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Efficacy of Timolol in a Novel Intranasal Thermosensitive Gel for Hereditary Hemorrhagic Telangiectasia–Associated EpistaxisA Randomized Clinical Trial

Educational Objective
To assess the efficacy and safety of intranasal timolol delivered in a thermosensitive gel form vs thermosensitive gel alone in the treatment of hereditary hemorrhagic telangictasia.
1 Credit CME
Key Points

Question  Is an intranasal thermosensitive timolol gel safe and efficacious in treating moderate-to-severe recurrent hereditary hemorrhagic telangiectasia (HHT)–associated epistaxis?

Findings  This randomized clinical trial with 27 patients found that thermosensitive gel, regardless of the presence of timolol, was highly effective and safe for HHT-associated epistaxis. Timolol thermosensitive gel may be more efficacious than thermosensitive gel alone, but larger studies are needed.

Meaning  Physicians treating patients with HHT-associated epistaxis should consider a thermosensitive gel (with or without timolol) as a safe and effective topical nasal therapy.


Importance  Other than nasal moisturizers, no standard-of-care medical therapy exists for epistaxis in hereditary hemorrhagic telangiectasia (HHT). With epistaxis as the greatest cause of morbidity in patients with HHT, there is a need to identify effective topical therapies.

Objective  To determine the efficacy and safety of an intranasal timolol thermosensitive gel vs placebo thermosensitive gel in treating HHT-associated epistaxis.

Design, Setting, and Participants  This double-blind, placebo-controlled randomized clinical trial was conducted from October 29, 2019, to May 20, 2020, at a tertiary care center. A total of 27 patients with HHT and moderate-to-severe epistaxis were recruited and included in this prespecified analysis: 14 in the timolol group and 13 in the placebo group. Inclusion criteria included (1) age 18 years or older, (2) clinical or genetic diagnosis of HHT, (3) screening Epistaxis Severity Score (ESS) of 4 or greater and 2 or more nosebleeds cumulatively lasting at least 5 minutes per week, (4) stable epistaxis pattern over the preceding 3 months, and (5) no change in epistaxis treatment or nasal hygiene regimen in the preceding month. Exclusion criteria included (1) contraindications to systemic β-blocker administration, (2) use of medications interacting with timolol, (3) use of antiangiogenic medications in the last month before recruitment, and (4) use of anticoagulants, antiplatelets, or fibrinolytic therapies within the last month.

Interventions  Novel thermosensitive intranasal timolol (0.1%) gel vs placebo thermosensitive gel applied twice daily to each nostril for 8 weeks.

Main Outcomes and Measures  The primary outcome was the median change in ESS and percentage of participants reaching the minimal clinically important difference in ESS. Secondary outcomes were changes in Clinical Global Impression–Severity and Clinical Global Impression–Improvement scores, Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia, and hemoglobin level.

Results  Of 27 participants randomized (median [range] age, 55 [20-76] years; 14 women [52%]; 25 White [93%]), a total of 23 patients with HHT completed the primary outcome measure. Within the timolol gel and placebo gel groups, respectively, the median change (range) in ESS was 2.32 (0.22 to 5.97) vs 1.96 (−0.91 to 5.98), and 9 of 11 (82%) vs 9 of 12 (75%) participants experienced a clinically meaningful improvement in ESS. Twenty-two of the 23 participants (96%) reported improvement via the Clinical Global Impression–Improvement score, with 81% vs 58% of participants reporting reduced severity of epistaxis in the timolol vs placebo group, respectively. Of participants completing the Nasal Outcome Score for Epistaxis in HHT at follow-up visit, 7 of 10 (70%) in the timolol group achieved a clinically important difference vs 5 of 10 (50%) in the placebo group. There was no change in hemoglobin level between or within groups. Zero participants in the placebo group and 2 of 13 (15%) in the timolol group withdrew because of adverse events.

Conclusions and Relevance  Thermosensitive gel, alone or in combination with timolol, was highly effective in reducing HHT-associated epistaxis. The timolol group had greater improvement in epistaxis and quality of life than the placebo group, but effect estimates were imprecise, and no definitive conclusions on the superiority of timolol can be drawn. Physicians treating patients with HHT-associated epistaxis should consider a thermosensitive gel (with or without timolol) for their patients.

Trial Registration  ClinicalTrials.gov Identifier: NCT04139018

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Article Information

Accepted for Publication: July 27, 2020.

Corresponding Author: Jay F. Piccirillo, MD, Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine in St Louis, 660 S Euclid Ave, Campus Box 8115, St Louis, MO 63110 (piccirij@wustl.edu).

Published Online: September 17, 2020. doi:10.1001/jamaoto.2020.3025

Author Contributions: Dr Piccirillo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Peterson, Lee, Kallogjeri, Chakinala, Piccirillo.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Peterson, Chakinala, Piccirillo.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Peterson, Kallogjeri.

Obtained funding: Peterson, Piccirillo.

Administrative, technical, or material support: Peterson, Lee.

Supervision: Lee, Chakinala, Piccirillo.

Conflict of Interest Disclosures: Dr Piccirillo reported receiving grants from the National Institutes of Health, the Foundation at Barnes-Jewish Hospital, and the Washington University Institute of Clinical and Translational Sciences during the conduct of the study. Mr Peterson reported receiving a stipend from the National Center for Advancing Translational Sciences of the National Institutes of Health during the conduct of the study. Dr Kallogjeri reported owning stock from and serving as consultant for PotentiaMetrics outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported in part by the STAR Award (00752; Dr Piccirillo) from the Washington University Institute of Clinical and Translational Sciences (UL1TR002345), by the National Center for Advancing Translational Sciences of the National Institutes of Health (TL1TR002344; Dr Piccirillo and Mr Peterson), and by the Foundation for Barnes-Jewish Hospital for the Otolaryngology Surgical Outcomes and Quality Improvement Unit at Barnes-Jewish Hospital Award 154092; Dr Piccirillo).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: Dr Piccirillo is Editor and Dr Kallogjeri is Statistics Editor of JAMA Otolaryngology–Head & Neck Surgery, but they were not involved in the editorial review or decision to accept this study for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: Sara Kukuljan, BS, RN, helped coordinate institutional review board approval of the protocol for the project; Marianne Clancy, RDH, MPA, Nicole Schaefer, BS, and the whole Cure Hereditary Hemorrhagic Telangiectasia team helped in recruitment and reaching out to the Hereditary Hemorrhagic Telangiectasia online community; Scott E. Olitsky, MD, reviewed and promoted the conception and design of the trial; and Jason Jerusik, PharmD, Advanced Rx, served as the research pharmacist. No compensation was given to those acknowledged, and the study team has received written permission to include them in the acknowledgments.

Additional Information: All information and materials in the manuscript are original. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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