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

Primary Purpose

Hereditary Hemorrhagic Telangiectasia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Timolol Gel
Placebo Gel
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hereditary Hemorrhagic Telangiectasia focused on measuring Epistaxis

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Washington University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Timolol Gel Arm

Placebo Gel Arm

Arm Description

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.

Participants in the placebo gel arm will receive the gel itself with no active medication.

Outcomes

Primary Outcome Measures

Change in Assisted Epistaxis Severity Scale (aESS) Score From Baseline at 8 Week Follow-up
Assessment of epistaxis severity will be obtained by the validated instrument, the Epistaxis Severity Score (ESS). 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. The scoring and MCID of the aESS is the same as the ESS. The aESS references a participant's epistaxis over the past 1 month, and the change in aESS was calculated as the aESS score at 8 weeks minus the aESS score at baseline.

Secondary Outcome Measures

Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale
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."

Full Information

First Posted
October 23, 2019
Last Updated
July 29, 2021
Sponsor
Washington University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT04139018
Brief Title
Timolol Gel for Epistaxis in Hereditary Hemorrhagic Telangiectasia
Acronym
ETIC-HHT
Official Title
Efficacy of a Timolol Gel in the Care for Epistaxis in Patients With Hereditary Hemorrhagic Telangiectasia: A Double-Blinded, Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
October 20, 2019 (Actual)
Primary Completion Date
May 20, 2020 (Actual)
Study Completion Date
May 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Washington University School of Medicine

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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: 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hereditary Hemorrhagic Telangiectasia
Keywords
Epistaxis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
27 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Timolol Gel Arm
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo Gel Arm
Arm Type
Placebo Comparator
Arm Description
Participants in the placebo gel arm will receive the gel itself with no active medication.
Intervention Type
Drug
Intervention Name(s)
Timolol Gel
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Gel
Intervention Description
Placebo gel is prepared with poloxamers and no active ingredients.
Primary Outcome Measure Information:
Title
Change in Assisted Epistaxis Severity Scale (aESS) Score From Baseline at 8 Week Follow-up
Description
Assessment of epistaxis severity will be obtained by the validated instrument, the Epistaxis Severity Score (ESS). 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. The scoring and MCID of the aESS is the same as the ESS. The aESS references a participant's epistaxis over the past 1 month, and the change in aESS was calculated as the aESS score at 8 weeks minus the aESS score at baseline.
Time Frame
Baseline to 8-week follow-up
Secondary Outcome Measure Information:
Title
Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale
Description
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."
Time Frame
Scores at 8-week follow-up only

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jay F Piccirillo, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
32940653
Citation
Peterson AM, Lee JJ, Kallogjeri D, Schneider JS, Chakinala MM, Piccirillo JF. Efficacy of Timolol in a Novel Intranasal Thermosensitive Gel for Hereditary Hemorrhagic Telangiectasia-Associated Epistaxis: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2020 Nov 1;146(11):1006-1014. doi: 10.1001/jamaoto.2020.3025.
Results Reference
derived

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Timolol Gel for Epistaxis in Hereditary Hemorrhagic Telangiectasia

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