Efficacy of a Bevacizumab Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) (ALEGORI)

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare (~ 1/6000) but ubiquitous genetic disease. It is associated with abnormal angiogenesis and autosomal dominant inheritance, leading to telangiectasias and arteriovenous fistulae. More than 95% of patients are concerned by epistaxis (nosebleeds). These events are spontaneous, repeated, irregular, both diurnal and nocturnal, a source of anemia, disabling and very socially embarrassing.

Anti-angiogenic treatments, including bevacizumab, are a new therapeutic option in HHT.

The aim of this study is to evaluate 3 months after the end of the treatment the efficacy on the duration of the nosebleeds with 3 different doses (25, 50 and 75 mg) of bevacizumab administered as a nasal spray in a repeated manner (3 administrations) in patients with Hereditary Hemorrhagic Telangiectasia complicated by nosebleeds.

This randomized, double-blind, placebo-controlled, seamless phase II/III study is to be carried out on 4 groups of 20 patients for first step and 2 groups of 20 to 40 patients for second step

Study Overview

• Status: Terminated
• Conditions: Epistaxis; Hereditary Hemorrhagic Telangiectasia
• Intervention / Treatment: Drug: placebo; Drug: Bevacizumab

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Bron, France, 69677
    • Hôpital Louis Pradel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years.
• Patients who have given their free informed and signed consent.
• Patients affiliated to a social security scheme or similar.
• Patients monitored for clinically confirmed HHT (presence of at least 3 Curaçao criteria) and/or confirmed by molecular biology.
• Patients who have not undergone nasal surgery in the 3 months prior to inclusion.
• Patient with nosebleeds of a monthly duration of more than 20 minutes and justified by follow-up grids completed for at least the 3 months prior to the time of inclusion.

Exclusion Criteria:

• Women who are pregnant or likely to become so in the course of the study.
• Patients not affiliated to a social security scheme.
• Patients who are protected adults under the terms of the law (French Public Health Code).
• Refusal to consent.
• Patients for whom the diagnosis of HHT has not been confirmed clinically and/or by molecular biology.
• Patients with an on-going infectious condition.
• Participation in another clinical trial within the 28 days prior to inclusion.
• Known hypersensitivity to the active ingredient or one of the excipients.
• Known hypersensitivity to products of Chinese hamster ovary cells (CHO) or other human or humanized recombinant antibodies.
• Patients who have incompletely filled in the nosebleed grids in the 3 months preceding the treatment.
• Patients who do not present with nosebleeds with a monthly average duration over the 3 months preceding the treatment of more than 20 minutes ((duration M1 + duration M2 + duration M3) / 3). Remark: only the 3 months strictly preceding the treatment will be taken into account, even if the grids have been completed over a longer period.
• Patients who have received Avastin® intravenously in the 6 months prior to inclusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bevacizumab 25mg; Three administrations of 25 mg of Bevacizumab spaced of 14 days	Drug: Bevacizumab; Other Names: Three administrations of Bevacizumab spaced of 14 days
Experimental: Bevacizumab 50mg; Three administrations of 50 mg of Bevacizumab spaced of 14 days	Drug: Bevacizumab; Other Names: Three administrations of Bevacizumab spaced of 14 days
Experimental: Bevacizumab 75mg; Three administrations of 75 mg of Bevacizumab spaced of 14 days	Drug: Bevacizumab; Other Names: Three administrations of Bevacizumab spaced of 14 days
Placebo Comparator: Placebo; Three administrations of placebo spaced of 14 days	Drug: placebo; Other Names: Three administrations of placebo spaced of 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mean duration of epistaxis	To evaluate 3 months after the end of the treatment the efficacy on the duration of the nosebleeds with 3 different doses (25, 50 and 75 mg) of bevacizumab administered as a nasal spray in a repeated manner (3 administrations).	3 months after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
adverse events	Adverse events observed along a repeated administration of bevacizumab (nasal spray administration) : evaluation by epistaxis monitoring along the study and by a clinical exam before each treatment and 6 months after the end of the treatment.	before and 6 months after treatment
mean monthly epistaxis duration	To evaluate the efficacy at 6 months after the end of the treatment on the duration of the nosebleeds for the dose retained versus placebo	6 months after the end of the treatment
frequency and duration of epistaxis	Evolution of the frequency and the mean monthly duration of epistaxis at 3 and 6 months for the dose retained	3 months and 6 months after the end of the treatment
Quality of life	Evolution of the quality of life score (SF-36) between the inclusion, 3 months and 6 months after the end of the treatment	3 months and 6 months aftert the end of the treatment
Number of red blood cells transfusion	Evolution of the number of red blood cells transfusion between the inclusion and 3 and 6 months after the end of the treatment.	3 months and 6 months after the end of the treatment
Change in hemoglobinemia and serum ferritin	Evolution of hemoglobinemia and serum ferritin at inclusion,3 and 6 months after the end of the treatment for the retained dose	1 month, 3 months and 6 months
Kinetics of monthly epistaxis duration	To describe the nosebleed kinetics for the dose retained and the placebo throughout the study	6 months

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Sophie DUPUIS-GIROD, MD, Service de génétique, Hôpital Louis Pradel, Hospices Civils de Lyon

Publications and helpful links

General Publications

• Dupuis-Girod S, Ambrun A, Decullier E, Fargeton AE, Roux A, Breant V, Colombet B, Riviere S, Cartier C, Lacombe P, Chinet T, Blivet S, Blondel JH, Gilbert-Dussardier B, Dufour X, Michel J, Harle JR, Dessi P, Faure F. Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial. JAMA. 2016 Sep 6;316(9):934-42. doi: 10.1001/jama.2016.11387.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: April 1, 2014
• First Submitted That Met QC Criteria: April 3, 2014
• First Posted (Estimate): April 8, 2014

Study Record Updates

• Last Update Posted (Estimate): November 20, 2015
• Last Update Submitted That Met QC Criteria: November 19, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Bevacizumab; Epistaxis
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Congenital Abnormalities; Hematologic Diseases; Hemorrhage; Hemorrhagic Disorders; Otorhinolaryngologic Diseases; Hemostatic Disorders; Signs and Symptoms, Respiratory; Nose Diseases; Cardiovascular Abnormalities; Vascular Malformations; Epistaxis; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: 2013.827