TIMolol nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia (HHT) – Study protocol of the prospective, randomized, double-blind, controlled cross-over TIM-HHT trial

Abstract

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an inherited orphan disease, in which the absence of capillary beds between arterioles and venules lead to arteriovenous shunts. Epistaxis is the core symptom. Several case reports have described the nonselective beta-adrenergic receptor antagonist timolol as a successful treatment method of nosebleeds due in HHT patients. OBJECTIVE: TIM-HHT is a single-site, prospective, randomized, placebo-controlled, double-blind, cross-over study to investigate whether the efficacy of standard laser treatment of epistaxis in HHT patients can be increased by the additional use of timolol nasal spray (1 mg/d). METHODS: Twenty patients will be randomly allocated to one of two treatment sequences. Primary outcome is the severity of epistaxis determined by the Epistaxis Severity Score (ESS). Secondary outcomes are subjective satisfaction, quality of life, as well as the hemoglobin, ferritin, and transferrin levels of the participating patients. Safety outcome is assessed by means of pulse, blood pressure, and adverse events. CONCLUSION: TIM-HHT will evaluate the efficacy and safety of timolol as an additional treatment of epistaxis in HHT patients in a three-month trial period. Benzalkonium chloride is used as a placebo, which has no documented positive effect on the nasal mucosa and hence on epistaxis in HHT patients (in contrast to saline). TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00020994. Registered on 10 March 2020

TIMolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (TIM-HHT)—A Prospective, Randomized, Double-Blind, Controlled, Cross-Over Trial

“…An overview of the course of the study is shown in Figure 1. A detailed flow schedule of all visits has been published elsewhere [10].…”

“…The Center of Orphan Diseases (FSER e.V./Förderverein für seltene Erkrankungen, Regensburg, Germany) of the University Hospital Regensburg and the German HHT foundation (Morbus Osler Selbsthilfe e.V., Berlin, Germany)supported the study financially. A detailed description of the study protocol has been published elsewhere [10]. For the sake of completeness, this section again summarizes the most important aspects of the course of the study.…”

“…Exclusion criteria according to patient reports and review of medical documentation available at the time of study inclusion were: pregnancy, bronchial or chronic obstructive pulmonary disease, bradycardia, hypotension, severe peripheral circulatory disorders, cardiac failure, cardiac contraindications to beta blockers, patients with diabetes, hyperthyroidism, pheochromocytoma, muscle weakness or myasthenia gravis, severe anaphylactic reactions to various allergens, patients performing or planning desensitization, patients with hypersensitivity to the IMP or placebo in past medical history, patients with concomitant ingestion of oral medication interfering with beta blocker treatment (e.g., CYP2D6 inhibitors, calcium channel blockers) or concomitant medication with anticoagulants or beta blockers (systemically or ophthalmologically). Termination of existing iron therapy with iron tablets or infusions or the start of iron therapy with iron tablets or infusions within one month before study enrolment until conclusion of the study was prohibited, as was endonasal surgery under general anesthesia within the last three months before and during participation [10].…”

“…Sample size calculation for the trial resulted in a total sample size of n = 19 patients to achieve a power of 80% for the analysis of the primary endpoint. A detailed description of the sample size calculation can be found in the published study protocol [10].…”