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

Study Overview
=================
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

Official Title
-----------------
Efficacy of Nintedanib Per os as a Treatment for Epistaxis in HHT Disease. A National, Randomized, Multicentre Phase II Study

Conditions
-----------------
Telangiectasia, Hereditary Hemorrhagic, Rendu Osler Disease

Intervention / Treatment
-----------------
* Drug: Nintedanib 150 mg and 100 mg soft capsules
* Drug: Oral treatment of placebo soft capsule


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

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: Nintedanib<br>Oral treatment of Nintedanib 150 mg soft capsule | Drug: Nintedanib 150 mg and 100 mg soft capsules<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Oral treatment of placebo soft capsule | Drug: Oral treatment of placebo soft capsule<br>* Placebo soft capsules (identical to 150 mg and 100 mg soft capsules)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epistaxis duration assessed on epistaxis grids completed by the patients. |  | 12 weeks | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hereditary Hemorrhagic Telangiectasia (HHT), antiangiogenic therapy, Tyrosine Kinase Inhibitor, Nintedanib