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

NCT03954782 | Completed Phase 2 DMC

• 2 other identifiers: 69HCL19_00032019-002593-31
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 8

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

Conditions

Telangiectasia, Hereditary Hemorrhagic; Rendu Osler Disease

Keywords

Hereditary Hemorrhagic Telangiectasia (HHT); antiangiogenic therapy; Tyrosine Kinase Inhibitor; Nintedanib

Outcome Measures

Primary Outcomes (1)

• Epistaxis duration assessed on epistaxis grids completed by the patients.

  12 weeks

Secondary Outcomes (19)

• 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

  12 weeks

• Efficacy or nintedanib assessed by ESS questionnaire

  24 weeks

Study Arms (2)

Nintedanib

EXPERIMENTAL

Oral treatment of Nintedanib 150 mg soft capsule

Drug: Nintedanib 150 mg and 100 mg soft capsules

Placebo

PLACEBO COMPARATOR

Oral treatment of placebo soft capsule

Drug: Oral treatment of placebo soft capsule

Interventions

Nintedanib 150 mg and 100 mg soft capsules DRUG

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.

Nintedanib

Oral treatment of placebo soft capsule DRUG

Placebo soft capsules (identical to 150 mg and 100 mg soft capsules)

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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).
• Patients with QTc prolongation
• Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients.
• Unhealed wound.

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (8)

CHU d'Angers

Angers, France

Location

Hôpital Femme-Mère-Enfant-Centre de Référence pour la maladie de Rendu-Osler

Bron, France

Location

CHU Clermont Ferrand

Clermont-Ferrand, France

Location

CHU de Marseille-Hôpital la conception

Marseille, France

Location

CHU de Montpellier-Hôpital St Eloi

Montpellier, France

Location

Hôpital Tenon

Paris, France

Location

CHRU - Hôpital J.Bernard

Poitiers, France

Location

CHU de Rennes-Hôpital Pontchaillou

Rennes, France

Location

Related Publications (1)

• Hermann R, Grobost V, Le-Guillou X, Lavigne C, Parrot A, Riviere S, Seguier J, Fargeton AE, de-Montigny A, Huot M, Decullier E, Roux A, Gervaise C, Cartier C, Dufour X, Grall M, Jegoux F, Laccourreye L, Michel J, Saroul N, Wagner I, Kerjouan M, Dupuis-Girod S. Effect of oral nintedanib vs placebo on epistaxis in hereditary hemorrhagic telangiectasia: the EPICURE multicenter randomized double-blind trial. Angiogenesis. 2024 Dec 24;28(1):9. doi: 10.1007/s10456-024-09962-4.

  PMID: 39718659 RESULT

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic

Interventions

nintedanib

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Telangiectasis; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Sophie DUPUIS-GIROD

  Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2019
• First Posted: May 17, 2019
• Study Start: June 22, 2020
• Primary Completion: February 24, 2023
• Study Completion: February 24, 2023
• Last Updated: August 1, 2025

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

FR (8)