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ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia.

ABSTRACT: 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.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.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.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.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.ClinicalTrials.gov Identifier #NCT01507480.

SUBMITTER: Dupuis-Girod S

PROVIDER: S-EPMC4011923 | biostudies-literature | 2014 May-Jun

REPOSITORIES: biostudies-literature

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ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia.

Dupuis-Girod Sophie S Ambrun Alexis A Decullier Evelyne E Samson Géraldine G Roux Adeline A Fargeton Anne-Emmanuelle AE Rioufol Catherine C Schwiertz Verane V Disant François F Chapuis François F Donazzolo Yves Y Paintaud Gilles G Edery Patrick P Faure Frederic F

mAbs 20140130 3

<h4>Background</h4>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 sympto ...[more]

PMID: 24481211

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Project description:ImportanceEpistaxis is the greatest cause of morbidity in patients with hereditary hemorrhagic telangiectasia (HHT); because of this, a validated epistaxis-specific quality-of-life instrument for HHT should be made available.ObjectiveTo develop and validate an epistaxis-specific quality-of-life patient-reported outcome measure for HHT.Design, setting, and participantsThis survey study focused on the development and validation of the Nasal Outcome Score for Epistaxis (NOSE) in HTT (NOSE HHT) outcome measure with data prospectively collected from December 10, 2019, to March 15, 2020. A total of 401 patients were recruited from within the Cure Hemorrhagic Telangiectasia online patient advocacy social media network, the Washington University HHT Center of Excellence, and a randomized clinical trial investigating an intranasal timolol gel for HHT-associated epistaxis.Main outcomes and measuresFace and content validity, factor analysis, internal consistency as measured through Cronbach α, construct validity, responsiveness to change, and minimal clinically important difference.ResultsThe NOSE HHT was developed and validated with a possible score ranging discretely from 0 to 4 for each of the 29 items and a total score ranging continuously from 0 to 4 after dividing by the total number of items answered. A total of 401 participants completed the NOSE HHT. Factor analysis identified 3 factors that matched the a priori specified subgroups of particular aspects of life affected by HHT-associated epistaxis: physical problems (mean [SD] magnitude, 1.59 [0.83]), functional limitations (mean [SD] magnitude, 1.28 [0.84]), and emotional consequences (mean [SD] magnitude, 1.95 [1.02]). The instrument had high internal consistency with an overall Cronbach α of 0.960. Convergent validity determined the total NOSE HHT score to be a strong predictor of disease severity; total NOSE HHT score can be split up into the following epistaxis severity categories: mild (0-1), moderate (1.01-2), and severe (>2). The instrument was found to be sensitive to change, and the minimal clinically important difference for the total NOSE HHT score was 0.46.Conclusions and relevanceEvaluation of the consistency, reliability, and responsiveness of the NOSE HHT survey found it to be a valid instrument to assess severity and change in epistaxis. Study results suggest that the NOSE HHT survey is clinically applicable and useful as an outcome measure of future HHT-associated epistaxis trials.

Project description:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by the presence of telangiectasias and arteriovenous malformations in various organs and organ systems, including the liver. The most frequent clinical manifestation of HHT is epistaxis.In 2010 (January-December inclusive) 51 patients with HHT were admitted to the ENT ward of our hospital for epistaxis, and in accordance with routine protocols, all 51 underwent abdominal ultrasonography in our department to detect hepatovascular lesions. They included 27 males (53%) and 24 (47%) females ranging in age from 11 to 86 years (mean 48.5 years). The sample was selected in an arbitrary manner to take maximum advantage of the hospital stay and monitor patients from regions other than our own.Retrospective analysis of the findings from these sonographic examinations revealed hepatic HHT in 27 (53%) of the 51 patients. Nineteen (70%) of these (age range 40-86 years, mean 63) had vascular malformations of various dimensions but no portal hypertension; the other eight (30%) (age range 39-81 years, mean 60) had vascular malformations plus portal hypertension.Our retrospective analysis indicates that a significant number of patients can have unrecognized hepatic involvement; that the appearance of hepatic lesions can be fairly unpredictable, even when the HHT has been diagnosed for years and the patients are already symptomatic; and that the hepatic lesions are frequently progressive. Therefore, regular sonographic follow-up is advisable for patients with HHT.The limitations of this study are related to the small number of patients examined and to the fact that all of them were symptomatic. Further study is therefore needed (especially in asymptomatic patients) to define the indications for hepatic sonography and the optimum examination schedule.Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by the presence of telangiectasias and arteriovenous malformations in various organs and organ systems, including the liver. The most frequent clinical manifestation of HHT is epistaxis.In 2010 (January–December inclusive) 51 patients with HHT were admitted to the ENT ward of our hospital for epistaxis, and in accordance with routine protocols, all 51 underwent abdominal ultrasonography in our department to detect hepatovascular lesions. They included 27 males (53%) and 24 (47%) females ranging in age from 11 to 86 years (mean 48.5 years). The sample was selected in an arbitrary manner to take maximum advantage of the hospital stay and monitor patients from regions other than our own.Retrospective analysis of the findings from these sonographic examinations revealed hepatic HHT in 27 (53%) of the 51 patients. Nineteen (70%) of these (age range 40–86 years, mean 63) had vascular malformations of various dimensions but no portal hypertension; the other eight (30%) (age range 39–81 years, mean 60) had vascular malformations plus portal hypertension.Our retrospective analysis indicates that a significant number of patients can have unrecognized hepatic involvement; that the appearance of hepatic lesions can be fairly unpredictable, even when the HHT has been diagnosed for years and the patients are already symptomatic; and that the hepatic lesions are frequently progressive. Therefore, regular sonographic follow-up is advisable for patients with HHT.The limitations of this study are related to the small number of patients examined and to the fact that all of them were symptomatic. Further study is therefore needed (especially in asymptomatic patients) to define the indications for hepatic sonography and the optimum examination schedule.

Project description:BACKGROUND:Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events. RESULTS:Sixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11?months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4?months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1-3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1-3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p?<?0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p?<?0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males (p?=?0.009), and in patients with ENG pathogenic variants (p?=?0.012). One fatal AE was possibly related to bevacizumab (average incidence rate: 1.5 per 100 person-years); 3 fatal AEs were possibly related to thalidomide (average incidence rate: 4 per 100 person-years). CONCLUSIONS:With potential increase in use of Bevacizumab and Thalidomide in HHT patients, data presented support appropriate weighing of the toxicities which can arise in HHT settings and the practice recommendations for their prevention and management.

Dataset Information

ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia.

Publications

ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia.

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