Clinical trial NCT01752049
Conditions: Hereditary Hemorrhagic Telangiectasia
Keywords: Hereditary Hemorrhagic Telangiectasia Anti-angiogenic Therapy vascular malformations HHT
Sponsor: Unity Health Toronto
Start date: 2013-05-01; Completion date: 2019-08-30
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hereditary hemorrhagic telangiectasia (HHT) is a hereditary vascular condition characterized by the development of abnormal connections between arteries and veins throughout the body, called vascular malformations. These abnormal blood vessels are referred to as arteriovenous malformations (AVM) if they are large and telangiectasias if they are small. Telangiectasias develop due to irregular growth of blood vessels.

Anti-angiogenic therapy, such as the drug Apo-Timop, curbs the growth of new blood vessels. Apo-Timop is included in a class of medications called beta-blockers. Anti-angiogenic therapies exert their beneficial effects in a number of ways: by disabling the agents that activate and promote cell growth, or by directly blocking the growing blood vessel cells.

The investigators think that anti-angiogenic therapy may lead to the shrinking of telangiectasia in people with HHT. The investigators hope that this study will provide us with proof of this concept and might lead to the development and study of anti-angiogenic therapies to help improve the lives of individuals with vascular malformations.

Detailed description:
This is a small study of 5 patients from St. Michael's Hospital who have HHT and at least 5 typical telangiectasias.

Patients who anticipate a major surgery during this study or are pregnant, breast feeding or on other beta blocker medication may not enroll in this study.

This study lasts 12 weeks (84 days). During this time, subjects will apply a drop of either Apo-timop 0.5% or a placebo solution to 4 telangiectasias twice daily.

The active study medication is called Apo-Timop and is a clear liquid solution stored in a bottle. An eye dropper is used for application.

* Apo-timop will be applied to 3 telangiectasias and
* a placebo will be applied to one telangiectasia A placebo is an inactive substance, with no active medication in it, and it looks the same as the real medication. There is no potential harm of receiving the placebo. It is necessary to use a placebo to make sure that the effect of Apo-timop can be determined without any bias.

Subjects will receive four numbered bottles for every 28 day period as well as a photo which indicates which bottle is to be applied to which telangiectasia.

Neither the subject nor the research staff will know which telangiectasia will receive the placebo.

Apo-timop, is not part of the standard therapeutic regimen for HHT. It is a Health Canada approved medication which is applied as an eye drop, that has been shown to reduce pressure in the eye and is commonly used for glaucoma.

Arms: arm 1: Drug: • Topical timolol maleate 0.5% drops

* Topical timolol maleate 0.5% drops
* Applied twice daily for 12 weeks (84 days) or until disappearance of lesions
* Study drops will be applied to 3 cutaneous telangiectasias per patient telangiectasia per patient). arm 2: placebo saline drops

-Applied twice daily for 12 weeks (84 days) or until disappearance of lesions to one cutaneous telangiectasias per patient.
Interventions: intervention 1: Topical timolol maleate intervention 2: placebo saline drops
Intervention descriptions: intervention 1: * Topical timolol maleate 0.5% drops
* Applied twice daily for 12 weeks (84 days) or until disappearance of lesions
* Study drops will be applied to 3 cutaneous telangiectasias per patient intervention 2: Applied twice daily for 12 weeks (84 days) or until disappearance of lesions to 1 cutaneous telangiectasias per patient.

Protocol documents:
Prot_SAP_000.pdf: 
Rare Diseases Clinical Research Network 
Brain Vascular Malformation Consortium 
 
Study Title: Topical Anti-angiogenic Therapy for 
Telangiectasia in HHT: Proof of Concept  
 
Short Name: BVMC 6207 
 
 
NCT# 01752049 
 
 
Study Chair 
Marie E. Faughnan MD MSc FRCPC 
Director of the Toronto HHT Center 
St. Michael’s Hospital,  
Professor, University of Toronto 
Toronto, Ontario Canada 
 


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Rare Diseases Clinical Research Network 
 
Topical Anti-angiogenic Therapy for 
Telangiectasia in HHT: Proof of Concept  
 
Brain Vascular Malformation Consortium 
 
 
This protocol is for research purposes only, and should not be copied, 
redistributed or used for any other purpose.  The procedures in this protocol 
are intended only for use by Consortium investigators in carefully controlled 
settings.  The Chair of this study should be consulted before using or 
attempting any procedure in this protocol. 
 
