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

Telangiectasia, Hereditary Hemorrhagic Clinical Trial

— EPICURE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03954782
• Other study ID #: 69HCL19_0003
• Secondary ID: 2019-002593-31
• Status: Completed
• Phase: Phase 2
• Start date: June 22, 2020
• Est. completion date: February 24, 2023

Study information

• Verified date: August 2023
• Source: Hospices Civils de Lyon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 61
• Est. completion date: February 24, 2023
• Est. primary completion date: February 24, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Epistaxis
• Telangiectasia, Hereditary Hemorrhagic
• Telangiectasis

Intervention

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.
• Oral treatment of placebo soft capsule
Placebo soft capsules (identical to 150 mg and 100 mg soft capsules)

Locations

Country	Name	City	State
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	CHU de Marseille-Hôpital la conception	Marseille
France	CHU de Montpellier-Hôpital St Eloi	Montpellier
France	Hôpital Tenon	Paris
France	CHRU - Hôpital J.Bernard	Poitiers
France	CHU de Rennes-Hôpital Pontchaillou	Rennes

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

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