Timolol Gel for Epistaxis in Hereditary Hemorrhagic Telangiectasia

This study is a double-blinded, placebo-controlled, 8-week randomized clinical trial investigating the efficacy of timolol gel in the management of epistaxis in adults with HHT.

The Specific Aims are to determine in adults with HHT-associated epistaxis:

• If topical timolol gel is more effective than placebo in reducing the frequency and severity of epistaxis.
• If topical timolol gel is more effective than placebo in improving hemoglobin levels.
• The frequency of adverse events, side effects, and safety profile of topical timolol gel delivered to the nasal mucosa.

Inclusion criteria

• Adults ages 20 and older
• Confirmed clinical (meeting at least 3 of the 4 Curaçao Criteria) or genetic diagnosis of HHT
• Epistaxis Severity Score (ESS) ≥ 4 and 2 or more nosebleeds per week with a cumulative nosebleed duration of at least 5 minutes per week
• Stable nasal hygiene and medical regimen for preceding 1 month
• Stable epistaxis pattern over the preceding 3 months

Exclusion criteria

• Contraindications for systemic β adrenergic blocker administration

• Hypersensitivity to β adrenergic blockers
• Asthma or bronchospasm
• Congestive heart failure with LVEF <40%
• Hereditary pulmonary arterial hypertension
• Baseline bradycardia (HR <55 beats per minute)
• Sick Sinus Syndrome
• 2nd or 3rd degree heart block, left or right bundle branch block, or bifasicular block
• Uncontrolled diabetes mellitus (most recent HbA1c >9%) or diabetic ketoacidosis within last 6 months
• Hypotension (systolic blood pressure < 90)
• Known hypersensitivity to timolol
• Severe peripheral circulatory disturbances (Raynaud phenomenon)
• Known intermediate or poor metabolizer variant of the liver enzyme CYP2D6
• Current use of any of the following known strong CYP2D6 inhibitors: fluoxetine (Prozac), paroxetine (Paxil), bupropion (Welbutrin), quinidine, quinine, ritonavir (Norvir), and terbinafine (Lamisil)
• Current use of the following other drugs known to pharmacodynamically interact with timolol: diltiazem, verapamil, digoxin, digitalis, propafenone, disopyramide, clonidine, flecainide, or lidocaine
• Patients currently treated or who plan to initiate treatment with β-blockers
• Use of any anti-angiogenic medication in the last month prior to recruitment, including bevacizumab, pazopanib, thalidomide, or lenalidomide
• Illicit drug use, except marijuana
• Known pheochromocytoma
• Use of anticoagulants, antiplatelet, or fibrinolytic therapies within the last month prior to recruitment, except for low-dose (81 mg or less) of aspirin
• Pregnancy or planned pregnancy in the next 6 months or currently breastfeeding
• Inability to read or understand English
• Inability to complete 8 weeks of therapy for any reason