Telangiectasia, Hereditary Hemorrhagic, Epistaxis
Conditions
Keywords
epistaxis, HHT, bevacizumab, tranexamic acid, nosebleed, estrogen
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.
Interventions
DRUGSterile saline
0.9%, 0.1 ml spray in each nostril bid
DRUGBevacizumab
1% solution in saline, 0.1 ml spray in each nostril bid
DRUGEstriol
0.1% suspension in methylcellulose, 0.1 ml spray in each nostril bid
DRUGTranexamic Acid
10% solution in saline, 0.1 ml spray in each nostril bid
Sponsors
HHT Foundation International
James Gossage
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Epistaxis | Weeks 5-12 of active treatment phase | Bleeding episodes per week |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Epistaxis | 5-12 weeks of active treatment | Total minutes of bleeding per week |
| Hoag Epistaxis Severity Score | 12 weeks | 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 | 12 weeks | grams/100 ml, assessed at week 12 |
| Number of Participants Requiring Red Blood Cell (RBC) Transfusion | 12 weeks | Number of participants requiring RBC transfusion during weeks 1-12 |
| Number of Participants With Treatment Failure | Baseline through 12 weeks | 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 |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from the HHT clinics at 6 sites if they met all of the following criteria: age \>=18; diagnosis of definite or possible HHT; epistaxis lasting at least 1 minute, occurring at least once weekly, and clinically stable during the preceding 8weeks; and had an Epistaxis Severity Score (ESS) of at least 3.0.
Pre-assignment details
123 patients provided consent but 1 withdrew consent and 1 was excluded due to brain arteriovenous malformation. Therefore 121 patients were randomized and included in participant flow. 1 patient in the estriol group was subsequently removed after it was discovered that she was taking estrogen outside the protocol (protocol violation).
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab Spray Bevacizumab: 1% solution in saline, 0.1 ml spray in each nostril bid | 29 |
| Estriol Spray Estriol: 0.1% suspension in methylcellulose, 0.1 ml spray in each nostril bid | 30 |
| Tranexamic Acid Spray Tranexamic Acid: 10% solution in saline, 0.1 ml spray in each nostril bid | 33 |
| Placebo Spray Sterile saline: 0.9%, 0.1 ml spray in each nostril bid | 28 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Observation Phase (Off Drug) | Lost to Follow-up | 0 | 2 | 2 | 0 |
| Observation Phase (Off Drug) | Other | 1 | 1 | 1 | 1 |
| Observation Phase (Off Drug) | Physician Decision | 0 | 1 | 2 | 0 |
| Observation Phase (Off Drug) | Withdrawal by Subject | 3 | 2 | 1 | 3 |
| Treatment Phase (on Drug) | Lack of Efficacy | 2 | 6 | 0 | 3 |
| Treatment Phase (on Drug) | Lost to Follow-up | 1 | 0 | 1 | 0 |
| Treatment Phase (on Drug) | Protocol Violation | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo Spray | Tranexamic Acid Spray | Estriol Spray | Bevacizumab Spray |
|---|---|---|---|---|---|
| Age, Continuous | 52.8 years | 53 years | 53 years | 56.6 years | 47.8 years |
| Definite HHT | 113 Participants | 26 Participants | 32 Participants | 29 Participants | 26 Participants |
| Epistaxis history | 7.0 bleeding episodes per week | 7.0 bleeding episodes per week | 7.8 bleeding episodes per week | 7.0 bleeding episodes per week | 10.0 bleeding episodes per week |
| Epistaxis severity score | 5.37 units on a scale | 5.71 units on a scale | 5.43 units on a scale | 5.19 units on a scale | 5.16 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 119 Participants | 28 Participants | 33 Participants | 30 Participants | 28 Participants |
| Sex: Female, Male Female | 52 Participants | 13 Participants | 14 Participants | 12 Participants | 13 Participants |
| Sex: Female, Male Male | 68 Participants | 15 Participants | 19 Participants | 18 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 30 | 0 / 33 | 0 / 28 |
| other Total, other adverse events | 24 / 29 | 25 / 30 | 26 / 33 | 23 / 28 |
| serious Total, serious adverse events | 0 / 29 | 0 / 30 | 0 / 33 | 0 / 28 |
Outcome results
Primary
Frequency of Epistaxis
Bleeding episodes per week
Time frame: Weeks 5-12 of active treatment phase
Population: Participants were included in this analysis (106) if they had at least 3 weeks of data during weeks 5-12; therefore the number of participants analyzed do not equal the number who finished the active treatment phase (120). 2 patients were lost to follow up, 5 dropped out before week 5, 6 filled out diaries incorrectly, and 1 had no diary.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Spray | Frequency of Epistaxis | 7.0 Bleeding episodes per week |
| Estriol Spray | Frequency of Epistaxis | 8.0 Bleeding episodes per week |
| Tranexamic Acid Spray | Frequency of Epistaxis | 7.5 Bleeding episodes per week |
| Placebo Spray | Frequency of Epistaxis | 8.0 Bleeding episodes per week |
p-value: 0.97ANOVA
Secondary
Duration of Epistaxis
Total minutes of bleeding per week
Time frame: 5-12 weeks of active treatment
Population: Participants were included in this analysis (112) if they had at least 3 weeks of data during weeks 5-12; therefore the number of participants analyzed do not equal the number who finished the active treatment phase (120). 2 patients were lost to follow up, 5 dropped out before week 5, and 1 had no epistaxis diary.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Spray | Duration of Epistaxis | 23.5 Total minutes of bleeding per week |
| Estriol Spray | Duration of Epistaxis | 36.5 Total minutes of bleeding per week |
| Tranexamic Acid Spray | Duration of Epistaxis | 44.5 Total minutes of bleeding per week |
| Placebo Spray | Duration of Epistaxis | 46 Total minutes of bleeding per week |
p-value: 0.47ANOVA
Secondary
Hemoglobin Level
grams/100 ml, assessed at week 12
Time frame: 12 weeks
Population: 8 participants who finished the active treatment phase did not have a hemoglobin level measured, and thus only 99 were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Spray | Hemoglobin Level | 12.8 gram/100 ml |
| Estriol Spray | Hemoglobin Level | 13.1 gram/100 ml |
| Tranexamic Acid Spray | Hemoglobin Level | 11.4 gram/100 ml |
| Placebo Spray | Hemoglobin Level | 13.8 gram/100 ml |
p-value: 0.43ANCOVA
Secondary
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.
Time frame: 12 weeks
Population: Participants were included in this analysis if they completed week 12 (phase 1) and filled out an ESS score. 1 participant each from the bevacizumab and placebo group did not fill out an ESS score at week 12.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Spray | Hoag Epistaxis Severity Score | 3.54 units on a scale (0-10) |
| Estriol Spray | Hoag Epistaxis Severity Score | 3.56 units on a scale (0-10) |
| Tranexamic Acid Spray | Hoag Epistaxis Severity Score | 4.06 units on a scale (0-10) |
| Placebo Spray | Hoag Epistaxis Severity Score | 3.74 units on a scale (0-10) |
p-value: <0.001Mixed Models Analysis
Secondary
Number of Participants Requiring Red Blood Cell (RBC) Transfusion
Number of participants requiring RBC transfusion during weeks 1-12
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab Spray | Number of Participants Requiring Red Blood Cell (RBC) Transfusion | 1 Participants |
| Estriol Spray | Number of Participants Requiring Red Blood Cell (RBC) Transfusion | 2 Participants |
| Tranexamic Acid Spray | Number of Participants Requiring Red Blood Cell (RBC) Transfusion | 5 Participants |
| Placebo Spray | Number of Participants Requiring Red Blood Cell (RBC) Transfusion | 3 Participants |
p-value: 0.42Fisher Exact
Secondary
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
Time frame: Baseline through 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab Spray | Number of Participants With Treatment Failure | 2 Participants |
| Estriol Spray | Number of Participants With Treatment Failure | 5 Participants |
| Tranexamic Acid Spray | Number of Participants With Treatment Failure | 0 Participants |
| Placebo Spray | Number of Participants With Treatment Failure | 3 Participants |
p-value: 0.08Fisher Exact