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

Primary Purpose

Telangiectasia, Hereditary Hemorrhagic, Epistaxis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sterile saline
Bevacizumab
Estriol
Tranexamic Acid
Sponsored by
James Gossage
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Telangiectasia, Hereditary Hemorrhagic focused on measuring epistaxis, HHT, bevacizumab, tranexamic acid, nosebleed, estrogen

Eligibility Criteria

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

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.

Sites / Locations

  • University of California Los Angeles
  • Georgia Regents University
  • Johns Hopkins University
  • Washington University School of Medicine
  • Oregon Health Sciences University
  • University of Utah

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Placebo spray

Bevacizumab spray

Estriol spray

Tranexamic acid spray

Arm Description

sterile saline

bevacizumab 1%

Estriol 0.1%

tranexamic acid 10%

Outcomes

Primary Outcome Measures

Frequency of Epistaxis
Bleeding episodes per week

Secondary Outcome Measures

Duration of Epistaxis
Total minutes of bleeding per week
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.
Hemoglobin Level
grams/100 ml, assessed at week 12
Number of Participants Requiring Red Blood Cell (RBC) Transfusion
Number of participants requiring RBC transfusion during weeks 1-12
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

Full Information

First Posted
August 1, 2011
Last Updated
October 9, 2018
Sponsor
James Gossage
Collaborators
HHT Foundation International
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1. Study Identification

Unique Protocol Identification Number
NCT01408030
Brief Title
North American Study of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
Acronym
NOSE
Official Title
North American Study of Epistaxis in HHT (NOSE)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
August 2011 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
James Gossage
Collaborators
HHT Foundation International

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Telangiectasia, Hereditary Hemorrhagic, Epistaxis
Keywords
epistaxis, HHT, bevacizumab, tranexamic acid, nosebleed, estrogen

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Placebo spray
Arm Type
Placebo Comparator
Arm Description
sterile saline
Arm Title
Bevacizumab spray
Arm Type
Active Comparator
Arm Description
bevacizumab 1%
Arm Title
Estriol spray
Arm Type
Active Comparator
Arm Description
Estriol 0.1%
Arm Title
Tranexamic acid spray
Arm Type
Active Comparator
Arm Description
tranexamic acid 10%
Intervention Type
Drug
Intervention Name(s)
Sterile saline
Other Intervention Name(s)
Saline
Intervention Description
0.9%, 0.1 ml spray in each nostril bid
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin, Vascular endothelial growth factor (VEGF) inhibitor
Intervention Description
1% solution in saline, 0.1 ml spray in each nostril bid
Intervention Type
Drug
Intervention Name(s)
Estriol
Other Intervention Name(s)
Estrogen
Intervention Description
0.1% suspension in methylcellulose, 0.1 ml spray in each nostril bid
Intervention Type
Drug
Intervention Name(s)
Tranexamic Acid
Other Intervention Name(s)
Lysteda
Intervention Description
10% solution in saline, 0.1 ml spray in each nostril bid
Primary Outcome Measure Information:
Title
Frequency of Epistaxis
Description
Bleeding episodes per week
Time Frame
Weeks 5-12 of active treatment phase
Secondary Outcome Measure Information:
Title
Duration of Epistaxis
Description
Total minutes of bleeding per week
Time Frame
5-12 weeks of active treatment
Title
Hoag Epistaxis Severity Score
Description
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.
Time Frame
12 weeks
Title
Hemoglobin Level
Description
grams/100 ml, assessed at week 12
Time Frame
12 weeks
Title
Number of Participants Requiring Red Blood Cell (RBC) Transfusion
Description
Number of participants requiring RBC transfusion during weeks 1-12
Time Frame
12 weeks
Title
Number of Participants With Treatment Failure
Description
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
Time Frame
Baseline through 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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: Spontaneous and recurrent epistaxis. Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose). Visceral lesions such as gastrointestinal telangiectasias and arteriovenous malformations (AVM) in lung, brain, spine and liver. A history of definite HHT in a first degree relative using these same criteria. Epistaxis of at least 1 minute (on average) and which occurs at least once weekly when averaged during the preceding 8 weeks. Epistaxis severity score (ESS) of at least 3.0. Age of at least 18 years. Written and informed consent obtained prior to study entry. Subject is able and willing to return for outpatient visits. 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). Negative pregnancy test at enrollment. Exclusion Criteria: Allergy to any of the active treatment agents or their spray additives. Estimated life expectancy less than 1 year. A psychiatric or substance abuse problem that is expected to interfere with study compliance. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James R Gossage, MD
Organizational Affiliation
Augusta University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Georgia Regents University
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Oregon Health Sciences University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
27599329
Citation
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.
Results Reference
derived
Links:
URL
http://www.hht.org
Description
HHT Foundation website

Learn more about this trial

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

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