Sophie Dupuis-Girod1, Alexis Ambrun2, Evelyne Decullier3, Géraldine Samson3, Adeline Roux3, Anne-Emmanuelle Fargeton1, Catherine Rioufol4, Verane Schwiertz5, François Disant2, François Chapuis3, Yves Donazzolo6, Gilles Paintaud7, Patrick Edery1, Frederic Faure2. 1. Hospices Civils de Lyon; Groupe Hospitalier Est; Service de Génétique et centre de référence pour la maladie de Rendu-Osler; Bron, France. 2. Hospices Civils de Lyon; Hôpital E. Herriot; Service d'ORL; Lyon, France. 3. 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. 4. 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. 5. Hospices Civils de Lyon; Centre Hospitalier Lyon Sud; Unité de Pharmacie Clinique Oncologique; Pierre-Bénite, France. 6. Eurofins-Optimed; Centre Hospitalier Lyon Sud; Pierre-Bénite, France. 7. CHRU de Tours; Laboratoire de Pharmacologie-Toxicologie; Tours, France.
Abstract
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 withHHT improves liver damage-related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable. PRIMARY 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. METHODOLOGY: 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. CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier #NCT01507480.
RCT Entities:
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. PRIMARY 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. METHODOLOGY: 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. CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier #NCT01507480.
Authors: Ilias Karapantzos; Nikolaos Tsimpiris; Dimitrios G Goulis; Helen Van Hoecke; Paul Van Cauwenberge; Vasilis Danielides Journal: Eur Arch Otorhinolaryngol Date: 2005-03-01 Impact factor: 2.503
Authors: C L Shovlin; A E Guttmacher; E Buscarini; M E Faughnan; R H Hyland; C J Westermann; A D Kjeldsen; H Plauchu Journal: Am J Med Genet Date: 2000-03-06
Authors: D W Johnson; J N Berg; M A Baldwin; C J Gallione; I Marondel; S J Yoon; T T Stenzel; M Speer; M A Pericak-Vance; A Diamond; A E Guttmacher; C E Jackson; L Attisano; R Kucherlapati; M E Porteous; D A Marchuk Journal: Nat Genet Date: 1996-06 Impact factor: 38.330
Authors: K A McAllister; K M Grogg; D W Johnson; C J Gallione; M A Baldwin; C E Jackson; E A Helmbold; D S Markel; W C McKinnon; J Murrell Journal: Nat Genet Date: 1994-12 Impact factor: 38.330