Efficacy of Intranasal Timolol for Hereditary Hemorrhagic Telangiectasia–Associated Epistaxis | Otolaryngology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

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.

Abstract

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

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

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.

References
1.
Grosse  SD , Boulet  SL , Grant  AM , Hulihan  MM , Faughnan  ME .  The use of US health insurance data for surveillance of rare disorders: hereditary hemorrhagic telangiectasia.   Genet Med. 2014;16(1):33-39. doi:10.1038/gim.2013.66 PubMedGoogle ScholarCrossref
2.
Zarrabeitia  R , Fariñas-Álvarez  C , Santibáñez  M ,  et al.  Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT).   Health Qual Life Outcomes. 2017;15(1):19. doi:10.1186/s12955-017-0586-z PubMedGoogle ScholarCrossref
3.
Whitehead  KJ , Sautter  NB , McWilliams  JP ,  et al.  Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial.   JAMA. 2016;316(9):943-951. doi:10.1001/jama.2016.11724 PubMedGoogle ScholarCrossref
4.
Mei-Zahav  M , Blau  H , Bruckheimer  E , Zur  E , Goldschmidt  N .  Topical propranolol improves epistaxis in patients with hereditary hemorrhagic telangiectasia—a preliminary report.   J Otolaryngol Head Neck Surg. 2017;46(1):58. doi:10.1186/s40463-017-0235-x PubMedGoogle ScholarCrossref
5.
Esteban-Casado  S , Martín de Rosales Cabrera  AM , Usarralde Pérez  A ,  et al.  Sclerotherapy and topical nasal propranolol: an effective and safe therapy for HHT-epistaxis.   Laryngoscope. 2019;129(10):2216-2223. doi:10.1002/lary.27930 PubMedGoogle ScholarCrossref
6.
Price  A , Rai  S , Mcleod  RWJ , Birchall  JC , Elhassan  HA .  Topical propranolol for infantile haemangiomas: a systematic review.   J Eur Acad Dermatol Venereol. 2018;32(12):2083-2089. doi:10.1111/jdv.14963 PubMedGoogle ScholarCrossref
7.
Storch  CH , Hoeger  PH .  Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action.   Br J Dermatol. 2010;163(2):269-274. doi:10.1111/j.1365-2133.2010.09848.x PubMedGoogle ScholarCrossref
8.
Albiñana  V , Recio-Poveda  L , Zarrabeitia  R , Bernabéu  C , Botella  LM .  Propranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia.   Thromb Haemost. 2012;108(1):41-53. doi:10.1160/TH11-11-0809 PubMedGoogle ScholarCrossref
9.
van de Donk  HJM , Merkus  FWHM .  Decreases in ciliary beat frequency due to intranasal administration of propranolol.   J Pharm Sci. 1982;71(5):595-596. doi:10.1002/jps.2600710530 PubMedGoogle ScholarCrossref
10.
Ichimura  K , Kikuchi  H , Imayoshi  S , Dias  MS .  Topical application of timolol decreases the severity and frequency of epistaxis in patients who have previously undergone nasal dermoplasty for hereditary hemorrhagic telangiectasia.   Auris Nasus Larynx. 2016;43(4):429-432. doi:10.1016/j.anl.2015.12.001 PubMedGoogle ScholarCrossref
11.
Olitsky  SE .  Topical timolol for the treatment of epistaxis in hereditary hemorrhagic telangiectasia.   Am J Otolaryngol. 2012;33(3):375-376. doi:10.1016/j.amjoto.2011.10.011 PubMedGoogle ScholarCrossref
12.
Epperla  N , Brilliant  MH , Vidaillet  H . Topical timolol for treatment of epistaxis in hereditary haemorrhagic telangiectasia associated with bradycardia: a look at CYP2D6 metabolising variants.  BMJ Case Rep. 2014;2014:bcr2013203056. doi:10.1136/bcr-2013-203056PubMed
13.
Dupuis-Girod  S , Pitiot  V , Bergerot  C ,  et al.  Efficacy of timolol nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial.   Sci Rep. 2019;9(1):11986. doi:10.1038/s41598-019-48502-9 PubMedGoogle ScholarCrossref
14.
Bhalerao  AV , Lonkar  SL , Deshkar  SS , Shirolkar  SV , Deshpande  AD .  Nasal mucoadhesive in situ gel of ondansetron hydrochloride.   Indian J Pharm Sci. 2009;71(6):711-713.Google Scholar
15.
Majithiya  RJ , Ghosh  PK , Umrethia  ML , Murthy  RS .  Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan.   AAPS PharmSciTech. 2006;7(3):67. doi:10.1208/pt070367 PubMedGoogle ScholarCrossref
16.
Nieminen  T , Lehtimäki  T , Mäenpää  J , Ropo  A , Uusitalo  H , Kähönen  M .  Ophthalmic timolol: plasma concentration and systemic cardiopulmonary effects.   Scand J Clin Lab Invest. 2007;67(2):237-245. doi:10.1080/00365510601034736 PubMedGoogle ScholarCrossref
17.
Volotinen  M , Hakkola  J , Pelkonen  O , Vapaatalo  H , Mäenpää  J .  Metabolism of ophthalmic timolol: new aspects of an old drug.   Basic Clin Pharmacol Toxicol. 2011;108(5):297-303. doi:10.1111/j.1742-7843.2011.00694.x PubMedGoogle ScholarCrossref
18.
Jagdale  S , Shewale  N , Kuchekar  BS .  Optimization of thermoreversible in situ nasal gel of timolol maleate.   Scientifica (Cairo). 2016;2016:6401267.doi:10.1155/2016/6401267PubMedGoogle Scholar
19.
Shovlin  CL , Guttmacher  AE , Buscarini  E ,  et al.  Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).   Am J Med Genet. 2000;91(1):66-67. doi:10.1002/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P PubMedGoogle ScholarCrossref
20.
Hoag  JB , Terry  P , Mitchell  S , Reh  D , Merlo  CA .  An epistaxis severity score for hereditary hemorrhagic telangiectasia.   Laryngoscope. 2010;120(4):838-843. doi:10.1002/lary.20818 PubMedGoogle ScholarCrossref
21.
Piccirillo  JF , Tierney  RM , Costas  I , Grove  L , Spitznagel  EL  Jr .  Prognostic importance of comorbidity in a hospital-based cancer registry.   JAMA. 2004;291(20):2441-2447. doi:10.1001/jama.291.20.2441 PubMedGoogle ScholarCrossref
22.
Yin  LX , Reh  DD , Hoag  JB ,  et al.  The minimal important difference of the epistaxis severity score in hereditary hemorrhagic telangiectasia.   Laryngoscope. 2016;126(5):1029-1032. doi:10.1002/lary.25669 PubMedGoogle ScholarCrossref
23.
Busner  J , Targum  SD .  The clinical global impressions scale: applying a research tool in clinical practice.   Psychiatry (Edgmont). 2007;4(7):28-37.PubMedGoogle Scholar
24.
Ware  JE  Jr , Sherbourne  CD .  The MOS 36-item short-form health survey (SF-36). I. conceptual framework and item selection.   Med Care. 1992;30(6):473-483. doi:10.1097/00005650-199206000-00002 PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close