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

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

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.

Study Overview

• Status: Completed
• Conditions: Telangiectasia, Hereditary Hemorrhagic; Osler Rendu Disease
• Intervention / Treatment: Drug: Timolol nasal spray; Drug: Placebo nasal spray

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bron, France, 69500
    • Hospices Civils de Lyon - Hôpital Femme Mère Enfant / Service de génétique Clinique

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): January 29, 2018

Study Registration Dates

• First Submitted: June 17, 2015
• First Submitted That Met QC Criteria: June 29, 2015
• First Posted (Estimate): June 30, 2015

Study Record Updates

• Last Update Posted (Actual): October 19, 2021
• Last Update Submitted That Met QC Criteria: October 14, 2021
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Hereditary Hemorrhagic Telangiectasia (HHT); Timolol; 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; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Timolol
• Other Study ID Numbers: 69HCL15_0063; 2015-000385-55 (EudraCT Number)