Timolol Gel for Epistaxis in Hereditary Hemorrhagic Telangiectasia (ETIC-HHT)

• ClinicalTrials.gov Identifier: NCT04139018
• Recruitment Status: Recruiting
• First Posted: October 25, 2019
• Last Update Posted: December 6, 2019
• Sponsor: Washington University School of Medicine
• Information provided by (Responsible Party): Jay F. Piccirillo, MD, Washington University School of Medicine

Study Description

Brief Summary:

This study is a double-blinded, randomized controlled trial to evaluate the efficacy of an intranasal topical timolol gel in the care for epistaxis in adults with hereditary hemorrhagic telangiectasia.

Condition or disease	Intervention/treatment	Phase
Hereditary Hemorrhagic Telangiectasia	Drug: Timolol Gel; Drug: Placebo Gel	Phase 2

Detailed Description:

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:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy of a Timolol Gel in the Care for Epistaxis in Patients With Hereditary Hemorrhagic Telangiectasia: A Double-Blinded, Randomized Controlled Trial
• Actual Study Start Date: October 20, 2019
• Estimated Primary Completion Date: October 20, 2020
• Estimated Study Completion Date: October 20, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Timolol Gel Arm; Participants in the timolol gel arm (active medication arm) will receive timolol nasal gel 0.1% with 0.5 mL applied to each nostril twice daily via a syringe that will amount to a 2 mg total daily dose.	Drug: Timolol Gel; Timolol nasal gel 0.1% will be prepared with a poloxamer gel (combination of poloxamer 188 and 407; pH adjusted to 4.5-6.5) and 0.5 ml applied to each nostril twice daily. The total daily dose would amount to 2 mg.
Placebo Comparator: Placebo Gel Arm; Participants in the placebo gel arm will receive the gel itself with no active medication.	Drug: Placebo Gel; Placebo gel is prepared with poloxamers and no active ingredients.

Outcome Measures

Primary Outcome Measures :

1. Epistaxis Severity Scale [ Time Frame: Baseline to 8-week follow-up ]
   Assessment of epistaxis severity will be obtained by the validated instrument, the Epistaxis Severity Score (ESS).(Hoag et al. 2010) To complete the ESS, patients are asked to consider typical symptoms over the previous 3 months. The ESS contains 6 items - frequency, duration, and intensity of nosebleeds, whether patient has sought medication attention, whether patient is anemic, and whether patient has received a blood transfusion. The overall score ranges from 0 to 10, with severity of nosebleed based on score graded as None composite score of 0-1, Mild 1-4, Moderate 4-7, and Severe as 7-10.The minimal important difference noticeable by both patients and clinicians in the ESS scoring system is estimated as a change of 0.71.(Yin et al. 2016) With the 8-week duration of our trial, patients will complete the Assisted Epistaxis Severity Scale (aESS), which references their epistaxis over the past 1 month.

Secondary Outcome Measures :

1. Clinical Global Impression - Improvement (CGI-I) Score [ Time Frame: Baseline to 8-week follow-up ]
   CGI-I is a global rating of improvement scale, which requires subjects to rate their degree of improvement on a seven-point scale: "Compared to your condition at admission to the project [prior to medication initiation], how would you rate your overall response: 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment." (Busner J, Targum SD. 2007).
2. Mean Change in Hemoglobin [ Time Frame: Baseline to 8-week follow-up ]

   Hemoglobin is a protein in red blood cells which contains iron.Hemoglobin is involved in the transport of oxygen and carbon dioxide. Red blood cells get their color from hemoglobin. Hemoglobin test measures serum hemoglobin level and levels lower than normal means a low red blood cell count or anemia. Anemia can have many different causes, including vitamin deficiencies, bleeding and chronic diseases. Hemoglobin serum values are often measured in patients with HHT to assess for anemia.

   The normal range for hemoglobin is:

   Men, 13.5 to 17.5 grams per deciliter Women, 12.0 to 15.5 grams per deciliter

   Change in hemoglobin values are often used to measure the impact of epistaxis treatment.

3. HHT endoscopic scale (HES) [ Time Frame: Baseline to 8-week follow-up ]
   The HHT Endoscopy Score (HES) is an endoscopy staging score developed as a way to quantify the severity of the patient's nasal telangiectasias as seen on physical exam.(Reh et al. 2014) The HES was shown to correlate with the ESS. Its parameters are telangiectasia sites, patterns, crusting, location, perforation, density, and relative AVMs.

Eligibility Criteria

• Ages Eligible for Study: 20 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

1. Contraindications for systemic β adrenergic blocker administration

   1. Hypersensitivity to β adrenergic blockers
   2. Asthma or bronchospasm
   3. Congestive heart failure with LVEF <40%
   4. Hereditary pulmonary arterial hypertension
   5. Baseline bradycardia (HR <55 beats per minute)
   6. Sick Sinus Syndrome
   7. 2nd or 3rd degree heart block, left or right bundle branch block, or bifasicular block
   8. Uncontrolled diabetes mellitus (most recent HbA1c >9%) or diabetic ketoacidosis within last 6 months
   9. Hypotension (systolic blood pressure < 90)
2. Known hypersensitivity to timolol
3. Severe peripheral circulatory disturbances (Raynaud phenomenon)
4. Known intermediate or poor metabolizer variant of the liver enzyme CYP2D6
5. Current use of any of the following known strong CYP2D6 inhibitors: fluoxetine (Prozac), paroxetine (Paxil), bupropion (Welbutrin), quinidine, quinine, ritonavir (Norvir), and terbinafine (Lamisil)
6. Current use of the following other drugs known to pharmacodynamically interact with timolol: diltiazem, verapamil, digoxin, digitalis, propafenone, disopyramide, clonidine, flecainide, or lidocaine
7. Patients currently treated or who plan to initiate treatment with β-blockers
8. Use of any anti-angiogenic medication in the last month prior to recruitment, including bevacizumab, pazopanib, thalidomide, or lenalidomide
9. Illicit drug use, except marijuana
10. Known pheochromocytoma
11. Use of anticoagulants, antiplatelet, or fibrinolytic therapies within the last month prior to recruitment, except for low-dose (81 mg or less) of aspirin
12. Pregnancy or planned pregnancy in the next 6 months or currently breastfeeding
13. Inability to read or understand English
14. Inability to complete 8 weeks of therapy for any reason

Contacts and Locations

Contacts

Contact: Andrew M Peterson; 314-747-0910; apeterson22@wustl.edu

Contact: Sara Kukuljan, RN; 314-362-7563; kukuljas@wustl.edu

Locations

United States, Missouri

Washington University; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Andrew M. Peterson 314-747-0910 apeterson22@wustl.edu

Contact: Sara Kukuljan, BS, RN, CCRC (314) 362-7563 kukuljas@wustl.edu

Sponsors and Collaborators

Washington University School of Medicine

Investigators

• Principal Investigator: Jay F Piccirillo, MD; Washington University School of Medicine

More Information

• Responsible Party: Jay F. Piccirillo, MD, Professor and Vice Chair for Research, Department of Otolaryngology - Head and Neck Surgery, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT04139018
• Other Study ID Numbers: 201908160
• First Posted: October 25, 2019
• Last Update Posted: December 6, 2019
• Last Verified: December 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Jay F. Piccirillo, MD, Washington University School of Medicine:

Epistaxis

Additional relevant MeSH terms:

Epistaxis; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Vascular Diseases; Cardiovascular Diseases; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Hemorrhage; Pathologic Processes; Signs and Symptoms, Respiratory; Signs and Symptoms; Hemostatic Disorders; Hemorrhagic Disorders; Hematologic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Timolol; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents