Efficacy of Nintedanib for Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) Patients (EPISTOP)
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ClinicalTrials.gov Identifier: NCT04976036 |
Recruitment Status :
Recruiting
First Posted : July 26, 2021
Last Update Posted : July 26, 2022
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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.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Telangiectasia, Hereditary Hemorrhagic | Drug: Nintedanib Drug: Placebo | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 48 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Primary Purpose: | Treatment |
Official Title: | Phase II Monocentric Randomized Study on Efficacy of Nintedanib for Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) Patients |
Actual Study Start Date : | May 5, 2022 |
Estimated Primary Completion Date : | April 2024 |
Estimated Study Completion Date : | September 2024 |
Arm | Intervention/treatment |
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Experimental: Nintedanib
nintedanib 150 mg once a day for 2 weeks, then twice a day for 14 weeks
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Drug: Nintedanib
150 mg oral nintedanib soft caps, once a day for 2 weeks and twice a day for 10 weeks (12 hours interval) |
Placebo Comparator: Placebo
placebo 150 mg once a day for 2 weeks, then twice a day for 14 weeks
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Drug: Placebo
150 mg oral placebo soft caps, once a day for 2 weeks and twice a day for 10 weeks (12 hours interval) |
- Change of epistaxis duration in minutes under nintedanib treatment as compared to placebo in HHT patients. [ Time Frame: Week 0 to week 7 ]
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).
- Change in number of epistaxis episodes per 4 weeks [ Time Frame: Secondary endpoints will be evaluated at week 8, 16, 20, 24 and 32 ]Number of epistaxis will be recorded daily by participants on the daily grid and the number of episodes per 4 weeks will be compared between baseline and treatment period at V3-V6
- Change in the Nasal Outcome for Epistaxis in Hereditary Hemorrhagic Telangiectasia score [ Time Frame: Secondary endpoints will be evaluated at week 8, 16, 20, 24 and 32 ]The Nasal Outcome for Epistaxis in Hereditary Hemorrhagic Telangiectasia (NOSE HHT questionnaire) wil be used to measure physical, social and emotional impacts of epistaxis. It is a 29-items questionnaire using a Likert scale. A higher score indicates a worse outcome. Comparison will be made between the observation period and the treatment period and follow-up.
- Change in number of blood transfusions per 4 weeks [ Time Frame: Secondary endpoints will be evaluated at week 8, 12, 16, 20, 24 and 32 ]Participants will record number of blood transfusions on the daily grid. Comparison will be made between the observation period and the treatment period and follow-up.
- Change in epistaxis severity score (ESS) [ Time Frame: Secondary endpoints will be evaluated at week 8, 16, 24 and 32 ]Epistaxis Severity Score (ESS) is a 6-item score. Each answer gives a number of points which is multiplied by a coefficient. The sum of the 6 answers provides the score. A higher score indicates a worse outcome. The score during the observation period will be compared to the score during the treatment period and follow-up.
- Change in number of iron infusions per 4 weeks [ Time Frame: Secondary endpoints will be evaluated at week 8, 12, 16, 20, 24 and 32 ]Participants will record the number of iron perfusions on the daily grid. Comparison will be made between the observation period and the treatment period and follow-up.
- Change in hemoglobin level in g/l [ Time Frame: Secondary endpoints will be evaluated at week 8, 12, 16, 20, 24 and 32 ]Comparison will be made between the observation period and the treatment period and follow-up.
- Change in ferritin level in ng/ml [ Time Frame: Secondary endpoints will be evaluated at week 8, 12, 16, 20, 24 and 32 ]Comparison will be made between the observation period and the treatment period and follow-up.
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion criteria:
- 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
Exclusion criteria:
- 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
- Surgery within the last 3 months or planned within the next 9 months
- Recent unhealed wound
- Any other serious underlying medical condition that could interfere with the study treatment and potential adverse events
- Any mental or other impairment that may compromise compliance with the study requirements.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04976036
Contact: Romain Lazor, MD | +41213144746 | romain.lazor@chuv.ch | |
Contact: Estelle Clement, RN | estelle.clement@chuv.ch |
Switzerland | |
Respiratory medicine Department, Lausanne University Hospital | Recruiting |
Lausanne, Vaud, Switzerland, 1011 | |
Contact: Romain Lazor, MD 0041213144746 romain.lazor@chuv.ch | |
Principal Investigator: Romain Lazor, MD |
Responsible Party: | Dr. Romain Lazor, Head of interstitial and rare lung disease Unit, Principal investigator, Centre Hospitalier Universitaire Vaudois |
ClinicalTrials.gov Identifier: | NCT04976036 |
Other Study ID Numbers: |
1199-0433 |
First Posted: | July 26, 2021 Key Record Dates |
Last Update Posted: | July 26, 2022 |
Last Verified: | March 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | Data are available on request. |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
nintedanib epistaxis treatment |
Epistaxis Telangiectasis Telangiectasia, Hereditary Hemorrhagic Vascular Diseases Cardiovascular Diseases Nose Diseases Respiratory Tract Diseases Otorhinolaryngologic Diseases Hemorrhage Pathologic Processes Signs and Symptoms, Respiratory |
Hemostatic Disorders Hemorrhagic Disorders Hematologic Diseases Vascular Malformations Cardiovascular Abnormalities Congenital Abnormalities Nintedanib Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |