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

Study Overview
=================
Brief Summary
-----------------
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

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

Conditions
-----------------
Hereditary Hemorrhagic Telangiectasia, Epistaxis

Intervention / Treatment
-----------------
* Drug: Bevacizumab
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab 25mg<br>Three administrations of 25 mg of Bevacizumab spaced of 14 days | Drug: Bevacizumab<br> <br> * Other names: Three administrations of Bevacizumab spaced of 14 days;|
| Experimental: Bevacizumab 50mg<br>Three administrations of 50 mg of Bevacizumab spaced of 14 days | Drug: Bevacizumab<br> <br> * Other names: Three administrations of Bevacizumab spaced of 14 days;|
| Experimental: Bevacizumab 75mg<br>Three administrations of 75 mg of Bevacizumab spaced of 14 days | Drug: Bevacizumab<br> <br> * Other names: Three administrations of Bevacizumab spaced of 14 days;|
| Placebo Comparator: Placebo<br>Three administrations of placebo spaced of 14 days | Drug: placebo<br> <br> * 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Epistaxis, Bevacizumab