Efficacy of Nintedanib Per os as a Treatment for Epistaxis in HHT Disease.

Phase 2

Completed

• Conditions: Telangiectasia, Hereditary Hemorrhagic; Rendu Osler Disease
• Interventions: Drug: Oral treatment of placebo soft capsule; Drug: Nintedanib 150 mg and 100 mg soft capsules

• Registration Number: NCT03954782
• Lead Sponsor: Hospices Civils de Lyon

Brief Summary

The recognized manifestations of HHT are all due to abnormalities in vascular structure. Epistaxis are spontaneous, very variable, may occur as often as several times every day, and are recurrent in 90% of patients and associated with chronic and severe anemia in 2-10%. They also significantly reduce quality of life.

Blood transfusions are sometimes required in 10-30% of patients. Previous studies showed that antiangiogenic treatments such as anti-VEGF treatment (bevacizumab) administered intravenously was efficient on epistaxis and dramatically reduced nosebleeds.

Tyrosine kinase inhibitors are anti-angiogenic molecules which are available orally and could therefore overcome the difficulties encountered with bevacizumab. The investigator hypothesized that nintedanib, acting by indirect inhibition of the VEGF receptor should allow a reduction of epistaxis in HHT patient.

Nintedanib has been used in one HHT patient following the diagnosis of Insterstitial Pulmonary Fibrosis (published case report in 2017, Kovacs et al) with encouraging results.

The aim is to evaluate efficacy of nintedanib for the treatment of epistaxis in HHT patients

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-05-15
• Study First Submitted QC: 2019-05-15
• Study First Posted: 2019-05-17
• Study Start: 2020-06-22
• Primary Completion: 2023-02-24
• Study Completion: 2023-02-24
• Status Verified: 2023-08
• Last Update Submitted: 2023-08-03
• Last Update Posted: 2023-08-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 61

Inclusion Criteria

• Age > 18 years old
• 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 and/or with molecular biology confirmation
• Patient with an Epistaxis Severity Score (ESS) > 4

Read More

Exclusion Criteria

• Pregnant woman or woman of child bearing potential
• Woman who are breast feeding.
• Patient who is protected adults under the terms of the law (French Public Health Code).
• Participation in another interventional clinical trial which may interfere with the proposed trial
• Active infection.
• (AST, ALT > 1,5 fold upper limit of normal (ULN) and/or Bilirubin > 1,5 fold upper limit of normal (ULN).
• Severe renal impairment
• Presence of non-treated pulmonary arteriovenous malformations accessible to a treatment on CT scan within 5 years.
• Patients with hemoptysis or hematuria within 12 weeks prior to inclusion.
• Patients with active gastro-intestinal (GI) bleeding or GI ulcers within 12 months prior to inclusion.
• Presence of cerebral arteriovenous malformation.
• Patients who require full-dose therapeutic anticoagulation (e.g. vitamin K antagonist or heparin, dabigatran) or high dose antiplatelet therapy, , patients under anticoagulation with rivaroxaban, apixaban and epixaban.
• Patients with P-glycoprotein (P-gp) substrates/inducers/inhibitors (e.g.: ketoconazole, erythromycin, cyclosporine, rifampicin, carbamazepine, phenytoin, and St. John's Wort).
• Patients with known coronary artery disease or recent history of myocardial infarction (within 1 year).
• Known inherited predisposition to thrombosis or thrombotic events( including stroke and transient ischemic attack, excluded superficial venous thrombosis) within 12 months prior to inclusion.
• Patients with QTc prolongation
• Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients.
• Patient who incompletely filled in epistaxis grids within 8 weeks prior to inclusion.
• Patient who have received intravenous bevacizumab within 6 months prior to inclusion.
• Patient who had surgery (including ENT (Ear, Nose and Throat Specialist) surgery) within 12 weeks prior to inclusion.
• Unhealed wound.
• Planned major surgery within the next 3 months, including liver transplantation, major abdominal or intestinal surgery.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Oral treatment of placebo soft capsule	Oral treatment of placebo soft capsule
Nintedanib	Nintedanib 150 mg and 100 mg soft capsules	Oral treatment of Nintedanib 150 mg soft capsule

Primary Outcome Measures

Name	Time	Method
Epistaxis duration assessed on epistaxis grids completed by the patients.	12 weeks

Secondary Outcome Measures

Name	Time	Method
hemoglobin level	24 weeks
number of adverse events	24 weeks
Efficacy or nintedanib assessed by ESS (Epistaxis Severity Score) questionnaire	12 weeks	This score assess the severity of epistaxis (minimum 0 corresponds to "none" and maximum 10 corresponds to"severe")
Efficacy or nintedanib assessed by ESS questionnaire	24 weeks	This score assess the severity of epistaxis (minimum 0 corresponds to "none" and maximum 10 corresponds to"severe")
Quality of life assessed by SF36 (Short Form 36) questionnaire	12 weeks
number of iron infusions	24 weeks
ferritin level	24 weeks
duration of epistaxis all over the study. Assessment on epistaxis grids completed by the patients.	12 weeks
Quality of life assessed by SF36 questionnaire	24 weeks
duration of epistaxis assessed on epistaxis grids completed by the patients.	12 weeks
frequency of epistaxis assessed on epistaxis grids completed by the patients.	24 weeks
number of red blood cell transfusions	24 weeks

Trial Locations

Locations (8)

CHU de Marseille-Hôpital la conception; 🇫🇷 Marseille, France

CHU d'Angers; 🇫🇷 Angers, France

Hôpital Femme-Mère-Enfant-Centre de Référence pour la maladie de Rendu-Osler; 🇫🇷 Bron, France

CHU Clermont Ferrand; 🇫🇷 Clermont-Ferrand, France

CHRU - Hôpital J.Bernard; 🇫🇷 Poitiers, France

CHU de Montpellier-Hôpital St Eloi; 🇫🇷 Montpellier, France

CHU de Rennes-Hôpital Pontchaillou; 🇫🇷 Rennes, France

Hôpital Tenon; 🇫🇷 Paris, France