North American Study of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) (NOSE)

North American Study of Epistaxis in HHT (NOSE)

The purpose of the NOSE Study is to carefully examine the efficacy and safety of 3 nasal sprays (bevacizumab, estriol, and tranexamic acid), compared to placebo, for the treatment of HHT related nosebleeds.

Study Overview

• Status: Completed
• Conditions: Epistaxis; Telangiectasia, Hereditary Hemorrhagic
• Intervention / Treatment: Drug: Sterile saline; Drug: Bevacizumab; Drug: Estriol; Drug: Tranexamic Acid

Detailed Description

140 patients with moderate to severe epistaxis secondary to HHT will be randomized to receive one of four intranasal sprays for a period of 12 weeks and then followed for an additional 12 weeks off therapy. Enrollment will occur over a period of 18-36 months. The primary endpoint will be the frequency of epistaxis. Secondary endpoints will include duration of epistaxis, the Hoag Epistaxis Severity Score (ESS), a quality of life survey, satisfaction with treatment, hemoglobin and ferritin levels, transfusion requirements, and treatment failure. The sprays will be: saline spray (Placebo); estriol 0.1% in methylcellulose suspension (EST); tranexamic acid 10% in saline (TA), and bevacizumab 1% in saline (BEV). All sprays will be applied to the nasal mucosa by an identical spray bottle at a dose of 0.1 ml per nostril twice daily (total dose of 0.4 ml daily). Thus, the delivered doses will be: EST, 0.4 mg/day; TA, 40 mg/day; BEV, 4 mg/day.

• Study Type: Interventional
• Enrollment (Actual): 123
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Regents University
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. A diagnosis of definite or possible HHT by the Curacao criteria (Shovlin 2000) or a positive DNA test for HHT (as characterized by a disease causing mutation in the gene coding for endoglin, activin like kinase 1, or SMAD-4). According to the Curacao criteria, a definite diagnosis of HHT is defined as having at least 3 of the following criteria while a possible diagnosis is defined as 2 criteria:

   1. Spontaneous and recurrent epistaxis.
   2. Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose).
   3. Visceral lesions such as gastrointestinal telangiectasias and arteriovenous malformations (AVM) in lung, brain, spine and liver.
   4. A history of definite HHT in a first degree relative using these same criteria.
2. Epistaxis of at least 1 minute (on average) and which occurs at least once weekly when averaged during the preceding 8 weeks.
3. Epistaxis severity score (ESS) of at least 3.0.
4. Age of at least 18 years.
5. Written and informed consent obtained prior to study entry.
6. Subject is able and willing to return for outpatient visits.
7. The epistaxis is considered to be clinically stable during the past 8 weeks in the clinical judgment of the investigator (i.e. no major changes in frequency or duration of epistaxis or in transfusion requirements).
8. Negative pregnancy test at enrollment.

Exclusion Criteria:

1. Allergy to any of the active treatment agents or their spray additives.
2. Estimated life expectancy less than 1 year.
3. A psychiatric or substance abuse problem that is expected to interfere with study compliance.
4. History of deep venous thrombosis (DVT), pulmonary embolism (PE), acute myocardial infarction (MI), arterial thromboembolism, or ischemic stroke in the past 6 months.6. History of receiving more than 12 units of red blood cells in the past 12 weeks.

7. Presence of an untreated coagulopathy that is felt to be contributing to the 5. History of estrogen receptor positive breast cancer. epistaxis. 8. Presence of active disseminated intravascular coagulation. 9. Uncontrolled hypertension (systolic BP >160 and/or diastolic BP >100). 10. Presence of untreated brain AVM. 11. Presence of active malignancy in the brain, lung, or colon. 12. Presence of symptomatic heart failure. 13. Use of estrogens, epsilon aminocaproic acid, tranexamic acid, or thalidomide by any route for more than 1 week in the past 12 weeks. Any use of a VEGF inhibitor by any route in the past 24 weeks.

14. Baseline use of the following anticoagulants is not allowed: warfarin or other vitamin K antagonists at any dose; unfractionated or low molecular weight heparins at standard doses for treatment of venous thromboembolism (VTE); or aspirin at >325 mg/day. Baseline use of the following anticoagulants is allowed: heparins at standard doses for VTE prophylaxis; clopidogrel; or aspirin at ≤325 mg/day.

15. Addition of new treatments for epistaxis in the past 12 weeks (including laser ablation of nasal telangiectasias and over the counter medications).

16. Presence of another overt cause (e.g. overt gastrointestinal bleeding) that is felt to be significantly contributing to anemia.

17. Lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo spray; sterile saline	Drug: Sterile saline; 0.9%, 0.1 ml spray in each nostril bid; Other Names: Saline
ACTIVE_COMPARATOR: Bevacizumab spray; bevacizumab 1%	Drug: Bevacizumab; 1% solution in saline, 0.1 ml spray in each nostril bid; Other Names: Avastin; Vascular endothelial growth factor (VEGF) inhibitor
ACTIVE_COMPARATOR: Estriol spray; Estriol 0.1%	Drug: Estriol; 0.1% suspension in methylcellulose, 0.1 ml spray in each nostril bid; Other Names: Estrogen
ACTIVE_COMPARATOR: Tranexamic acid spray; tranexamic acid 10%	Drug: Tranexamic Acid; 10% solution in saline, 0.1 ml spray in each nostril bid; Other Names: Lysteda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Epistaxis	Bleeding episodes per week	Weeks 5-12 of active treatment phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Epistaxis	Total minutes of bleeding per week	5-12 weeks of active treatment
Hoag Epistaxis Severity Score	Hoag Epistaxis Severity Score (ESS) is based on 6 nosebleed variables such as frequency and duration which are entered by patients. The ESS has a minimum value of 0 and maximum value of 10, with 10 representing more severe epistaxis.	12 weeks
Hemoglobin Level	grams/100 ml, assessed at week 12	12 weeks
Number of Participants Requiring Red Blood Cell (RBC) Transfusion	Number of participants requiring RBC transfusion during weeks 1-12	12 weeks
Number of Participants With Treatment Failure	Treatment failure is defined as the occurrence of one or more of the following during the study: need for nasal surgery or chemical cautery or other new treatment modality to control epistaxis; transfusion of more than 12 units of RBC; severe complications such as acute myocardial infarction, venous thromboembolism, brain hemorrhage; or death	Baseline through 12 weeks

Collaborators and Investigators

• Sponsor: James Gossage
• Collaborators: HHT Foundation International
• Investigators: Principal Investigator: James R Gossage, MD, Augusta University

Publications and helpful links

General Publications

• Whitehead KJ, Sautter NB, McWilliams JP, Chakinala MM, Merlo CA, Johnson MH, James M, Everett EM, Clancy MS, Faughnan ME, Oh SP, Olitsky SE, Pyeritz RE, Gossage JR. Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial. JAMA. 2016 Sep 6;316(9):943-51. doi: 10.1001/jama.2016.11724.

Helpful Links

• HHT Foundation website

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (ACTUAL): September 1, 2014
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: August 1, 2011
• First Submitted That Met QC Criteria: August 1, 2011
• First Posted (ESTIMATE): August 2, 2011

Study Record Updates

• Last Update Posted (ACTUAL): October 19, 2018
• Last Update Submitted That Met QC Criteria: October 9, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: estrogen; bevacizumab; epistaxis; tranexamic acid; HHT; nosebleed
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Congenital Abnormalities; Hematologic Diseases; Hemorrhage; Hemorrhagic Disorders; Otorhinolaryngologic Diseases; Hemostatic Disorders; Signs and Symptoms, Respiratory; Nose Diseases; Cardiovascular Abnormalities; Vascular Malformations; Epistaxis; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antifibrinolytic Agents; Hemostatics; Coagulants; Bevacizumab; Tranexamic Acid; Estrogens; Endothelial Growth Factors
• Other Study ID Numbers: GHSU 1008041

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO