Efficacy of Nintedanib for Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) Patients

NCT04976036 | Recruiting Phase 2 DMC

• 1 other identifier: 1199-0433
• Study Type: interventional
• Target: 48
• Locations: 2 countries
• Sites: 3

Brief Summary

Patients affected by hereditary hemorrhagic telangiectasia (HHT) very often suffer from recurrent nosebleeds called epistaxis. There is no treatment currently available to reduce the frequency or severity of epistaxis. This research project will examine the effect of nintedanib, a capsule to be taken twice a day, on the frequency and severity of epistaxis in HHT. The study will take place at the Respiratory medicine department of the Lausanne University Hospital (Centre hospitalier universitaire vaudois, CHUV). The investigators will recruit about 48 participants with HHT, who will be divided in 2 groups. Each group will perform the same examinations and follow-up visits. The study will begin with 2 months of observation during which subjects will be asked to fill a diary to record the number and duration of epistaxis episodes. The diary will be filled daily for the entire duration of the study, i.e. 8 months. After 2 months of observation, the treatment phase will begin. Participants will take a capsule (nintedanib 150 mg or placebo) once a day for 2 weeks, then twice a day for 14 weeks. In case of intolerance at the dose of 2 capsules per day, the treatment may be reduced to 1 capsule per day. Subjects will also have to mention on the diary any blood transfusion, iron perfusion, and any symptoms they may be experiencing. Following the 16 weeks of treatment, an 8-week follow-up period will allow to observe the effects of nintedanib after the end of the treatment period, and to monitor any unexpected adverse events.

Conditions

Telangiectasia, Hereditary Hemorrhagic

Keywords

nintedanib; epistaxis; treatment

Outcome Measures

Primary Outcomes (1)

• Change of epistaxis duration in minutes under nintedanib treatment as compared to placebo in HHT patients.

  The primary outcome will be the proportion of patients with at least 30% change of monthly epistaxis duration in minutes after 16 weeks of study treatment (at V6, week 24) compared to baseline (V1, week 8) assessed in nintedanib arm and in placebo arm. * The monthly epistaxis duration after 16 weeks of study treatment is defined as the average of epistaxis duration during the last 12 weeks of study treatment (minutes/4-weeks period averaged for weeks 12 to 24, i.e. V3 to V6) * The monthly epistaxis duration at baseline is defined as the average of epistaxis duration during the observation period (minutes/4-weeks period averaged for weeks 1 to 8, i.e. V0 to V1).

  Week 0 to week 7

Secondary Outcomes (7)

• Change in number of epistaxis episodes per 4 weeks

  Secondary endpoints will be evaluated at week 8, 16, 20, 24 and 32

• Change in the Nasal Outcome for Epistaxis in Hereditary Hemorrhagic Telangiectasia score

  Secondary endpoints will be evaluated at week 8, 16, 20, 24 and 32

• Change in number of blood transfusions per 4 weeks

  Secondary endpoints will be evaluated at week 8, 12, 16, 20, 24 and 32

• Change in epistaxis severity score (ESS)

  Secondary endpoints will be evaluated at week 8, 16, 24 and 32

• Change in number of iron infusions per 4 weeks

  Secondary endpoints will be evaluated at week 8, 12, 16, 20, 24 and 32

Study Arms (2)

Nintedanib

EXPERIMENTAL

nintedanib 150 mg once a day for 2 weeks, then twice a day for 14 weeks

Drug: Nintedanib

Placebo

PLACEBO COMPARATOR

placebo 150 mg once a day for 2 weeks, then twice a day for 14 weeks

Drug: Placebo

Interventions

Nintedanib DRUG

150 mg oral nintedanib soft caps, once a day for 2 weeks and twice a day for 10 weeks (12 hours interval)

Nintedanib

Placebo DRUG

150 mg oral placebo soft caps, once a day for 2 weeks and twice a day for 10 weeks (12 hours interval)

Placebo

Eligibility Criteria

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

You may qualify if:

• signed informed consent
• definite HHT disease (defined as the presence of a pathogenic mutation in one of the HHT genes, or the presence of 3 out of 4 Curaçao clinical criteria)
• age ≥18 years at the time of informed consent
• moderate to serious epistaxis defined as Epistaxis Severity Score (ESS) ≥2.5
• absence of cerebral arteriovenous malformation demonstrated by brain imaging

You may not qualify if:

• Women who are pregnant or breastfeeding
• For women of childbearing potential (WOCBP, see Annex VII for definition), non-agreement to follow instructions for method(s) of contraception for the heterosexual couple (see Annex VII for instructions) during the treatment period and follow-up, or at least 3 months after the last dose of IMP, or if there are concerns that they will not reliably comply with the contraception requirements.
• Acute infection
• aspartate aminotransferase (AST), or alanine aminotransferase (ALT), or total bilirubin \>1.5x (or \>2.5x in patients known for Gilbert's syndrome) the upper limit of normal
• Renal clearance by Cockcroft-Gault formula \<30 ml/min
• Untreated pulmonary arteriovenous malformation (if vaso-occlusion is technically feasible)
• Hemoptysis or hematuria within the last 12 months
• Ulcus or active gastric bleeding within the last 12 months
• Anticoagulant or antiplatelets treatment
• Coronary heart disease
• Thrombotic event within the last 12 months
• Long QT syndrome (on ECG performed at screening)
• Known allergy to nintedanib, soya, peanuts
• Bevacizumab, pazopanib or other anti-angiogenic treatments within the last 12 months
• Concomitant treatment with ketoconazole, erythromycin, rifampicin, carbamazepine, phenytoin, St John's Wort

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: collaborator
• Dr. Romain Lazor: lead
• Boehringer Ingelheim: collaborator

Study Sites (3)

Lyon University Hospital, Dpt of genetics

Bron, 69677, France

RECRUITING

Clermont-Ferrand university hospital

Clermont-Ferrand, 63000, France

RECRUITING

Angiology Department, Lausanne University Hospital

Lausanne, Canton of Vaud, 1011, Switzerland

COMPLETED

Related Publications (2)

• Robert F, Desroches-Castan A, Bailly S, Dupuis-Girod S, Feige JJ. Future treatments for hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2020 Jan 7;15(1):4. doi: 10.1186/s13023-019-1281-4.

  PMID: 31910860 RESULT

• Kovacs-Sipos E, Holzmann D, Scherer T, Soyka MB. Nintedanib as a novel treatment option in hereditary haemorrhagic telangiectasia. BMJ Case Rep. 2017 Jun 26;2017:bcr2017219393. doi: 10.1136/bcr-2017-219393.

  PMID: 28652319 RESULT

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic; Epistaxis

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; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Respiratory; Signs and Symptoms

Central Study Contacts

Romain Lazor, MD

CONTACT

+41 79 556 21 69; romain.lazor@chuv.ch

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: April 10, 2021
• First Posted: July 26, 2021
• Study Start: May 5, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: March 11, 2026

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share

Locations

FR (2); CH (1)