ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia.
BACKGROUND
Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity. Management of this symptom has no standard, and local treatments are often aggressive. Their efficacy is variable and has not been proven. Anti-angiogenic drugs, such as bevacizumab, are a new treatment strategy. Its systemic administration in patients with HHT improves liver damage-related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable.


OBJECTIVE
To evaluate the tolerance of increasing doses of bevacizumab administered as a nasal spray in patients with HHT-related epistaxis. Secondary objectives were to study the bioavailability and efficacy of bevacizumab against epistaxis when given as a nasal spray.


METHODS
Phase 1, randomized, double-blind, placebo-controlled, monocentric study performed sequentially (dose escalation) on 5 groups of 8 patients. Each group was made up of 6 verum and 2 placebos. Five increasing doses of bevacizumab nasal spray (25 mg/mL) were evaluated: 12.5, 25, 50, 75 and 100 mg.


RESULTS
A total of 40 patients were included between October 2011 and October 2012. Bevacizumab nasal spray was well tolerated in all patients and the drug was not detected in their serum. No dose limiting toxicity was observed. No efficacy was observed at any dose in this study.


CONCLUSIONS
Based on these results, bevacizumab nasal spray is a safe treatment of epistaxis in HHT. However, a randomized Phase 2 study is needed to determine its efficacy.


BACKGROUND
ClinicalTrials.gov Identifier #NCT01507480.
Hospices Civils de Lyon; Groupe Hospitalier Est; Service de Génétique et centre de référence pour la maladie de Rendu-Osler; Bron, France.
Sophie
S
Dupuis-Girod
Hospices Civils de Lyon; Hôpital E. Herriot; Service d'ORL; Lyon, France.
Alexis
A
Ambrun
Hospices Civils de Lyon; pôle IMER; Unité de Recherche Clinique; Lyon, France; Université de Lyon; EAM Santé Individu Société 4128; Lyon, France; Université Lyon 1; Lyon, France.
Evelyne
E
Decullier
Hospices Civils de Lyon; pôle IMER; Unité de Recherche Clinique; Lyon, France; Université de Lyon; EAM Santé Individu Société 4128; Lyon, France; Université Lyon 1; Lyon, France.
Géraldine
G
Samson
Hospices Civils de Lyon; pôle IMER; Unité de Recherche Clinique; Lyon, France; Université de Lyon; EAM Santé Individu Société 4128; Lyon, France; Université Lyon 1; Lyon, France.
Adeline
A
Roux
Hospices Civils de Lyon; Groupe Hospitalier Est; Service de Génétique et centre de référence pour la maladie de Rendu-Osler; Bron, France.
Anne-Emmanuelle
AE
Fargeton
Hospices Civils de Lyon; Centre Hospitalier Lyon Sud; Unité de Pharmacie Clinique Oncologique; Pierre-Bénite, France; EMR 3738 CTO Ciblage Thérapeutique en Oncologie; UFR Lyon Sud; Pierre-Bénite, France.
Catherine
C
Rioufol
Hospices Civils de Lyon; Centre Hospitalier Lyon Sud; Unité de Pharmacie Clinique Oncologique; Pierre-Bénite, France.
Verane
V
Schwiertz
Hospices Civils de Lyon; Hôpital E. Herriot; Service d'ORL; Lyon, France.
François
F
Disant
Hospices Civils de Lyon; pôle IMER; Unité de Recherche Clinique; Lyon, France; Université de Lyon; EAM Santé Individu Société 4128; Lyon, France; Université Lyon 1; Lyon, France.
François
F
Chapuis
Eurofins-Optimed; Centre Hospitalier Lyon Sud; Pierre-Bénite, France.
Yves
Y
Donazzolo
CHRU de Tours; Laboratoire de Pharmacologie-Toxicologie; Tours, France.
Gilles
G
Paintaud
Hospices Civils de Lyon; Groupe Hospitalier Est; Service de Génétique et centre de référence pour la maladie de Rendu-Osler; Bron, France.
Patrick
P
Edery
Hospices Civils de Lyon; Hôpital E. Herriot; Service d'ORL; Lyon, France.
Frederic
F
Faure
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000068258:Bevacizumab; D001803:Blood Transfusion; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D004844:Epistaxis / Q000209:etiology* / Q000628:therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D059085:Nasal Sprays; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications* / Q000628:therapy*; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D059085:Nasal Sprays; D000068258:Bevacizumab
Hereditary hemorrhagic telangiectasia; Phase 1 clinical study; bevacizumab; epistaxis; nasal spray; rare diseases