Clinical trial NCT03227263: BABH Study: Efficacy and Safety of Bevacizumab on Severe Bleedings Associated With Hemorrhagic Hereditary Telangiectasia (HHT).
Official title: BABH Study: Efficacy and Safety of Bevacizumab on Severe Bleedings Associated With Hemorrhagic Hereditary Telangiectasia (HHT). A National, Multicenter Phase III Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rendu Osler Disease
Telangiectasia, Hereditary Hemorrhagic
Keywords: Hereditary Hemorrhagic Telangiectasia (HHT)
VEGF therapy
Bevacizumab
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2017-07-24
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


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 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

Primary outcomes:
measure: number of red blood cell transfusions
timeFrame: 6 months
Secondary outcomes:
measure: hemoglobin
timeFrame: 3 months
measure: hemoglobin
timeFrame: 6 months
measure: epistaxis frequency
timeFrame: 3 months before treatment up to 6 months from the inclusion
measure: duration of nosebleeds
timeFrame: 3 months before treatment up to 6 months from the inclusion
measure: digestive vascular malformations
timeFrame: 6 months
measure: quality of life (SF36).
timeFrame: 3 months
measure: quality of life (SF36).
timeFrame: 6 months
measure: severity epistaxis score (ESS).
timeFrame: 3 months
measure: severity epistaxis score (ESS).
timeFrame: 6 months.
measure: To evaluate pharmacokinetics of bevacizumab dose
timeFrame: Before each 6 infusions
measure: To evaluate pharmacokinetics of bevacizumab dose
timeFrame: 2 hours after the first treatment infusion
measure: adverse events
timeFrame: up to 6 months
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU d'Angers
city: Boulogne Billancourt
country: France
facility: Hôpital Ambroise Paré
city: Bron
country: France
facility: Hôpital Femme Mère Enfant
city: Montpellier
country: France
facility: CHU de Montpellier Hôpital St Eloi
Study officials:
affiliation: Hospices Civils de Lyon
name: DUPUIS-GIROD, MD
role: PRINCIPAL_INVESTIGATOR
References: