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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04139018
Recruitment Status : Recruiting
First Posted : October 25, 2019
Last Update Posted : December 6, 2019
Sponsor:
Information provided by (Responsible Party):
Jay F. Piccirillo, MD, Washington University School of Medicine

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.

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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


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.




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.



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04139018


Contacts
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Contact: Andrew M Peterson 314-747-0910 apeterson22@wustl.edu
Contact: Sara Kukuljan, RN 314-362-7563 kukuljas@wustl.edu

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

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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    Key Record Dates
Last Update Posted: December 6, 2019
Last Verified: December 2019

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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:
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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