Efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial

Sophie Dupuis-Girod,Evelyne Decullier,Vincent Pitiot,Jean-Charles Letievant,Pierre Philouze,Anne-Emmanuelle Fargeton,Marjolaine Beaudoin,Frédéric Faure,Bettina Colombet,Cyrille Bergerot,Valentine Bréant

doi:10.1038/s41598-019-48502-9

Abstract

Hereditary hemorrhagic telangiectasia is a rare vascular genetic disease. Epistaxis is the most frequent and disabling manifestation, and timolol appears to be a new therapeutic option as non-selective beta-blockers have in vitro and in vivo anti-angiogenic properties. Our main objective was to evaluate the efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. This study is a single-center, randomized, phase 2, double-blind placebo-controlled study with an allocation ratio of 1:1. It was proposed to patients with hereditary hemorrhagic telangiectasia monitored at the French Reference Center, and we included patients aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis. The treatment was self-administered by the patient with a posology of one spray (50 µL) of timolol 0.5% or placebo in each nostril twice a day for 28 consecutive days. The primary efficacy endpoint was mean monthly epistaxis duration, assessed by monitoring epistaxis grids. A total of 58 patients were randomized and treated. The baseline characteristics were similar in the 2 groups. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 26 patients receiving the drug in comparison with the placebo group (p = 0.54). Toxicity was low and no severe adverse events were reported. One limitation is that we included all HHT patients with nosebleeds and did not take into account history of nasal surgery or nasal crusts. Timolol, administered by nasal spray at a dose of 0.25 mg in each nostril twice a day for 28 consecutive days, did not improve epistaxis in patients with hereditary hemorrhagic telangiectasia at 4 months after the beginning of the treatment.

Highlights

® in Man #187300) characterized by recurrent epistaxis, telangiectasia and visceral arteriovenous malformations (AVM) affecting lungs, liver, gastrointestinal tract and brain
Timolol did not reduce the duration of epistaxis in HHT patients compared to placebo
As observed in other studies in HHT15,16, epistaxis duration is highly variable from one patient to another and in a same patient over time, good responses to a treatment in case reports[13] or small series without a placebo group[17] need to be interpreted with caution

Summary

Introduction

® in Man #187300) characterized by recurrent epistaxis, telangiectasia and visceral arteriovenous malformations (AVM) affecting lungs, liver, gastrointestinal tract and brain. The most frequent expression of HHT is the occurrence of repeated severe and disabling epistaxis[2] which can cause chronic anemia, and can require iron supplementation and multiple blood transfusions. Management of this major symptom is not well-established and often demands local treatments or medication whose efficacy is not sufficiently documented[3,4]. Propranolol anti-angiogenic properties were demonstrated in 2008 in the treatment of infantile hemangioma[12] and in HHT, with one case report indicating that intranasal timolol (0.5% ophthalmic solution) reduced the frequency and severity of epistaxis in one HHT patient, after 3–4 days of treatment[13]. On the basis of these encouraging results, and based on previous study results using anti-angiogenic treatments in HHT like bevacizumab and thalidomide[8], we planned a phase 2 study to evaluate, over a 3 month-period after the end of the treatment, the efficacy on the duration of nosebleeds at a dose of 50 μL timolol (total of 1 mg/d) vs placebo administered in each nostril twice a day for 28 consecutive days in patients with HHT complicated by nosebleeds (main outcome)

Objectives

Methods

Conclusion