Clinical trial NCT04139018
Conditions: Hereditary Hemorrhagic Telangiectasia
Keywords: Epistaxis
Sponsor: Washington University School of Medicine
Start date: 2019-10-20; Completion date: 2020-05-20
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: Participants in the placebo gel arm will receive the gel itself with no active medication.
Interventions: intervention 1: Timolol Gel intervention 2: Placebo Gel
Intervention descriptions: intervention 1: 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. intervention 2: Placebo gel is prepared with poloxamers and no active ingredients.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
I. TITLE 
 
Efficacy of a Timolol Gel in the Care for Epistaxis in Patients with Hereditary Hemorrhagic 
Telangiectasia: A Double-Blinded, Randomized Controlled Trial (ETIC HHT Trial) 
 
II. SITE INVESTIGATORS 
 
Washington University Hereditary Hemorrhagic Telangiectasia (HHT) Center of Excellence  
Jay F. Piccirillo, MD, FACS 
Murali Chakinala, MD  
 
III. Trial Registration 
 
Prior to enrollment of the first subject, the trial protocol will be registered in ClinicalTrials.gov. 
 
NCT: NCT04139018 
 
Document Date: 11/1/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
IV. ABSTRACT 
 
Hereditary hemorrhagic telangiectasia is an autosomal dominant inherited disorder that progressively 
manifests with telangiectasias, mucosal bleeding, and possibly solid organ hemorrhage within the first few 
decades of life. Epistaxis is the most common presentation of the disease, with the vast majority of HHT 
patients developing recurrent epistaxis by the age of 20. Epistaxis alone has been shown to be the biggest 
contributor of morbidity and decreased quality of life in HHT patients. While a variety of medications and 
procedures have been tried to prevent the bleeding in HHT patients with epistaxis, no standard of care 
exists as each therapy has its own drawbacks. As a result, there is a need to further investigate potential 
therapies to prevent blood loss and iron deficiency anemia, and to improve the quality of life in HHT 
patients with moderate to severe epistaxis. Propranolol and timolol, nonselective beta blockers, in a topical 
gel form, are promising therapies to reduce epistaxis and reduce the likelihood of systemic side effects. The 
mechanism of action is proposed to be due to indirect shunting of catecholamines towards the alpha-1 
receptor and possible direct anti-angiogenic effects. Timolol is an available topical therapy in infantile 
hemangiomas and may play a role in the prevention and treatment of epistaxis in HHT. Due to 
propranolol’s toxicity to nasal cilia, timolol is the more favorable of the two drugs. Thus, we propose 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. 
The study population will consist of: adults with confirmed clinical (meeting at least 3 of the 4 Curaçao 
Criteria) or genetic diagnosis of HHT; Epistaxis Severity Score (ESS) ≥ 4 and 2 or more nosebleeds per 
week with a cumulative nosebleed duration of at least 5 (or 10) minutes per week; stable nasal hygiene and 
medical regimen for preceding 1 month; stable epistaxis pattern over the preceding 3 months.  We will 
recruit subjects from the Washington University Hereditary Hemorrhagic Telangiectasia (HHT) Center of 
Excellence, Froedtert & Medical College of Wisconsin Center of Excellence, and The CureHHT Participate 
in Research website.  The intervention will be prepared and dispensed by Advanced Rx Pharmacy, 
Plymouth Meeting, Pennsylvania.  Timolol nasal gel 0.1% will be prepared with a poloxamer gel and 0.5 ml 
applied to each nostril twice daily. The total daily dose will amount to 2 mg. Placebo gel is prepared with 
poloxamers and no active ingredients.  Timolol is odorless so the research subjects should not be able to 
identify the placebo gel from the active gel. The primary outcome will be the difference in the mean pre- to 
post-intervention change in the ESS among the subjects in the two intervention arms.  The 95%CI around 
this effect size will be determined to assess the precision of the observed effect and whether a clinically 
meaningful difference is plausible given the observed results. A total sample size of 24 patients is required 
to allow us to detect with 80% power at the 2-sided alpha level of 0.05 a difference of 62% or more in the 
percent of subjects who experience reduction of severity of bleeds between treatment groups.  Considering 
a 20% drop out rate, we plan to enroll 30 subjects in the study.  
 
V. STATEMENT OF RESEARCH PROBLEM 
 
BACKGROUND 
 
Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal dominant disorder that leads to 
abnormal formation of blood vessels throughout the body.(McDonald, Bayrak-Toydemir, and Pyeritz 2011) 


 
 
Patient symptoms primarily consist of bleeding from various mucosal surfaces from telangiectasias 
(dilated capillaries) across the total body to more severe or life-threatening hemorrhage from arterio-
venous malformations (AVMs) in the lung, brain, or liver. The telangiectasias tend to spontaneously 
rupture, most commonly resulting in nasal or gastrointestinal bleeding. Diagnosis of HHT is currently with 
the use of the Curaçao Criteria, which involves a combination of epistaxis, telangiectasias, visceral lesions 
(AVMs), and a family history of a first degree relative with HHT. Symptoms are age-dependent and 
gradually emerge over time.(Faughnan et al. 2011)  By age 20, more than 75% of patients with HHT have 
developed recurrent epistaxis.(Dheyauldeen, Abdelnoor, and Bachmann-Harildstad 2011) Epistaxis is the 
leading cause of morbidity and decreased quality of life in these patients. 
 
TREATMENT 
 
A variety of medical and surgical treatments are available for epistaxis. A recent evidence-based review was 
performed to provide treatment information.(Halderman et al. 2018) The authors used the Oxford levels of 
evidence(Group 2011) to grade the methodological quality of each article and the strength of the evidence.  
A total of 123 abstracts were reviewed covering systemic hormonal therapy, thalidomide, tranexamic acid, 
and propranolol.  Of the 123 abstracts, 18 articles were of sufficient methodological quality to be included.  
Systemic hormonal therapy delivered as selective estrogen receptor modulators (raloxifene and tamoxifen) 
and topical estriol was described in 5 articles.(Albinana et al. 2012; Minami and Haji 2016; Whitehead et 
al. 2016; Yaniv et al. 2009; Yaniv et al. 2011)  The level of evidence for systemic hormonal therapy was 
rated as Grade C and the authors concluded that hormonal therapy has potential benefits of improvement 
in frequency, severity, and number of epistaxis episodes.  Thalidomide has antiangiogenic properties and 
has been used to treat epistaxis and gastrointestinal bleeding. The review identified 4 articles that 
described observational studies of the impact of low-dose thalidomide (50-200 mg/d) on frequency and 
severity of epistaxis.(Fang et al. 2017; Invernizzi et al. 2015; Lebrin et al. 2010; Peng et al. 2015) The 
aggregate level of evidence of the four studies was Grade C and the authors concluded that improvements 
in patients’ bleeding without serious side effects were observed at the lower doses. Tranexamic acid (TXA) 
decreases the conversion of plasminogen to plasmin and thus stabilizes blood clots.  The authors reviewed 
5 articles, 2 of which were double-blinded randomized placebo clinical trials, that examined oral and 
topical TXA.(Fernandez et al. 2007; Gaillard et al. 2014; Geisthoff et al. 2014; Whitehead et al. 2016; Zaffar 
et al. 2015)  The results of the two clinical trials of oral TXA failed to show a change in hemoglobin level but 
did show improvements in various epistaxis parameters. The authors concluded that oral TXA is likely 
associated with a reduction in epistaxis without serious side effects, but additional high-quality studies are 
needed.  The one clinical trial to examine the impact of topical TXA showed no benefit.   
 
 
The Use of β-Blockers in the Management of HHT-Associated Epistaxis 
 
β-blockers have several possible biological mechanisms of action to reduce HHT-associated epistaxis and 
several studies in humans to suggest a clinically meaningful effect.  The β-blockers propranolol and timolol 
have been studied the most. 
Propranolol.  The non-selective beta-blocker propranolol is used both topically and systemically 
to treat superficial and deep infantile hemangiomas, respectively.(Price et al. 2018)  While the precise 
mechanism is unclear, it is likely a combination of vasoconstrictive properties of the drug as well as anti-
angiogenic effects(Storch and Hoeger 2010) and decreased migration of endothelial cells in vitro.(Albinana 
et al. 2012) Infantile hemangiomas and HHT have similar pathophysiologic mechanisms, both showing 
dysregulated angiogenesis and high levels of tissue VEGF.(Przewratil, Sitkiewicz, and Andrzejewska 2010; 
Zheng et al. 2013)  For these reasons, oral and topical propranolol has been identified as a treatment for 
HHT-associated epistaxis.  The systematic review identified two small studies(Contis et al. 2017; Mei-
Zahav et al. 2017) and the aggregate level of evidence was rated as Grade C.  The one study of oral 
propranolol(Contis et al. 2017) included 10 patients in a retrospective case series and 11 patients in a 


 
 
prospective design. In both the retrospective and prospective series, patients reported a significant 
reduction in epistaxis severity and frequency. Only one patient had to discontinue therapy due to 
hypotension.  In a retrospective case series of topical propranolol by investigators at the National HHT 
Center in Israel(Mei-Zahav et al. 2017), clinically significant reduction in frequency and severity of 
epistaxis as measured by the Epistaxis Severity Scale (ESS)(Hoag et al. 2010) was reported. In addition, 
the investigators report improvement in hemoglobin levels. Without a control group, however, it is difficult 
to conclude that the beneficial outcomes were due to the propranolol or to increased moisture from the gel.  
The authors of the systematic review(Halderman et al. 2018) concluded about the use of propranolol 
“Efficacy, or lack thereof, needs to be determined in large, well-designed studies before further use can be 
promoted”. 
 
Recent Study. At the 13th HHT International Scientific Conference (June 13-16, 2019), the same 
National HHT Center in Israel investigation team lead by Dr. Mei-Zahav reported on the results of a Phase 
II randomized clinical trial followed by an open-label study of topical propranolol gel. The study included 
20 subjects equally divided and randomized to propranolol 1.5% in a topical gel vs. topical gel alone for 8 
weeks. Approximated data (raw data not yet available) from Mei-Zahav showed that the average within 
subject decrease in ESS in the propranolol group was 2.03 points (SD=1.7) and in the placebo group it was 
0.48 points (SD=0.8) for a mean difference of 1.55 points (95% CI: 0.30 to 2.80; Cohen’s d = 1.2) in favor 
of propranolol group (Figure 1).  
 
 
Figure 1. Change in Epistaxis Severity Score (pre – post) as a Function of Intervention Arm 
 
In Figure 2, the spaghetti plot shows individual subject change in Epistaxis Severity Score for the subjects 
in the placebo and propranolol gel arms. Of the 10 patients in the propranolol group, 8 (80%) experienced 
a clinically meaningful difference while 4 of the 10 (40%) patients in the placebo group experienced a 
clinically meaningful difference (difference in proportion of 40%; 95% CI -2.3% to 67%).  
 
 
 
Figure 2. Individual Subject Change in Epistaxis Severity Score as a Function of 
Intervention Arm 
 
Quality of life, as measured by the SF-12 improved in the propranolol group from 35±7 to 41±7. There were 
no cardiovascular adverse effects noted in the trial, and the most common side effect was a burning 


 
 
sensation on application of the gel to the nasal mucosa. The severity was usually mild and resolved within 
1-2 weeks in most patients. The other side effect noted was rhinorrhea, which was severe in two patients, 
resulting in withdrawal of the two patients during the open label period. While 13 out of the 16 patients 
that received propranolol have continued to use it topically off label, the investigators feel there is a need to 
modify the drug delivery system and/or the drug preparation to minimize further the side effects. 
 
Intranasal Propranolol is Not Well Tolerated and is Associated with Adverse Effects on Ciliated 
Epithelium.  Several studies demonstrated that intranasal propranolol is not well tolerated and is 
associated with arrested cilia movement. Van de Donk et al found that doses as low as 0.1% propranolol 
had a deleterious effect on the cilia of chicken and human tissue.(Merkus et al. 2006)  In Figure 3, the 
effect of propranolol on the ciliary beat frequency over time is shown. As can be seen, propranolol 0.1%, 
which is considerably lower than the 1.5% dosage used in the Mei-Zahav study, arrested ciliary movement 
within 20 minutes.  The authors concluded that the effect was irreversible since movement did not return 
within 2 hours after drug was rinsed away. 
 
Figure 3. The effect of 0.1% propranolol-HCL on the cilia beat frequency of human 
adenoids. LR – Locke-Ringer solution (control). Reprinted from The Influence of Drugs on 
Nasal Ciliary Movement.(Hermens and Merkus 1987)  
 
 
Duchateau et al studied three different propranolol HCL formulations - oral, sublingual, and intranasal in 
8 heathy male volunteers.(Duchateau, Zuidema, and Merkus 1986) The 5-mg intranasal dose was 
administered as a solution of propranolol HCL in 0.2 ml 2% methylcellulose gel, pH 7.4. The authors found 
that propranolol was rapidly absorbed from the nasal cavity but was not well tolerated as its use was 
associated with nasal burning immediately after administration.  The authors concluded that chronic use of 
propranolol should be discouraged due to local side effects of stinging sensation in the nose and 
ciliotoxicity. 
 
Timolol. Timolol is a non-selective ß-blocker eliminated by the liver and primarily metabolized by 
CYP2D6. Topic timolol has been used to treat superficial hemangiomas in infants.(Sorrell and Chamlin 
2013)  Timolol has been shown to have vasoconstriction properties, causes endothelial cell apoptosis, and 
decreases VEGF expression.(Storch and Hoeger 2010)   
 
In a case report, Olitsky reported on the intranasal use of topical timolol for HHT-associated 
epistaxis.(Olitsky 2012) The 48-year patient had had multiple procedures and treatments in the past, 
including nasal cauterization and use of intranasal bevacizumab, but was experiencing 3 to 4 nosebleeds a 
day.  The patient was started on one drop of timolol 0.5% ophthalmic solution in each nostril three times 
per day. Significant reduction in the frequency and severity of epistaxis was reported in 3 to 4 days, 
remained after one month, and was not associated with change in blood pressure or heart rate during the 
treatment.   
 


 
 
A prospective study of the impact of timolol ophthalmic solution (0.5%) delivered as a nasal drop into each 
nostril 3 times daily for 3 months was performed in 12 HHT patients who had previously undergone nasal 
dermoplasty.(Ichimura et al. 2016)  The mean score of bleeding intensity and frequency were markedly 
reduced after treatment.  Two patients who had required transfusions before treatment did not need them 
afterward, and patients were generally satisfied with the treatment.  One patient, a 78-year-old male, 
developed disequilibrium, hypotension, and bradycardia on the second day of timolol. He then developed 
heart failure and was removed from the study. 
 
A third study reported on the use of intranasal timolol 0.5% ophthalmological solution in a 59-year-old 
man with a history of HHT-associated epistaxis but no known cardiac conditions.(Ichimura et al. 2016)  He 
had a significant family history of cardiac disease and developed lightheadedness and sinus bradycardia 
with right bundle branch block within 3 weeks of starting treatment.  The total daily dose of the patient in 
the case study was 6 mg/day, which is not excessive as the typical oral dose is 10 mg twice daily. The 
bradycardia and heart blocked stopped with cessation of timolol drops. Through genetic testing, he was 
subsequently discovered to be an intermediate metabolizer of CYP2D6 enzyme, which was felt to explain 
the bradycardia.  The CYP2D6 gene encodes an enzyme important in the metabolism of many commonly 
used medications. Variation in CYP2D6 is associated with inter-individual differences in medication 
response, and genetic testing is used to optimize medication therapy. 
 
 
Conclusion 
 
The mechanisms of action, published literature, and results of an unpublished study presented at the 13th 
HHT International Scientific Conference suggest a role of β-blockers in the management of HHT-
associated epistaxis.  The work by Mei-Zahav et al suggest propranolol gel may be an effective treatment 
for HHT-associated epistaxis. However, intranasal propranolol is not well tolerated and is associated with 
arrested cilia movement.  Topical timolol has advantages over propranolol in that it is well-tolerated and 
has been shown to not have an effect on nasal mucosa.(Jagdale, Shewale, and Kuchekar 2016) Patients 
with certain pre-existing heart conditions or metabolizing variants of the liver enzyme CYP2D6 are at 
increased risk for adverse effects of timolol ophthalmological solution.   
 
Given our understanding of the pathophysiology of HHT-associated epistaxis, mechanism of action, and 
pharmacokinetics of intranasal timolol, we believe it is now appropriate to conduct a Phase II double-
blinded, placebo controlled randomized clinical trial to evaluate the efficacy of intranasal timolol gel.  The 
results of this Phase II study will provide additional information on the benefits and risks of intranasal 
timolol, which can be used to inform the design of a definitive Phase III study. 
 
VI. SPECIFIC AIMS 
 
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, and safety profile of topical timolol gel delivered to the nasal mucosa of HHT 
patients. 
 
VII. DESIGN PLAN 
 
Study Type 


 
 
 
The study will be a multi-site, double-blind, placebo-controlled randomized clinical trial performed at two 
tertiary academic medical center HHT Centers of Excellence.   
 
Blinding 
 
Research participants and the members of the investigative team who will have direct subject interaction 
will be blinded to treatment assignment.  The research statistician, Dr. Kallogjeri, will not be blinded.  All 
subject assessments will be performed without knowledge of treatment. 
 
Study Population 
Inclusion Criteria:  
1) 
Adults ages 18 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 
a. Hypersensitivity to β adrenergic blockers 
b. Asthma or bronchospasm 
c. Congestive heart failure with LVEF <40% 
d. Hereditary pulmonary arterial hypertension 
e. Baseline bradycardia (HR <55 beats per minute) 
f. Sick Sinus Syndrome 
g. 2nd or 3rd degree heart block, left or right bundle branch block, or bifasicular block 
h. Uncontrolled diabetes mellitus (most recent HbA1c >9%) or diabetic ketoacidosis 
within last 6 months 
i. 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 
 
Eligibility Determination 
 
To determine potential eligibility for the study, the research team will query the medical record based on 
the following inclusion/exclusion criteria: 
• Age (18 years or older) 
• Medication history to assess current use of a β-blocker (exclusion) 
• Allergy history to timolol (exclusion) 
• Changes in epistaxis care in the last month (exclusion) 
• Use of illicit drugs (exclusion) 
• History of unresected pheochromocytoma (exclusion) 
 
For those meeting the selection criteria, we will access name, telephone number, age, sex, and date/time of 
any clinic visits related to HHT and/or epistaxis.  
 
Recruitment and Consent Process 
 
Washington University Hereditary Hemorrhagic Telangiectasia (HHT) Center of 
Excellence.  Adult HHT patients will be recruited from the Washington University Hereditary 
Hemorrhagic Telangiectasia (HHT) Center of Excellence database and the EPIC electronic medical record. 
Advertisements describing the study will be posted in the WU Department of Otolaryngology-Head & Neck 
Surgery clinic and the Division of Pulmonary Medicine. We will attempt to recruit minorities through the 
assistance of Ms. Sara Kukuljan, Department of Otolaryngology-Head and Neck Surgery Subject 
Recruitment Coordinator.  However, HHT is quite rare in people of African descent and so recruitment of 
African-Americans with HHT-associated epistaxis is expected to be quite low. 
 
Froedtert & Medical College of Wisconsin Center of Excellence.  Research subjects will be 
recruited from HHT patients seeking care from any of the participating physicians at the HHT Center for 
Advanced Care - Froedtert Hospital. 
 
CureHHT Website. Trial information, including inclusion and exclusion criteria, will be posted on 
CureHHT website Participate in Research page [https://curehht.org/research/participate-in-research/] 
 
Eligible patients who present to clinic or respond to advertisements will be approached by a research team 
member to review the informed consent process and thoroughly discuss the research protocol, potential 
benefits, and risks of the study.  The informed consent discussion will take place with the patient and any 
available family members in person. Any subsequent questions or concerns from the potential participant 
and any family members will also be addressed at that time. After discussion, the patient will be asked to 
re-summarize the steps involved in the study to ensure understanding. If interested, written consent will be 
obtained. Patients will be reminded that study participation is voluntary and will in no way affect their 
current or future care. 
 
Variables Under Study 
 
Assisted Epistaxis Severity Score (aESS). Assessment of epistaxis severity will be obtained by the 
validated instrument, the Epistaxis Severity Score (ESS).(Hoag et al. 2010) (Appendix 1) To complete the 
ESS, patients are asked to consider typical symptoms over the previous 3 months. However, with the 8-
week duration of our trial, patients will complete the aESS in reference to their epistaxis over the past 1 
month. 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.(Yin et al. 2016) 
 
HHT Endoscopy Score (HES).  The HHT Endoscopy Score (HES) is an endoscopy staging score 
developed as a way to quantify the severity of the patient’s nasal telangiectasias as seen on physical 
exam.(Reh et al. 2014) The HES was shown to correlate with the ESS. Its parameters are telangiectasia 
sites, patterns, crusting, location, perforation, density, and relative AVMs. Scoring of the HES is illustrated 
in Appendix 2.  
 
Epistaxis-Specific Quality-Of-Life Questionnaire (EQQoL).  The EQQoL measures 13 items that 
focus on the impact of epistaxis on the patient’s physical, functional, and emotional status and quality of 
life.(Ingrand et al. 2011)  The EQQoL was shown to have satisfactory psychometric properties and when 
combined with the SF-36 measures both disease-specific and general quality of life. See Appendix 3 for 
questionnaire. 
 
Short Form (SF-36).  The Medical Outcomes Short Form-36 (SF-36) was developed for use in clinical 
practice and research to measure general physical functional and quality of life.(Ware and Sherbourne 
1992)  The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in 
physical activities because of health problems; 2) limitations in social activities because of physical or 
emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily 
pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities 
because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. See 
Appendix 4 for questionnaire.  
 
Patient Satisfaction with Treatment.  The Treatment Satisfaction Questionnaire for Medication 
Version II (TSQMII) was is an 11-question questionnaire adapted and validated from the TSQM v. I in 
order to more precisely collect information (fewer questions and more consistent wording) regarding four 
general topics of patient satisfaction with treatment: effectiveness, side effects, convenience, and overall 
satisfaction. (See Appendix 5 questionnaire)(Atkinson et al. 2005; Atkinson et al. 2004) 
 
Clinical Global Impression Scale (CGI).  The overall response to treatment will be measured with the 
Clinical Global Impression (CGI) scale. The CGI Scale measures response to treatment for a number of 
disorders and has good internal consistency and validity.(Dunlop, Gray, and Rapaport 2017) Upon 
completion of the study, subjects will be asked to answer the following question: "Overall, how would you 
rate your response to treatment?" Response options are: Very Much Improved, Much Improved, 
Minimally Improved, No Change, Minimally Worse, Much Worse, and Very Much Worse. 
 
Epistaxis, Transfusion, and Compliance (ETC) Logs.  Patients will be asked to use the Cure HHT 
app from the online app store if they have a mobile device capable of this feature. It will include a daily 
reminder to track epistaxis frequency and severity, energy levels, if they received a blood transfusion 
and/or iron transfusion, and if they took their medication. If the patient answers yes to the transfusion, he 
or she will be prompted to describe the details of the transfusion, including quantity of units received.  The 
app can directly share the information with the study team at the patient’s request.  
 
If patients are not able to use the app for any reason, a text message and/or email will be sent to the patient 
each evening via the REDCap™ (Research Electronic Database) website that will ask questions about the 
frequency and severity of epistaxis and energy level that replicates the Cure HHT app. The REDCap™ 


 
 
survey will assess for compliance by asking if the research subject has used the assigned treatment that 
day. Once each week, the survey will ask the subject if he or she received a blood transfusion that week. 
REDCap™ is a password-protected site that will keep the information confidential.  
 
Methods 
 
Demographic information, including age, gender, and race, will be collected from each enrolled patient. 
Data will be collected regarding the duration of each patient’s epistaxis history, previous treatments, and 
estimation of the average number of nosebleeds per day; HHT treatment history; co-morbid conditions, 
such as hypertension, inhalant allergies, and other blood dyscrasias; risk factors, such as cigarette 
smoking, use of CPAP, and use of supplemental oxygen; and medications associated with increased 
bleeding.   
 
At the initial visit, research subjects will complete the informed consent process, SF-36, ESS, baseline 
electrocardiogram (ECG), CYP2D6 enzyme allele, blood pressure (BP), and heart rate (HR). ECGs are to be 
read by Dr. Murali Chakinala. Subjects will undergo a directed otolaryngology physical exam by Dr. 
Piccirillo that will include nasal endoscopy to describe nasal mucosa telangiectasias. Dr. Piccirillo will rate 
the nasal mucosa telangiectasias using the HES.  Patients will be scheduled for phlebotomy to obtain a 
blood specimen to measure hemoglobin levels prior to beginning therapy. Baseline daily iron 
supplementation will also be recorded and it will be recommended to the patient not to alter their daily 
supplementation of iron or other treatments, unless indicated by a change in epistaxis frequency.  
 
Upon demonstration that patient does not have the CYP2D6 allele associated with a low or intermediate 
metabolizer of timolol and successful completion of questionnaires, physical examination, and laboratory 
tests, subjects will be randomized to receive either timolol gel or placebo.  
 
Pharmaceutical Preparation. The intervention will be prepared and dispensed by Advanced Rx 
Pharmacy, Plymouth Meeting, Pennsylvania.  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. Placebo gel is prepared with poloxamers and no active 
ingredients.  Timolol is odorless so the research subjects should not be able to identify the placebo gel from 
the active gel. 
 
Subjects will be instructed to apply 0.5 ml to the nasal mucosa of each nostril twice daily via 20 mL 
syringes. The gel will be dispensed in an amber vial with an adapter to which the syringe can attach in 
order to draw out the medication for each dose. Patients will be supplied with one syringe per day for a 
total of 56 syringes. They will be given alcohol wipes to clean the syringe between the morning and evening 
gel application. When the syringes are distributed, the research assistants will make sure that the patient 
understands how to apply correctly the medication to the nasal cavity. 
 
BP and HR measurements will be obtained by the subject weekly at home with the use of the blood 
pressure monitor given to them at the beginning of the study and blood pressures will be reported via the 
use of REDCap™. Subjects will also be instructed to report any local or systemic side effects throughout the 
duration of the study. Telephone calls with the study team at the end of Week 1 and again at Week 4 will be 
arranged.  
 
After 8 weeks of intervention, subjects will be asked to return to clinic and the physician will perform nasal 
endoscopy and complete the HES scale.  Subjects will have blood pressure and heart rate measurements. 
Subjects will complete the SF-36, ESS, CGI, EQQoL, and the TSQMII questionnaires. To assess the quality 
of the blind, subjects will be asked which arm of the study they thought they were randomized.  Subjects 


 
 
will also be asked whether they would recommend the treatment to a friend or family member if they 
suffered with HHT-associated epistaxis.  A follow-up blood draw to measure hemoglobin and hematocrit 
will be completed.  
 
It will be emphasized to the patient not to change their current nasal hygiene regimen (e.g., nasal saline 
spray) or other chronic treatments (e.g., tranexamic acid).  
 
Primary Outcome: 
1) Mean change in Epistaxis Severity Score (ESS) between baseline and follow-up. 
 
Secondary Outcomes: 
1) Clinical Global Impression – Improvement (CGI-I) Score 
2) Mean change in hemoglobin  
3) Change in intensity of telangiectasias in the nasal mucosa as determined by the HHT endoscopic 
scale (HES) 
 
 
 
 
Summary of Project Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VIII. SAMPLE SIZE AND PLANNED STATISTICAL ANALYSIS 
 
Sample Size 
 
Sample size estimate for the proposed study were derived from the single study(Ichimura et al. 2016) of 
within subject change in severity of epistaxis associated with timolol ophthalmic solution (0.5%) as a nasal 
drop. In that study, 9 of the 11 subjects (82%) experienced a reduction in the severity of bleeds as measured 
on a 5-point Likert scale. We hypothesize a similar response (82%) in our proposed study among subjects 
randomized to receive timolol gel and a 20% response rate among subjects randomized to placebo gel, 
corresponding to a difference of 62%. 
 
A power analysis was performed using Fisher’s exact test in G-Power 3.1.2.  We estimate that a total sample 
size of 24 patients (ie., 12 in each arm) is needed to allow us to detect with 80% power at the 2-sided alpha 
level of 0.05 a difference of 62% or more in the percent of subjects who experience reduction of severity of 
 
 
Eligible 
patients 
Baseline 
 
ESS, SF-36, ACE-27, 
HES, energy level, 
EQQoL, CYP2D6, Hb 
Week 1 
Follow-up 
 
ESS, SF-36, ACE-27, 
HES, CGI-I, energy level, 
EQQoL, Hb 
 
Week 8 
Week 4 
Phone call 
Timolol 
Placebo 


 
 
bleeds between treatment groups.  Considering a 20% drop out rate, we plan to enroll 30 subjects in the 
study. 
 
Statistical Analysis 
 
Standard descriptive statistics will be used to describe distribution of baseline characteristics in each of the 
study groups. The effect of the intervention will be measured as the difference in the within-subject change 
(baseline – 8-week follow-up) in ESS scores between the two treatment groups calculated as shown below. 
 
1) 
Within subject difference with each treatment group 
 
ΔESSTimolol = (ESSTimolol_base – ESSTimolol_8-Week) 
ΔESSControl = (ESSTimolol_base – ESSTimolol_8-Week) 
 
 
2) 
Between treatment difference 
 
ΔESSTimolol - ΔESSControl 
 
The 95%CI around this effect size will be determined to assess the precision of the observed effect and 
whether a clinically meaningful difference is plausible given the observed results.  
 
An independent sample t-test will be used to compare the change in scores between the two study groups. 
If potential confounding factors are identified, a mixed model analysis will be employed to compare the 
change in the scores between the two study groups after controlling for potential confounding factors.  
 
Appropriate analyses will be performed for the secondary outcome measures.  
 
IX. EXEMPTION FROM IND REQUIREMENTs 
 
The use of timolol in topical nasal gel is a change in the approved route of administration. An exemption 
from IND requirements will be requested as the proposed use of timolol in this study fulfills all of the 
criteria for exemption. 
 
1) Timolol is lawfully marketed in the United States. 
2) This study is not intended to be reported to the FDA in support of a new indication or significant 
change in labeling. 
3) This study is not intended to support a significant change in the advertising for the drug. 
4) The study does not involve a route of administration, dose, patient population, or other factor that 
significantly increases the risk (or decreases the acceptability of the risk) associated with the use of 
timolol. 
5) The study will be conducted in compliance with the requirements for review by an IRB (21 CFR part 
56) and with the requirements for informed consent (21 CFR part 50). 
6) The study is not intended to promote or commercialize timolol. 
 
X. ASSESSMENT OF TREATMENT SAFETY 
 
Treatment Safety 
 
Treatment safety information comes from three different sources. First, a study was conducted to assess 
the properties of 1% (10 mg) topical intranasal timolol gel and to optimize controlled release in situ nasal 


 
 
delivery.(Jagdale, Shewale, and Kuchekar 2016)  The authors studied timolol and Poloxamer 407 polymer 
interaction and were able to show that there was no chemical reaction between timolol and the 
polymer.(Nieminen et al. 2007; Volotinen et al. 2011)  The authors also demonstrated no histological 
changes to nasal mucosa after the study.  The authors concluded that the combination of timolol with 
Poloxamer 407 was associated with adequate gelation temperature, mucoadhesive strength, and in situ 
controlled release of timolol.  They concluded that timolol gel is safe for nasal administration.  Second, 
Olitsky studied intranasal delivery of one drop of timolol 0.5% as ophthalmic solution to each nostril three 
times daily for a total daily dose of 1.5 mg in one adult patient with HHT-associated epistaxis.(Olitsky 
2012) The drug was well tolerated with no change in blood pressure or heart rate; no other side effects 
were reported.  Third, timolol 0.5% ophthalmic drops administered intranasally has been associated with 
systemic side effects, especially in patients with CYP2D6 enzyme variants.(Epperla, Brilliant, and Vidaillet 
2014) Ocular administration of timolol has been associated with systemic adverse effects, including 
bradycardia.(Canpolat et al. 2013; Nieminen et al. 2007; Volotinen et al. 2011) (See Appendix 6 – Adverse 
Reactions). Among the various symptoms of systematically absorbed ophthalmic timolol, change in heart 
rate is the most frequent and is more likely with the 0.5% aqueous rather than the 0.1% hydrogel 
formulation.(Nieminen et al. 2007) Since the pharmacokinetics of timolol are dependent on the CYP2D6 
polymorphic enzyme, the individual patient phenotype for this enzyme will dictate plasma concentrations 
and frequency of adverse events. Four major phenotypes of CYP2D6 metabolizers have been identified: 
Poor, Intermediate, Extensive, and Ultrarapid.(Ingelman-Sundberg and Rodriguez-Antona 2005; Sikka et 
al. 2005; Volotinen et al. 2011) In one study, it was found that Poor metabolizers had a 2.5-fold higher 
plasma concentration than Extensive metabolizers after application of timolol 0.5% aqueous eye 
drops.(Nieminen et al. 2007). Timolol eye drops delivered intranasally was associated with greater β-
blockade in Poor metabolizers as compared with Extensive metabolizers. Thus, the metabolism of 
systematically absorbed timolol is clearly related to the phenotype of the individual for the CYP2D6 
enzyme. 
 
 
 
Frequency of Different CYP2D6 Alleles in the Population  
 
The frequency of different CYP2D6 alleles and thus the ability to metabolize timolol was studied in 
population of 104,509 de-identified patient samples from across the United States between February 2015 
and March 2016.(Del Tredici et al. 2018) The frequency distribution of various phenotypes of CYP2D6 
alleles was observed to be: ultra-rapid metabolizers (2.2%), normal metabolizers (81%), intermediate 
metabolizers (11%), and poor metabolizers (6%). Therefore, an estimated total of 17% or 5 subjects 
otherwise eligible for the study would be expected to be at increased risk of side effects due to timolol 
compared to the normal metabolizers and therefore will be excluded.  
 
While ophthalmic solution is readily absorbed into the blood stream, CYP2D6 genetic testing is not 
commonly done for open-angle glaucoma patients prior to initiation of timolol therapy. To prevent 
cardiovascular side effects, it is recommended that glaucoma patients be screened for coexisting conditions 
and consideration of genetic phenotypic CYP2D6 status testing if readily available.(Maenpaa and Pelkonen 
2016) 
 
In this study, all eligible patients will undergo CYP2D6 testing, ECG, BP, and HR readings at initial visit. 
Patients with a CYP2D6 allele that is associated with an intermediate or poor metabolizer or an ECG that 
demonstrates conduction abnormalities, such as second-degree and third-degree AV block and/or 
clinically significant bradycardia will be excluded from the study.  Enrolled patients will be given a blood 
pressure monitor by the study team and taught how to use it at their baseline visit. They will be instructed 
to take and report weekly BP and HR to the study team in addition to local or systemic side effects. Patients 


 
 
will be called at the end of Week 1 and Week 4 of the study to answer any questions or concerns they may 
have as well as to ask if they have experienced any side effects. During these phone calls, patients will be 
asked whether they have changed their daily iron supplementation or blood transfusion pattern from 
baseline. If patients have an increase in nosebleeds for any reason, they will be asked to contact the study 
team or report to the emergency department, depending on the severity.  
 
Any of the following will be considered an indication to stop the study: 
1) Asymptomatic systolic BP drop to less than 80 mmHg or a drop of 20% from baseline systolic BP 
2) Symptomatic blood pressure drop 
3) A drop of HR to less than 50/min 
4) Any clinical signs of heart block  
5) Grade >2 local or systemic side effects, such as local irritation or an allergic reaction to the 
medication 
6) Patient’s request or physician’s determination of continuing the study to be no longer safe  
In the event of a Serious Adverse Event determined by the PI to necessitate the breaking of the blind, the 
intervention assignment will be revealed by Dr. Kallogjeri to the medical staff doctor caring for the patient. 
In the event Dr. Kallogjeri is unable to be reached in a time needed, to assure the safety of the subject, the 
blind can be broken by Sara Kukuljan, RN or Dr. Piccirillo and information will be shared with the medical 
staff assuming care for the research subject.  
 
XI.  Data and Safety Monitoring 
 
The specific monitoring plan for this study is based on the potential risk of participation and size and 
complexity of the planned investigation.  Based on these considerations, this study will have a monitoring 
board comprised of Dr. Piccirillo, Dr. Chakinala, Ms. Kukuljan, and Dr. Kallogjeri, the study biostatistician. 
The monitoring board will meet to review data at least every 6 months.  All reports of a Serious Adverse 
Event (SAE) or an Unexpected Adverse Event will be investigated by the monitoring team and reported to 
Washington University HRPO according to the reporting requirements. 
 
 
 
 
XII.  Ethical considerations 
While patients will be randomly selected to receive timolol, an FDA-approved drug, the efficacy and safety, 
including local and/or systemic reactions, are largely unknown when applied in topical gel form. Patients 
will be informed in the informed consent process that they may or may not personally benefit from the 
study and that the data obtained from the study will be used to inform the future care of HHT patients with 
epistaxis. There will be phone assistance available 24/7 during the study period to report any possible 
adverse reactions. To reduce the risk of breach of confidentiality, all data forms with identifying 
information will be kept in locked cabinets and only members of the study team will have access to secured 
files. There are no financial conflicts of interest. 
 
XIII. REFERENCES 
 
 
• Albinana, V., L. Recio-Poveda, R. Zarrabeitia, C. Bernabeu, and L.M. Botella. 2012. Propranolol as 
antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia. Thromb 
Haemost 108: 41-53. 


 
 
• Atkinson, M.J., R. Kumar, J.C. Cappelleri, and S.L. Hass. 2005. Hierarchical construct validity of 
the treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
pharmacy consumers. Value Health 8 Suppl 1: S9-S24. 
• Atkinson, M.J., A. Sinha, S.L. Hass, S.S. Colman, R.N. Kumar, M. Brod, and C.R. Rowland. 2004. 
Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire 
for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes 
2: 12. 
• Canpolat, U., K.M. Gurses, K. Aytemir, and A. Oto. 2013. Severe bradycardia and syncope due to 
topical ophthalmic timolol. Herz 38: 556-7. 
• Contis, A., N. Gensous, J.F. Viallard, C. Goizet, C. Leaute-Labreze, and P. Duffau. 2017. Efficacy and 
safety of propranolol for epistaxis in hereditary haemorrhagic telangiectasia: retrospective, then 
prospective study, in a total of 21 patients. Clin Otolaryngol 42: 911-7. 
• Del Tredici, A.L., A. Malhotra, M. Dedek, F. Espin, D. Roach, G.D. Zhu, J. Voland, and T.A. Moreno. 
2018. Frequency of CYP2D6 Alleles Including Structural Variants in the United States. Front 
Pharmacol 9: 305. 
• Dheyauldeen, S., M. Abdelnoor, and G. Bachmann-Harildstad. 2011. The natural history of epistaxis 
in patients with hereditary hemorrhagic telangiectasia in the Norwegian population: a cross-
sectional study. Am J Rhinol Allergy 25: 214-8. 
• Duchateau, G.S., J. Zuidema, and F.W. Merkus. 1986. Bioavailability of propranolol after oral, 
sublingual, and intranasal administration. Pharm Res 3: 108-11. 
• Dunlop, B.W., J. Gray, and M.H. Rapaport. 2017. Transdiagnostic Clinical Global Impression 
Scoring for Routine Clinical Settings. Behav Sci (Basel) 7. 
• Epperla, N., M.H. Brilliant, and H. Vidaillet. 2014. Topical timolol for treatment of epistaxis in 
hereditary haemorrhagic telangiectasia associated with bradycardia: a look at CYP2D6 metabolising 
variants. BMJ Case Rep 2014. 
• Fang, J., X. Chen, B. Zhu, H. Ye, W. Zhang, J. Guan, and K. Su. 2017. Thalidomide for Epistaxis in 
Patients with Hereditary Hemorrhagic Telangiectasia: A Preliminary Study. Otolaryngol Head Neck 
Surg 157: 217-21. 
• Faughnan, M.E., V.A. Palda, G. Garcia-Tsao, U.W. Geisthoff, J. McDonald, D.D. Proctor, J. Spears, 
D.H. Brown, E. Buscarini, M.S. Chesnutt, V. Cottin, A. Ganguly, J.R. Gossage, A.E. Guttmacher, 
R.H. Hyland, S.J. Kennedy, J. Korzenik, J.J. Mager, A.P. Ozanne, J.F. Piccirillo, D. Picus, H. 
Plauchu, M.E. Porteous, R.E. Pyeritz, D.A. Ross, C. Sabba, K. Swanson, P. Terry, M.C. Wallace, C.J. 
Westermann, R.I. White, L.H. Young, R. Zarrabeitia, and H.H.T.F.I.-G.W. Group. 2011. 
International guidelines for the diagnosis and management of hereditary haemorrhagic 
telangiectasia. J Med Genet 48: 73-87. 
• Fernandez, L.A., E.M. Garrido-Martin, F. Sanz-Rodriguez, J.R. Ramirez, C. Morales-Angulo, R. 
Zarrabeitia, A. Perez-Molino, C. Bernabeu, and L.M. Botella. 2007. Therapeutic action of tranexamic 
acid in hereditary haemorrhagic telangiectasia (HHT): regulation of ALK-1/endoglin pathway in 
endothelial cells. Thromb Haemost 97: 254-62. 
• Gaillard, S., S. Dupuis-Girod, F. Boutitie, S. Riviere, S. Moriniere, P.Y. Hatron, G. Manfredi, P. 
Kaminsky, A.L. Capitaine, P. Roy, F. Gueyffier, H. Plauchu, and A.S. Group. 2014. Tranexamic acid 
for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled 
trial in a rare disease. J Thromb Haemost 12: 1494-502. 


 
 
• Geisthoff, U.W., U.T. Seyfert, M. Kubler, B. Bieg, P.K. Plinkert, and J. Konig. 2014. Treatment of 
epistaxis in hereditary hemorrhagic telangiectasia with tranexamic acid - a double-blind placebo-
controlled cross-over phase IIIB study. Thromb Res 134: 565-71. 
• Group, O.C.E.-B.M.L.o.E.W. 2011. The Oxford 2011 Levels of Evidence. Available at 
http://www.cebm.net/ocebm-levels-of-evidence/. 
• Halderman, A.A., M.W. Ryan, C. Clark, R. Sindwani, D.D. Reh, D.M. Poetker, R. Invernizzi, and B.F. 
Marple. 2018. Medical treatment of epistaxis in hereditary hemorrhagic telangiectasia: an evidence-
based review. Int Forum Allergy Rhinol 8: 713-28. 
• Hermens, W.A., and F.W. Merkus. 1987. The influence of drugs on nasal ciliary movement. Pharm 
Res 4: 445-9. 
• Hoag, J.B., P. Terry, S. Mitchell, D. Reh, and C.A. Merlo. 2010. An epistaxis severity score for 
hereditary hemorrhagic telangiectasia. Laryngoscope 120: 838-43. 
• Ichimura, K., H. Kikuchi, S. Imayoshi, and M.S. Dias. 2016. 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 43: 429-32. 
• Ingelman-Sundberg, M., and C. Rodriguez-Antona. 2005. Pharmacogenetics of drug-metabolizing 
enzymes: implications for a safer and more effective drug therapy. Philos Trans R Soc Lond B Biol 
Sci 360: 1563-70. 
• Ingrand, I., P. Ingrand, B. Gilbert-Dussardier, G. Defossez, V. Jouhet, V. Migeot, X. Dufour, and 
J.M. Klossek. 2011. Altered quality of life in Rendu-Osler-Weber disease related to recurrent 
epistaxis. Rhinology 49: 155-62. 
• Invernizzi, R., F. Quaglia, C. Klersy, F. Pagella, F. Ornati, F. Chu, E. Matti, G. Spinozzi, S. Plumitallo, 
P. Grignani, C. Olivieri, R. Bastia, F. Bellistri, C. Danesino, M. Benazzo, and C.L. Balduini. 2015. 
Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary 
haemorrhagic telangiectasia: results of a non-randomised, single-centre, phase 2 study. Lancet 
Haematol 2: e465-73. 
• Jagdale, S., N. Shewale, and B.S. Kuchekar. 2016. Optimization of Thermoreversible In Situ Nasal 
Gel of Timolol Maleate. Scientifica (Cairo) 2016: 6401267. 
• Lebrin, F., S. Srun, K. Raymond, S. Martin, S. van den Brink, C. Freitas, C. Breant, T. Mathivet, B. 
Larrivee, J.L. Thomas, H.M. Arthur, C.J. Westermann, F. Disch, J.J. Mager, R.J. Snijder, A. 
Eichmann, and C.L. Mummery. 2010. Thalidomide stimulates vessel maturation and reduces 
epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 16: 420-8. 
• Maenpaa, J., and O. Pelkonen. 2016. Cardiac safety of ophthalmic timolol. Expert Opin Drug Saf 15: 
1549-61. 
• McDonald, J., P. Bayrak-Toydemir, and R.E. Pyeritz. 2011. Hereditary hemorrhagic telangiectasia: 
an overview of diagnosis, management, and pathogenesis. Genet Med 13: 607-16. 
• Mei-Zahav, M., H. Blau, E. Bruckheimer, E. Zur, and N. Goldschmidt. 2017. Topical propranolol 
improves epistaxis in patients with hereditary hemorrhagic telangiectasia - a preliminary report. J 
Otolaryngol Head Neck Surg 46: 58. 
• Merkus, P., F.A. Ebbens, B. Muller, and W.J. Fokkens. 2006. Influence of anatomy and head 
position on intranasal drug deposition. European Archives of Oto-rhino-laryngology 263: 827-32. 
• Minami, K., and T. Haji. 2016. Intranasal topical estrogen in the management of epistaxis in 
hereditary hemorrhagic telangiectasia. Acta Otolaryngol 136: 528-31. 


 
 
• Nieminen, T., T. Lehtimaki, J. Maenpaa, A. Ropo, H. Uusitalo, and M. Kahonen. 2007. Ophthalmic 
timolol: plasma concentration and systemic cardiopulmonary effects. Scand J Clin Lab Invest 67: 
237-45. 
• Olitsky, S.E. 2012. Topical timolol for the treatment of epistaxis in hereditary hemorrhagic 
telangiectasia. Am J Otolaryngol 33: 375-6. 
• Peng, H.L., Y.F. Yi, S.K. Zhou, S.S. Xie, and G.S. Zhang. 2015. Thalidomide Effects in Patients with 
Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic 
Zebrafish Model. Chin Med J (Engl) 128: 3050-4. 
• Price, A., S. Rai, R.W.J. McLeod, J.C. Birchall, and H.A. Elhassan. 2018. Topical propranolol for 
infantile haemangiomas: a systematic review. J Eur Acad Dermatol Venereol 32: 2083-9. 
• Przewratil, P., A. Sitkiewicz, and E. Andrzejewska. 2010. Local serum levels of vascular endothelial 
growth factor in infantile hemangioma: intriguing mechanism of endothelial growth. Cytokine 49: 
141-7. 
• Reh, D.D., L.X. Yin, K. Laaeq, and C.A. Merlo. 2014. A new endoscopic staging system for hereditary 
hemorrhagic telangiectasia. Int Forum Allergy Rhinol 4: 635-9. 
• Sikka, R., B. Magauran, A. Ulrich, and M. Shannon. 2005. Bench to bedside: Pharmacogenomics, 
adverse drug interactions, and the cytochrome P450 system. Acad Emerg Med 12: 1227-35. 
• Sorrell, J., and S.L. Chamlin. 2013. Topical timolol 0.5% gel-forming solution for small deep facial 
infantile hemangiomas. Pediatr Dermatol 30: 592-4. 
• Storch, C.H., and P.H. Hoeger. 2010. Propranolol for infantile haemangiomas: insights into the 
molecular mechanisms of action. Br J Dermatol 163: 269-74. 
• Volotinen, M., J. Hakkola, O. Pelkonen, H. Vapaatalo, and J. Maenpaa. 2011. Metabolism of 
ophthalmic timolol: new aspects of an old drug. Basic Clin Pharmacol Toxicol 108: 297-303. 
• Ware, J.E., and C.D. Sherbourne. 1992. The MOS 36 Item Short-Form Health Survey (SF-36): I. 
Conceptual framework and item selection. Med. Care 30: 473-83. 
• Whitehead, K.J., N.B. Sautter, J.P. McWilliams, M.M. Chakinala, C.A. Merlo, M.H. Johnson, M. 
James, E.M. Everett, M.S. Clancy, M.E. Faughnan, S.P. Oh, S.E. Olitsky, R.E. Pyeritz, and J.R. 
Gossage. 2016. Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With 
Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial. JAMA 316: 943-51. 
• Yaniv, E., M. Preis, T. Hadar, J. Shvero, and M. Haddad. 2009. Antiestrogen therapy for hereditary 
hemorrhagic telangiectasia: a double-blind placebo-controlled clinical trial. Laryngoscope 119: 284-
8. 
• Yaniv, E., M. Preis, J. Shevro, B. Nageris, and T. Hadar. 2011. Anti-estrogen therapy for hereditary 
hemorrhagic telangiectasia - a long-term clinical trial. Rhinology 49: 214-6. 
• Yin, L.X., D.D. Reh, J.B. Hoag, S.E. Mitchell, S.C. Mathai, G.M. Robinson, and C.A. Merlo. 2016. 
The minimal important difference of the epistaxis severity score in hereditary hemorrhagic 
telangiectasia. Laryngoscope 126: 1029-32. 
• Zaffar, N., T. Ravichakaravarthy, M.E. Faughnan, and N. Shehata. 2015. The use of anti-fibrinolytic 
agents in patients with HHT: a retrospective survey. Ann Hematol 94: 145-52. 
• Zheng, J.W., L. Zhang, Q. Zhou, H.M. Mai, Y.A. Wang, X.D. Fan, Z.P. Qin, X.K. Wang, and Y.F. 
Zhao. 2013. A practical guide to treatment of infantile hemangiomas of the head and neck. Int J Clin 
Exp Med 6: 851-60. 
 


 
 
 
 


 
 
XIV. APPENDICES 
 
Appendix 1 
Epistaxis Severity Score Questionnaire: 
 
 
 
 
Scoring Guide: 
 
 


 
 
 
 


 
 
Appendix 2. 
 
Scoring of the HHT Endoscopic Scoring System (HES). 
 
 
 
 


 
 
 
Appendix 3. Epistaxis-Specific Quality-of-Life Questionnaire (EQQoL) 
 
 
 
 
 


 
 
 
 
 
Appendix 4. 
SF-36: Accessible at https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/survey-
instrument.html 
 
 
Patient ID_______________________ Date__________ 
 
HEALTH 
 
 
 
RAND > RAND Health > Surveys > RAND Medical Outcomes Study > 36-Item Short Form Survey (SF-36) > 
 
 
36- Item Short Form Survey Instrument 
(SF-36) 
RAND 36-Item Health Survey 1.0 Questionnaire Items 
Choose one option for each questionnaire item. 
 
1. In general, would you say your health is: 
  1 - Excellent 
 2 - Very good 
  3 - Good 
  4 - Fair 
  5 - Poor 
 
 
2. Compared to one year ago, how would you rate your health in general now? 
  1 - Much better now than one year ago 
  2 - Somewhat better now than one year ago 
  3 - About the same 
  4 - Somewhat worse now than one year ago 
5 - Much worse now than one year ago 


 
 
 


 
 
The following items are about activities you might do during a typical day. Does 
your health now limit you in these activities? If so, how much? 
 
Yes, 
limited a 
lot 
Yes, 
limited a 
little 
No, not 
limited at 
all 
3. Vigorous activities, such as running, lifting heavy objects, 
participating in strenuous sports 
  1 
  2 
  3 
4. Moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf 
  1 
  2 
  3 
5. Lifting or carrying groceries 
  1 
  2 
  3 
6. Climbing several flights of stairs 
  1 
  2 
  3 
7. Climbing one flight of stairs 
  1 
  2 
  3 
8. Bending, kneeling, or stooping 
  1 
  2 
  3 
9. Walking more than a mile 
  1 
  2 
  3 
10. Walking several blocks 
  1 
  2 
  3 
11. Walking one block 
  1 
  2 
  3 
12. Bathing or dressing yourself 
1 
2 
3 
 
 


 
 
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of your physical health? 
 
 
13. Cut down the amount of time you spent on work or other activities 
 
14. Accomplished less than you would like 
 
15. Were limited in the kind of work or other activities 
 
16. Had difficulty performing the work or other activities (for example, it took extra 
Yes 
No 
 
 
 
1 
2 
 
 
 
1 
2 
 
 
 
1 
2 
effort) 
1 
2 
 
 
 
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? 
Yes 
No 
17. Cut down the amount of  time you spent on work or other activities 
  1 
  2 
 
18. Accomplished less than you would like 
  1 
  2 
 
19. Didn't do work or other activities as carefully as usual 
  1 
  2 
 
 
 
20. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with family, 
friends, neighbors, or groups? 
  1 - Not at all 
  2 - Slightly 
  3 - Moderately 
  4 - Quite a bit 
5 - Extremely 


 
 
 


 
 
21. How much bodily pain have you had during the past 4 weeks? 
  1 - None 
  2 - Very mild 
  3 - Mild 
  4 - Moderate 
  5 - Severe 
  6 - Very severe 
 
 
22. During the past 4 weeks, how much did pain interfere with your 
normal work (including both work outside the home and housework)? 
  1 - Not at all 
  2 - A little bit 
 3 - Moderately 
  4 - Quite a bit 
5 - Extremely 
 


 
 
These questions are about how you feel and how things have been with you 
during the past 4 weeks. For each question, please give the one answer that 
comes closest to the way you have been feeling. 
How much of the time during the past 4 weeks... 
 
All of 
Most 
A good 
Some 
A little 
None 
the 
of the 
bit of the 
of the 
of the 
of the 
time 
time 
time 
time 
time 
time 
23. Did you feel full of pep? 
  1 
  2 
  3 
  4 
  5 
  6 
24. Have you been a very nervous 
person? 
  1 
  2 
  3 
  4 
  5 
  6 
25. Have you felt so down in the 
dumps that nothing could cheer you 
up? 
  1 
  2 
  3 
  4 
  5 
  6 
26. Have you felt calm and peaceful? 
  1 
  2 
  3 
  4 
  5 
  6 
27. Did you have a lot of energy? 
  1 
  2 
  3 
  4 
  5 
  6 
28. Have you felt downhearted and 
blue? 
  1 
  2 
  3 
  4 
  5 
  6 
29. Did you feel worn out? 
  1 
  2 
  3 
  4 
  5 
  6 
30. Have you been a happy person? 
  1 
  2 
  3 
  4 
  5 
  6 
31. Did you feel tired? 
1 
2 
3 
4 
5 
6 
 
 
 
32. During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)? 
  1 - All of the time 
  2 - Most of the time 
  3 - Some of the time 
  4 - A little of the time 


 
 
5 - None of the time 
 


 
 
How TRUE or FALSE is each of the following statements for you. 
 
Definitely 
true 
Mostly 
true 
Don't 
know 
Mostly 
false 
Definitely 
false 
33. I seem to get sick a little easier than 
other people 
  1 
  2 
  3 
  4 
  5 
34. I am as healthy as anybody I know 
  1 
  2 
  3 
  4 
  5 
35. I expect my health to get worse 
  1 
  2 
  3 
  4 
  5 
36. My health is excellent 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
ABOUT 
The RAND Corporation is a research organization that develops solutions to public policy challenges to help make 
communities throughout the world safer and more secure, healthier and more prosperous. RAND is nonprofit, 
nonpartisan, and committed to the public interest. 
1776 Main Street 
  
Santa Monica, California 90401-3208
 
 
RAND® is a registered trademark. Copyright © 1994-2016 RAND Corporation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Appendix 5. 
Treatment Satisfaction Questionnaire for Medication Version II  
(TSQMII) 
 
Patient ID_________ Date________ 
1)  How satisfied or dissatisfied are you with the ability of the medication to prevent or treat your 
condition? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 
 
2) How satisfied or dissatisfied are you with the way the medication relieves your symptoms? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 
 
3) As a result of taking this medication, do you experience any side effects at all? 
1 Yes 
0 No 
 
4) How dissatisfied are you by side effects that interfere with your physical health and ability to 
function (e.g., strength, energy levels)? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Somewhat Dissatisfied 
4 Slightly Dissatisfied 
5 Not at all Dissatisfied 
 
5) How dissatisfied are you by side effects that interfere with your mental function (e.g., ability to 
think clearly, stay awake)? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Somewhat Dissatisfied 
4 Slightly Dissatisfied 
5 Not at all Dissatisfied 
 
6) How dissatisfied are you by side effects that interfere with your mood or emotions (e.g., 
anxiety/fear, sadness, irritation/anger)? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Somewhat Dissatisfied 


 
 
4 Slightly Dissatisfied 
5 Not at all Dissatisfied 
 
7) How satisfied or dissatisfied are you with how easy the medication is to use? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 
 
8) How satisfied or dissatisfied are you with how easy it is to plan when you will use the 
medication each time? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 
 
9) How satisfied or dissatisfied are you by how often you are expected to use/take the medication? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 
 
10) How satisfied are you that the good things about this medication outweigh the bad things? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
S24 Atkinson et al. 
6 Very Satisfied 
7 Extremely Satisfied 
 
11) Taking all things into account, how satisfied or dissatisfied are you with this medication? 
1 Extremely Dissatisfied 
2 Very Dissatisfied 
3 Dissatisfied 
4 Somewhat Satisfied 
5 Satisfied 
6 Very Satisfied 
7 Extremely Satisfied 


 
 
Appendix 6. 
Adverse Reactions. 
 
 
ADVERSE REACTIONS 
From NDA 18086/S-076 
Reference ID: 3969708 
Pages 9, 10 
Obtained from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018086s076lbl.pdf 
Accessed: July 23, 2019 
 
 
TIMOPTIC® 0.25% and 0.5% (TIMOLOL MALEATE OPHTHALMIC SOLUTION)  
 
The most frequently reported adverse experiences of timolol ophthalmic solution 
(approximately one in eight patients) have been burning and stinging of the eye upon 
instillation.  
 
The following additional adverse experiences have been reported less frequently with 
ocular administration of this or other timolol maleate formulations:  
 
A. 
BODY AS A WHOLE. Headache, asthenia/fatigue, and chest pain. 
B. 
CARDIOVASCULAR. Bradycardia, arrhythmia, hypotension, hypertension, 
syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, 
worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, 
edema, claudication, Raynaud's phenomenon, and cold hands and feet.  
C. 
DIGESTIVE. Nausea, diarrhea, dyspepsia, anorexia, and dry mouth. 
D. 
IMMUNOLOGIC. Systemic lupus erythematosus.  
E. 
NERVOUS SYSTEM/PSYCHIATRIC. Dizziness, increase in signs and 
symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, 
behavioral changes and psychic disturbances including depression, confusion, 
hallucinations, anxiety, disorientation, nervousness, and memory loss.  
F. 
SKIN. Alopecia and psoriasiform rash or exacerbation of psoriasis. 
G. 
HYPERSENSITIVITY. Signs and symptoms of systemic allergic reactions, 
including anaphylaxis, angioedema, urticaria, and localized and generalized rash. 
H. 
RESPIRATORY. Bronchospasm (predominantly in patients with preexisting 
bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and 
upper respiratory infections.  
I. 
ENDOCRINE. Masked symptoms of hypoglycemia in diabetic patients.  
J. 
SPECIAL SENSES. Signs and symptoms of ocular irritation including 
conjunctivitis, blepharitis, keratitis, ocular pain, discharge (e.g., crusting), foreign 
body sensation, itching and tearing, and dry eyes; ptosis; decreased corneal 
sensitivity; cystoid macular edema; visual disturbances including refractive 
changes and diplopia; pseudopemphigoid; choroidal detachment following 
filtration surgery; and tinnitus. 
K. 
UROGENITAL. Retroperitoneal fibrosis, decreased libido, impotence, and 
Peyronie's disease.