• number of adverse events [ Time Frame: 6 months ]
• number of adverse events [ Time Frame: 12 weeks ]
• number of adverse events [ Time Frame: 24 weeks ]
• Efficacy or nintedanib assessed by ESS (Epistaxis Severity Score) questionnaire [ Time Frame: 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 [ Time Frame: 24 weeks ]
  This score assess the severity of epistaxis (minimum 0 corresponds to "none" and maximum 10 corresponds to"severe")
• duration of epistaxis all over the study. Assessment on epistaxis grids completed by the patients. [ Time Frame: 12 weeks ]
• duration of epistaxis assessed on epistaxis grids completed by the patients. [ Time Frame: 24 weeks ]
• duration of epistaxis assessed on epistaxis grids completed by the patients. [ Time Frame: 12 weeks ]
• frequency of epistaxis assessed on epistaxis grids completed by the patients. [ Time Frame: 24 weeks ]
• Quality of life assessed by SF36 (Short Form 36) questionnaire [ Time Frame: 12 weeks ]
• Quality of life assessed by SF36 questionnaire [ Time Frame: 24 weeks ]
• number of red blood cell transfusions [ Time Frame: 12 weeks ]
• number of red blood cell transfusions [ Time Frame: 24 weeks ]
• number of iron infusions [ Time Frame: 12 weeks ]
• number of iron infusions [ Time Frame: 24 weeks ]
• hemoglobin level [ Time Frame: 12 weeks ]
• hemoglobin level [ Time Frame: 24 weeks ]
• ferritin level [ Time Frame: 12 weeks ]
• ferritin level [ Time Frame: 24 weeks ]

• number of adverse events [ Time Frame: 6 months ]
• number of adverse events [ Time Frame: 12 weeks ]
• number of adverse events [ Time Frame: 24 weeks ]
• Efficacy or nintedanib assessed by ESS (Epistaxis Severity Score) questionnaire [ Time Frame: 12 weeks ]
• Efficacy or nintedanib assessed by ESS questionnaire [ Time Frame: 24 weeks ]
• duration of epistaxis all over the study. Assessment on epistaxis grids completed by the patients. [ Time Frame: 12 weeks ]
• duration of epistaxis assessed on epistaxis grids completed by the patients. [ Time Frame: 24 weeks ]
• duration of epistaxis assessed on epistaxis grids completed by the patients. [ Time Frame: 12 weeks ]
• frequency of epistaxis assessed on epistaxis grids completed by the patients. [ Time Frame: 24 weeks ]
• Quality of life assessed by SF36 (Short Form 36) questionnaire [ Time Frame: 12 weeks ]
• Quality of life assessed by SF36 questionnaire [ Time Frame: 24 weeks ]
• number of red blood cell transfusions [ Time Frame: 12 weeks ]
• number of red blood cell transfusions [ Time Frame: 24 weeks ]
• number of iron infusions [ Time Frame: 12 weeks ]
• number of iron infusions [ Time Frame: 24 weeks ]
• hemoglobin level [ Time Frame: 12 weeks ]
• hemoglobin level [ Time Frame: 24 weeks ]
• ferritin level [ Time Frame: 12 weeks ]
• ferritin level [ Time Frame: 24 weeks ]

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

• Drug: Nintedanib 150 mg and 100 mg soft capsules
  Nintedanib 150 mg soft capsules twice daily approximately 12 hours apart (i.e. 300 mg/day) for 12 weeks. In case of adverse reaction a dose reduction at 200 mg/day (100 mg twice daily) can be prescribe.
• Drug: Oral treatment of placebo soft capsule
  Placebo soft capsules (identical to 150 mg and 100 mg soft capsules)

• Experimental: Nintedanib
  Oral treatment of Nintedanib 150 mg soft capsule
  Intervention: Drug: Nintedanib 150 mg and 100 mg soft capsules
• Placebo Comparator: Placebo
  Oral treatment of placebo soft capsule
  Intervention: Drug: Oral treatment of placebo soft capsule

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

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.