Efficacy of a Timolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) - (TEMPO)

Study Overview
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Brief Summary
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Timolol is a nonselective β-blocker commonly used in the treatment of glaucoma. Recently it has been used topically for the treatment of superficial hemangiomas. Because of its potential mechanism of action, it is possible that timolol could also be useful for the treatment of epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT). Moreover a case was reported in 2012 showing an improvement of nosebleeds with the use of topical nasal timolol. The aim of the study is to evaluate timolol nasal spray efficacy in HHT. The main objective of this trial is to evaluate, 3 months after the end of the treatment, the efficacy on the duration of nosebleeds of a 4 weeks timolol intranasal treatment in HHT patients with nosebleeds (>20 min/month). Secondary objectives are to evaluate the tolerance, the efficacy at 6 months after the end of the treatment, and the efficacy on anemia and on clinical parameters (nosebleeds, quality of life and blood transfusions). This is a prospective double blind phase II study, randomized versus placebo using an allocation ratio of 1:1. A total of 58 patients will be included. The product (solution with timolol at 0.5% or placebo) is self-administered by the patient with a posology of one spray (50 µL) in each nostril twice a day for 28 consecutive days.

Official Title
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Efficacy of a Timolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) - Randomized Trial Versus Placebo

Conditions
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Telangiectasia, Hereditary Hemorrhagic, Osler Rendu Disease

Intervention / Treatment
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* Drug: Timolol nasal spray
* Drug: Placebo nasal spray


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Patients who give voluntary, informed consent and sign a consent form. Patients affiliated with the French universal health care system Patients treated for HHT, that has been confirmed clinically (presence of at least 3 Curaçao criteria) and/or by molecular biology. Patients who present epistaxis averaging over 20 minutes in the three months before inclusion, justified by completed epistaxis tally sheets. Exclusion Criteria: Pregnant women or women who could become pregnant during the study, or during lactation Patients not affiliated with the French universal health care system Patients who are protected adults according to the terms of the law (French public health laws). Refusal to give consent. Patients whose HHT diagnosis has not be confirmed clinically and/or by molecular biology. Participation in another therapeutic trial which could interfere with the present trial (investigator jugement). Bronchial asthma, presence or history of severe chronic obstructive pulmonary disease Cardiac history : cardiac failure or cardiogenic shock. Atrioventricular block (second or third degrees) not controlled with pace-maker or sinus disease (included sinoatrial block) confirmed by ECG less than one year. Ongoing treatment by calcium antagonists (bépridil, diltiazem, verapamil) or antiarrhytmics (propafénone, quinidine, hydroquinidine, disopyramide) or clonidine or lidocaîne. Ongoing beta-blocker treatment. Bradycardia (<50 pulse per minute) Hypotension (PAS < 90 Hg mm) Angina Not controlled Pheochromocytoma Severe peripheral circulatory disturbances (Raynaud disease) Hypersensitivity to the active substance, any of the excipients or other beta-blocking agents Ongoing treatment by floctafénine or sultopride or amiodarone Patients who do not complete epistaxis grids for three months before treatment Patients who present epistaxis averaging below 20 minutes in the three months before inclusion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Timolol<br>Timolol 0.5% eye-drops solution packaged in a nasal spray device. | Drug: Timolol nasal spray<br>* Timolol 0.5% is administered by the patient with a posology of one spray (50 µL) in each nostril twice a day for 4 weeks.<br>|
| Placebo Comparator: Placebo<br>NaCl solution packaged in a nasal spray device. | Drug: Placebo nasal spray<br>* Placebo (NaCl) is administered by the patient with a posology of one spray (50 µL) in each nostril twice a day for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of timolol nasal spray on duration of nosebleeds for 3 months after the end of the treatment. | comparison of mean monthly epistaxis duration 3 months before the treatment and 3 months after the end of the treatment. | Day 0 (inclusion) ; up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance of timolol nasal spray in patients with HHT-related epistaxis | Tolerance will be evaluated by observing adverse effects and clinical examinations during the follow up period. | up to 7 months | 
| Efficacy on clinical criteria : epistaxis frequency . | Comparison of number of epistaxis before and after treatment. | Day 0 (inclusion) ; up to 4 months | 
| Efficacy on clinical criteria : biological parameters (hemoglobin and ferritin level). | Comparison of hemoglobin and ferritin level before and after treatment. | Day 0 (inclusion) ; up to 4 months | 
| Efficacy on clinical criteria : quality of life (SF36). | Comparison of SF36 questionnaire before and after treatment. | Day 0 (inclusion) ; up to 4 months | 
| Efficacy of timolol nasal spray on duration of nosebleeds for 6 months after the end of the treatment. | Comparison of mean monthly epistaxis duration 3 months before the treatment and 6 months after the end of the treatment. | Day 0 (inclusion) ; up to 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hereditary Hemorrhagic Telangiectasia (HHT), Antiangiogenic therapy, Timolol