**1. Introduction**

Hereditary hemorrhagic telangiectasia (HHT) (ORPHA774, HHT 1 OMIM# 187300 and HHT 2 OMIM# 600376) is an autosomal dominant vascular disorder that leads to abnormally dilated blood vessels and arteriovenous malformations. Telangiectases tend to rupture and result in recurrent gastrointestinal bleeding and spontaneous epistaxis, the latter being the most common clinical presentation of patients with HHT [1]. Severely affected individuals may have gushing bleeds several times a day, with consequent iron deficiency anemia and transfusion dependency [1]. Severe epistaxis is associated with significant impairment in daily life activity and decreased quality of life (QOL) [2–4], and is often resistant to standard measures [5].

Although the precise mechanism of arteriovenous malformations and telangiectases formation in HHT is unknown, dysregulation of angiogenesis has been shown to result in an unbalanced generation of abnormal blood vessels [6]. Several antiangiogenic therapeutic agents have been proposed. Bevacizumab, the most frequently used, has demonstrated limited success as a topical treatment of epistaxis [7,8], and significant side effects with systemic use [9].

The non-selective beta-blocker propranolol is commonly used as a topical and systemic treatment for infantile hemangioma [10], with proven anti-angiogenic effects [11]. We previously reported the efficacy of topical propranolol in an open-label study with six participants [12]. That report led us to conduct the current trial to evaluate the safety and efficacy of topical propranolol gel in the treatment of moderate to severe HHT-related epistaxis.

#### **2. Experimental Section**

This study was comprised of a double-blind placebo-controlled phase, with continuation to an open-label phase (Figure 1). Patients with HHT having refractory moderate to severe epistaxis were recruited from the Israeli National HHT Center at Schneider Children's Medical Center of Israel and Beilinson Medical Center. Study inclusion and exclusion criteria are summarized in Table 1. Patients with concomitant significant gastrointestinal bleeding were referred for systemic treatment and were not included in the study.

**Figure 1.** Study design.

#### **Table 1.** Inclusion and exclusion criteria.

Inclusion criteria:


Exclusion criteria:


The study was approved by the local ethics committee (RMC-0191-15) and by the Israel Ministry of Health (MOH, Clinical Trial Registration 20173382, www.health.gov.il/clinicaltrials). All the participants signed an inform consent.

Propranolol gel was prepared with propranolol HCl 1.5% in an isotonic solution and preserved hydroxyethyl cellulose 2% gel. The placebo gel was prepared with preserved hydroxyethyl cellulose 2% gel only. Patients were instructed to apply 0.5 cc propranolol or a placebo gel via a supplied 1 mL syringe, to the nasal mucosa of each nostril, twice daily.

Following screening, the patients were randomly assigned, at a 1:1 ratio, to be treated with propranolol gel or a placebo gel for a period of 8 weeks (the double-blind phase). Randomization was performed by the pharmacy, and the treatment team was blinded to the process. Following the double-blind phase, all the patients were offered to continue an open-label phase for an additional 8 weeks.

The study participants were examined at screening and randomization, and at the end of each treatment phase (the 8th and 16th weeks). Each visit included a recent medical history and physical examination; monitoring of side-effects; measurements of heart rate (HR), blood pressure (BP), blood hemoglobin (HB), and iron and ferritin levels; a rhinology examination; assessment of epistaxis severity according to the epistaxis severity score (ESS); and quality of life (QOL) according to the 12-Item Short Form Health Survey (SF-12) questionnaire. An electrocardiogram was performed at screening and repeated at the primary investigator's discretion.

Nasal endoscopy was performed at screening, and at the 8th and 16th weeks, by a highly trained rhinologist (ES), who was blinded to treatment allocation.

Patients' nasal cavities were decongested with lidocaine 1.5% and phenylephrine 1% spray prior to endoscopic examination with a zero-degree 4 mm endoscope connected to a high definition camera and monitor (Storz). Endoscopies were recorded and representative photographs of the nasal cavities were captured in a de-identified manner. Thus, all patient images were subsequently graded in an anonymized fashion at the conclusion of the study. Nasal involvement with disease at recruitment was graded as follows: mild-few punctate telangiectases, moderate-multiple telangiectases/large arteriovenous malformations involving the anterior nasal septum, and severe-diffuse involvement of the nasal mucosa with telangiectases. During follow up, endoscopies were defined as improved versus no change or worsened.

A telephone interview was performed at each mid-treatment period (4th and 12th week) and 4 weeks after the open-label phase (20th week) to assess efficacy and safety.

Participants were instructed at recruitment to fill out a daily epistaxis diary indicating the severity, frequency, and duration of the epistaxis episodes. Severity was recorded as mild-drops of blood (1), moderate- mild bleed and clots (2), or severe gushing or major clots (3).

Bleeding frequency was recorded as the number of episodes per day. The total minutes of epistaxis per day was recorded as the daily epistaxis duration. Participants were asked to mark in the diary when the medication was applied. Compliance was measured using the diary and by counting the empty syringes returned at every visit. Participants were instructed to measure their BP and HR weekly by their local health provider and to document these results in their diary. Participants were also asked to document any local or systemic symptoms and report them to the investigators.

Indications to terminate the study were any of the following criteria: a systolic BP drop to less than 80 mmHg or a drop of ≥20% from baseline systolic BP, a drop of HR to less than 50/min, any signs of heart block on the electrocardiogram, grade > 2 (CTCAE [15]) local or systemic side e ffects such as local irritation or an allergic reaction to the medication, and patient's or physician's request.

The primary outcome was the di fference in ESS drop between both groups. ESS was first calculated at randomization and was related to the prior 8 weeks, and then at the end of the double-blind period. The change in ESS from randomization to the end of the first 8-week period was compared between the propranolol and control groups. The secondary outcome measures were changes in blood hemoglobin (Hb) levels and intravenous iron, packed cell transfusion (PC) requirements, a change in the intensity of telangiectases in the nasal mucosa as documented by one otolaryngology surgeon (ES), and the change in QOL. In the open-label period the secondary outcome was ESS change from the beginning and the end of the open-label phase.
