Clinical trial NCT02484716: Efficacy of a Timolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) - (TEMPO)
Official title: Efficacy of a Timolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) - Randomized Trial Versus Placebo
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Telangiectasia, Hereditary Hemorrhagic
Osler Rendu Disease
Keywords: Hereditary Hemorrhagic Telangiectasia (HHT)
Antiangiogenic therapy
Timolol
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2015-06-30
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Efficacy of timolol nasal spray on duration of nosebleeds for 3 months after the end of the treatment.
timeFrame: Day 0 (inclusion) ; up to 4 months
Secondary outcomes:
measure: Tolerance of timolol nasal spray in patients with HHT-related epistaxis
timeFrame: up to 7 months
measure: Efficacy on clinical criteria : epistaxis frequency .
timeFrame: Day 0 (inclusion) ; up to 4 months
measure: Efficacy on clinical criteria : biological parameters (hemoglobin and ferritin level).
timeFrame: Day 0 (inclusion) ; up to 4 months
measure: Efficacy on clinical criteria : quality of life (SF36).
timeFrame: Day 0 (inclusion) ; up to 4 months
measure: Efficacy of timolol nasal spray on duration of nosebleeds for 6 months after the end of the treatment.
timeFrame: Day 0 (inclusion) ; up to 7 months
Other outcomes:
Locations:
city: Bron
country: France
facility: Hospices Civils de Lyon - Hôpital Femme Mère Enfant / Service de génétique Clinique
Study officials:
References: