasal Sprays; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A
D059085:Nasal Sprays; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab