Hereditary Hemorrhagic Telangiectasia
Conditions
Keywords
Epistaxis
Brief summary
This study is a double-blinded, randomized controlled trial to evaluate the efficacy of an intranasal topical timolol gel in the care for epistaxis in adults with hereditary hemorrhagic telangiectasia.
Detailed description
This study is a double-blinded, placebo-controlled, 8-week randomized clinical trial investigating the efficacy of timolol gel in the management of epistaxis in adults with HHT. The Specific Aims are to determine in adults with HHT-associated epistaxis: 1. If topical timolol gel is more effective than placebo in reducing the frequency and severity of epistaxis. 2. If topical timolol gel is more effective than placebo in improving hemoglobin levels. 3. The frequency of adverse events, side effects, and safety profile of topical timolol gel delivered to the nasal mucosa.
Interventions
DRUGTimolol Gel
Timolol nasal gel 0.1% will be prepared with a poloxamer gel (combination of poloxamer 188 and 407; pH adjusted to 4.5-6.5) and 0.5 ml applied to each nostril twice daily. The total daily dose would amount to 2 mg.
DRUGPlacebo Gel
Placebo gel is prepared with poloxamers and no active ingredients.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults ages 20 and older 2. Confirmed clinical (meeting at least 3 of the 4 Curaçao Criteria) or genetic diagnosis of HHT 3. Epistaxis Severity Score (ESS) ≥ 4 and 2 or more nosebleeds per week with a cumulative nosebleed duration of at least 5 minutes per week 4. Stable nasal hygiene and medical regimen for preceding 1 month 5. Stable epistaxis pattern over the preceding 3 months
Exclusion criteria
1. Contraindications for systemic β adrenergic blocker administration 1. Hypersensitivity to β adrenergic blockers 2. Asthma or bronchospasm 3. Congestive heart failure with LVEF \<40% 4. Hereditary pulmonary arterial hypertension 5. Baseline bradycardia (HR \<55 beats per minute) 6. Sick Sinus Syndrome 7. 2nd or 3rd degree heart block, left or right bundle branch block, or bifasicular block 8. Uncontrolled diabetes mellitus (most recent HbA1c \>9%) or diabetic ketoacidosis within last 6 months 9. Hypotension (systolic blood pressure \< 90) 2. Known hypersensitivity to timolol 3. Severe peripheral circulatory disturbances (Raynaud phenomenon) 4. Known intermediate or poor metabolizer variant of the liver enzyme CYP2D6 5. Current use of any of the following known strong CYP2D6 inhibitors: fluoxetine (Prozac), paroxetine (Paxil), bupropion (Welbutrin), quinidine, quinine, ritonavir (Norvir), and terbinafine (Lamisil) 6. Current use of the following other drugs known to pharmacodynamically interact with timolol: diltiazem, verapamil, digoxin, digitalis, propafenone, disopyramide, clonidine, flecainide, or lidocaine 7. Patients currently treated or who plan to initiate treatment with β-blockers 8. Use of any anti-angiogenic medication in the last month prior to recruitment, including bevacizumab, pazopanib, thalidomide, or lenalidomide 9. Illicit drug use, except marijuana 10. Known pheochromocytoma 11. Use of anticoagulants, antiplatelet, or fibrinolytic therapies within the last month prior to recruitment, except for low-dose (81 mg or less) of aspirin 12. Pregnancy or planned pregnancy in the next 6 months or currently breastfeeding 13. Inability to read or understand English 14. Inability to complete 8 weeks of therapy for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Assisted Epistaxis Severity Scale (aESS) Score From Baseline at 8 Week Follow-up | Baseline to 8-week follow-up | Assessment of epistaxis severity will be obtained by the validated instrument, the Epistaxis Severity Score (ESS). To complete the ESS, patients are asked to consider typical symptoms over the previous 3 months. The ESS contains 6 items - frequency, duration, and intensity of nosebleeds, whether patient has sought medication attention, whether patient is anemic, and whether patient has received a blood transfusion. The overall score ranges from 0 to 10, with severity of nosebleed based on score graded as None composite score of 0-1, Mild 1-4, Moderate 4-7, and Severe as 7-10.The minimal important difference noticeable by both patients and clinicians in the ESS scoring system is estimated as a change of 0.71. The scoring and MCID of the aESS is the same as the ESS. The aESS references a participant's epistaxis over the past 1 month, and the change in aESS was calculated as the aESS score at 8 weeks minus the aESS score at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale | Scores at 8-week follow-up only | CGI-I is a global rating of improvement scale, which requires subjects to rate their degree of improvement on a seven-point scale: Compared to your condition at admission to the project \[prior to medication initiation\], how would you rate your overall response: 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment. |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred from October 2019 through March 2020 at Washington University HHT Center of Excellence
Pre-assignment details
272 participants total were assessed for eligibility; 245 met exclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| Timolol Gel Arm Participants in the timolol gel arm (active medication arm) will receive timolol nasal gel 0.1% with 0.5 mL applied to each nostril twice daily via a syringe that will amount to a 2 mg total daily dose.
Timolol Gel: Timolol nasal gel 0.1% will be prepared with a poloxamer gel (combination of poloxamer 188 and 407; pH adjusted to 4.5-6.5) and 0.5 ml applied to each nostril twice daily. The total daily dose would amount to 2 mg. | 14 |
| Placebo Gel Arm Participants in the placebo gel arm will receive the gel itself with no active medication.
Placebo Gel: Placebo gel is prepared with poloxamers and no active ingredients. | 13 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Screen fail | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo Gel Arm | Total | Timolol Gel Arm |
|---|---|---|---|
| Age, Continuous | 52 years | 55 years | 58 years |
| Baseline Clinical Global Impression - Severity Mild Problem | 4 Participants | 7 Participants | 3 Participants |
| Baseline Clinical Global Impression - Severity Moderate/Severe Problem | 5 Participants | 15 Participants | 10 Participants |
| Baseline Clinical Global Impression - Severity No Problem | 0 Participants | 0 Participants | 0 Participants |
| Baseline Clinical Global Impression - Severity Problem as bad as it could be | 0 Participants | 0 Participants | 0 Participants |
| Baseline Clinical Global Impression - Severity Unknown | 4 Participants | 5 Participants | 1 Participants |
| Comorbidity Status Mild | 4 Participants | 7 Participants | 3 Participants |
| Comorbidity Status Moderate | 0 Participants | 1 Participants | 1 Participants |
| Comorbidity Status None | 8 Participants | 17 Participants | 9 Participants |
| Comorbidity Status Severe | 1 Participants | 2 Participants | 1 Participants |
| Hypertension | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 25 Participants | 14 Participants |
| Region of Enrollment United States | 13 participants | 27 participants | 14 participants |
| Seasonal Allergies | 9 Participants | 18 Participants | 9 Participants |
| Sex: Female, Male Female | 4 Participants | 14 Participants | 10 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 |
| other Total, other adverse events | 7 / 14 | 3 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 |
Outcome results
Primary
Change in Assisted Epistaxis Severity Scale (aESS) Score From Baseline at 8 Week Follow-up
Assessment of epistaxis severity will be obtained by the validated instrument, the Epistaxis Severity Score (ESS). To complete the ESS, patients are asked to consider typical symptoms over the previous 3 months. The ESS contains 6 items - frequency, duration, and intensity of nosebleeds, whether patient has sought medication attention, whether patient is anemic, and whether patient has received a blood transfusion. The overall score ranges from 0 to 10, with severity of nosebleed based on score graded as None composite score of 0-1, Mild 1-4, Moderate 4-7, and Severe as 7-10.The minimal important difference noticeable by both patients and clinicians in the ESS scoring system is estimated as a change of 0.71. The scoring and MCID of the aESS is the same as the ESS. The aESS references a participant's epistaxis over the past 1 month, and the change in aESS was calculated as the aESS score at 8 weeks minus the aESS score at baseline.
Time frame: Baseline to 8-week follow-up
Population: Analysis was used with intention-to-treat principles, so all patients enrolled with baseline data were included. Note: the screen fail participant within the timolol gel arm had no baseline data say they were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Timolol Gel Arm | Change in Assisted Epistaxis Severity Scale (aESS) Score From Baseline at 8 Week Follow-up | 2.32 units on a scale |
| Placebo Gel Arm | Change in Assisted Epistaxis Severity Scale (aESS) Score From Baseline at 8 Week Follow-up | 1.96 units on a scale |
Secondary
Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale
CGI-I is a global rating of improvement scale, which requires subjects to rate their degree of improvement on a seven-point scale: Compared to your condition at admission to the project \[prior to medication initiation\], how would you rate your overall response: 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment.
Time frame: Scores at 8-week follow-up only
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Timolol Gel Arm | Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale | No Change | 0 Participants |
| Timolol Gel Arm | Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale | Slightly Improved | 4 Participants |
| Timolol Gel Arm | Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale | Much Improved | 7 Participants |
| Placebo Gel Arm | Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale | No Change | 1 Participants |
| Placebo Gel Arm | Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale | Slightly Improved | 3 Participants |
| Placebo Gel Arm | Number of Participants With Improved Response on Clinical Global Impression - Improvement (CGI-I) Scale | Much Improved | 8 Participants |