BABH Study: Efficacy and Safety of Bevacizumab on Severe Bleedings Associated With Hemorrhagic Hereditary Telangiectasia (HHT).

Study Overview
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Brief Summary
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The recognized manifestations of HHT are all due to abnormalities of vascular structure. Epistaxis and digestive arteriovenous malformations may be responsible for severe hemorrhages in 5% of HHT patients, requiring repeated blood transfusions and are associated with high morbidity. There is currently no standard and efficient management of this severe symptom. It is also well known that HHT-associated hemorrhages have the greatest negative impact on quality of life among HHT patients, and is responsible for anemia, blood transfusions, hospitalizations, depressive syndrome and a high psycho-social impact. Since 2006, it has been suggested by animal models and then by clinical reports that anti-VEGF therapy may be useful to treat HHT. 4 case reports have been published on efficacy of intravenous bevacizumab, a humanized monoclonal antibody in HHT on severe hemorrhages. Intravenous bevacizumab has been used in a previous clinical trial to measure efficacy and tolerance of this drug in HHT patients with severe liver involvement. Furthermore, a reduction was observed in the duration of the nosebleeds after treatment and was encouraging to treat bleeding. We completed this study by a pharmacokinetic-pharmacodynamic (PK-PD) model in order to assess the individual concentration-effect relationship of bevacizumab. However, no randomized prospective study has been performed and published to evaluate the efficacy in this indication. A total of 24 patients will be randomized versus placebo in a multicenter phase III trial. The Avastin or placebo will be infused at 5mg/kg every 14 days with a total of 6 cures with a 3 months following period.

Official Title
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BABH Study: Efficacy and Safety of Bevacizumab on Severe Bleedings Associated With Hemorrhagic Hereditary Telangiectasia (HHT). A National, Multicenter Phase III Study

Conditions
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Rendu Osler Disease, Telangiectasia, Hereditary Hemorrhagic

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: sodium chloride 0.9%


Participation Criteria
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Eligibility Criteria
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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 three Curaçao criteria) and / or with molecular biology confirmation. Blood transfusions with the requirement for at least 4 units of blood in the 3-month period before study enrollment, related to epistaxis or digestive bleeding. Exclusion Criteria: Women who are pregnant or nursing (lactating), women of child-bearing potential without reliable contraception during the treatment and for at least 6 months after the last dose. 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 study. Active infection and/or fever>38°C Participation in another clinical trial within 28 days prior to inclusion. Hypersensitivity to the active substance or to any of the excipients. Known hypersensitivity to products of Chinese hamster ovary cells (CHO) or other recombinant human or humanized antibodies. Patients who have taken Avastin ® intravenously in the 6 months prior to inclusion. Patients who have had a therapeutic endoscopy for gastrointestinal bleeding or ENT surgery for epistaxis will have to wait at least 3 months less after treatment to be included if bleeding persists. Patients who had a surgery in the month prior inclusion or planned surgery within 6 months Severe peripheral arterial disease with ulcerations Unhealed wound Thrombosis in the 6 months prior to inclusion Anticoagulant treatment Uncontrolled high blood pressure

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab<br>Intravenous infusion of Bevacizumab at a dose of 5 mg/kg | Drug: Bevacizumab<br>* Bevacizumab (Avastin®) concentrate at 25mg/mL is diluted at 5 mg/kg for infusion every 14 days for 6 consecutive administrations<br>|
| Placebo Comparator: Placebo<br>0.9% of sodium chloride is infused every 14 days for 6 consecutive administrations | Drug: sodium chloride 0.9%<br>* 0.9% of sodium chloride is infused every 14 days for 6 consecutive administrations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of red blood cell transfusions |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hemoglobin | The relative evolution in hemoglobin level at 3 months after the beginning of the treatment is compared to the value measured at inclusion | 3 months | 
| hemoglobin | The relative evolution in hemoglobin level at 6 months after the beginning of the treatment is compared to the value measured at inclusion | 6 months | 
| epistaxis frequency | Comparison of an average over a 3-month period before and after the treatment. | 3 months before treatment up to 6 months from the inclusion | 
| duration of nosebleeds | Comparison of an average over a 3-month period before and after the treatment. | 3 months before treatment up to 6 months from the inclusion | 
| digestive vascular malformations | Comparison of digestive endoscopy before and after treatment if gastrointestinal bleeding have already externalized before treatment | 6 months | 
| quality of life (SF36). | Comparison of SF36 questionnaire before and after treatment. | 3 months | 
| quality of life (SF36). | Comparison of SF36 questionnaire before and after treatment. | 6 months | 
| severity epistaxis score (ESS). | Comparison of ESS questionnaire before and after treatment | 3 months | 
| severity epistaxis score (ESS). | Comparison of ESS questionnaire before and after treatment | 6 months. | 
| To evaluate pharmacokinetics of bevacizumab dose | Description of bevacizumab serum concentrations over time, the relationship between bevacizumab concentrations and adverse events and clinical/biological endpoints | Before each 6 infusions | 
| To evaluate pharmacokinetics of bevacizumab dose | Description of bevacizumab serum concentrations over time, the relationship between bevacizumab concentrations and adverse events and clinical/biological endpoints | 2 hours after the first treatment infusion | 
| adverse events | To assess the safety of bevacizumab.Tolerance will be evaluated by recording adverse events and by clinical examinations during the treatment period and the follow up period. | up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hereditary Hemorrhagic Telangiectasia (HHT), VEGF therapy, Bevacizumab