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

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

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

Study Overview

• Status: Completed
• 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

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sophie DUPUIS-GIROD, MD; Phone Number: +33 4 27 85 65 25; Email: sophie.dupuis-girod@chu-lyon.fr

Study Locations

• France
  • Angers, France
    • CHU d'Angers
  • Bron, France
    • Hôpital Femme-Mère-Enfant-Centre de Référence pour la maladie de Rendu-Osler
  • Clermont-Ferrand, France
    • CHU Clermont Ferrand
  • Marseille, France
    • CHU de Marseille-Hôpital la conception
  • Montpellier, France
    • CHU de Montpellier-Hôpital St Eloi
  • Paris, France
    • Hôpital Tenon
  • Poitiers, France
    • CHRU - Hôpital J.Bernard
  • Rennes, France
    • CHU de Rennes-Hôpital Pontchaillou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nintedanib; Oral treatment of Nintedanib 150 mg soft capsule	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.
Placebo Comparator: Placebo; Oral treatment of placebo soft capsule	Drug: Oral treatment of placebo soft capsule; Placebo soft capsules (identical to 150 mg and 100 mg soft capsules)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 to"severe")	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 to"severe")	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

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Sophie DUPUIS-GIROD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2020
• Primary Completion (Actual): February 24, 2023
• Study Completion (Actual): February 24, 2023

Study Registration Dates

• First Submitted: May 15, 2019
• First Submitted That Met QC Criteria: May 15, 2019
• First Posted (Actual): May 17, 2019

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Hereditary Hemorrhagic Telangiectasia (HHT); Nintedanib; Tyrosine Kinase Inhibitor; antiangiogenic therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Congenital Abnormalities; Hematologic Diseases; Hemorrhage; Hemorrhagic Disorders; Otorhinolaryngologic Diseases; Hemostatic Disorders; Signs and Symptoms, Respiratory; Nose Diseases; Cardiovascular Abnormalities; Vascular Malformations; Epistaxis; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: 69HCL19_0003; 2019-002593-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No