 
Study Chair 
Marie E. Faughnan MD MSc FRCPC 
Division of Respirology 
Director of the Toronto HHT Center 
St. Michael’s Hospital, University of Toronto 
Tel: 416-864-5412 (Mon-Fri 9am to 5pm) 
 
 
Sub-Investigators: 
 
Michelle Letarte,(basic scientist) PhD, Hospital for Sick Children, 
Toronto Canada 
 
Anne Curtis, MD, (dermatologist)University of Toronto Canada 
 
Peter Kertes, MD, (ophthalmologist) Sunnybrook Hospital, Toronto 
Canada 
 
Victor X.D Yang, MD PhD, (biomedical engineer with neurosurgical 
training) St. Michael’s Hospital/Ryerson University: Toronto Canada 
 
Henry Jakubovic, MD (dermato-pathologist) St. Michael’s Hospital, 
Toronto Canada 


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Table of Contents 
 
1.0 Protocol Synopsis .................................................................................................................. 3 
1.1 Overview ............................................................................................................................. 4 
2.0 Specific Aims (Hypothesis and Objectives) ....................................................................... 5 
3.0 Background ............................................................................................................................ 6 
4.0 Study Design and Methods .................................................................................................. 7 
4.1 Inclusion Criteria ................................................................................................................ 8 
4.2 Exclusion Criteria ............................................................................................................... 8 
4.3 Recruitment of Participants .............................................................................................. 8 
4.4 Retention Strategies .......................................................................................................... 8 
4.5 Data Elements .................................................................................................................... 9 
4.6 Schedule of Events ......................................................................................................... 10 
5.0 Data and Safety Monitoring Plan ...................................................................................... 11 
5.1 Study Oversight ............................................................................................................... 11 
5.2 Definitions and Standards .............................................................................................. 12 
5.3 Expected/Known Risks/Discomforts/Adverse Events Associated with Study 
Intervention and Procedures: Definition of Expected Adverse Events .......................... 12 
5.4 Reporting Timeline .......................................................................................................... 15 
5.5 RDCRN Adverse Event Data Management System (AEDAMS) ............................. 16 
5.6 Study Discontinuation ..................................................................................................... 16 
5.7 Subject Discontinuation .................................................................................................. 16 
5.8 Data Quality and Monitoring Measures ........................................................................ 17 
5.9 Quality Control: Study Related Procedures ................................................................ 17 
6.0 Statistical Considerations ................................................................................................... 17 
7.0 Data Management ............................................................................................................... 18 
7.1 Registration....................................................................................................................... 18 
7.2 Data Entry ......................................................................................................................... 19 
8.0 Human Subjects .................................................................................................................. 19 
8.1. GCP Statement ............................................................................................................... 19 
8.2. Risks ................................................................................................................................. 19 
8.3 Benefits ............................................................................................................................. 23 
8.4 Recruitment ...................................................................................................................... 23 
8.5 Written Informed Consent .............................................................................................. 24 
8.6 Process of Consent ......................................................................................................... 24 
9.0 References ........................................................................................................................... 25 
 
 
 
 


RDCRN Protocol # 6207      
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1.0 Protocol Synopsis 
Protocol Number: 
6207 
Protocol Title: 
Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of 
Concept  
Study Chair: 
Dr. Marie Faughnan 
Statistician: 
Dr. Charles McCulloch 
Consortium: 
Brain Vascular Malformation Consortium (BVMC) 
Participating Sites: 
St. Michael’s Hospital (Toronto, Canada) 
Sample Size: 
10 
Target Enrollment Period: 
November 2012 to November 2015 
Study Design: 
Interventional, Double blind placebo-controlled trial 
Primary Study Objective: 
Our objective is to prove the concept that a topical anti-angiogenic 
therapy will lead to regression of vascular malformations in patients 
with Hereditary Hemorrhagic Telangiectasia (HHT). 
Study Population and Main 
Eligibility/ Exclusion Criteria: 
Study Population: 
10 adult patients from St. Michael’s Hospital who have Hereditary 
Hemorrhagic Telangiectasia (HHT) and have at least 5 typical 
telangiectasias on their hands or face 
 
Inclusion criteria: 
1. Definite clinical or genetic diagnosis of HHT 
2. Known ENG or ALK1 mutation (personal or familial) 
3. Age ≥ 18 years 
4. At least 5 typical (round/ovoid, not spider or linear) 
cutaneous telangiectasia (size range 2-5mm) on  hands (not 
including lesions on over inter-phalangeal joints) or face 
Exclusion criteria: 
1. Contraindication to systemic beta-blocker (severe asthma, 
severe COPD, sinus bradycardia, 2nd or 3rd degree AV 
block, overt heart failure, hypotension, allergy/intolerance/ 
hypersensitivity to timolol) 
2. Current treatment with systemic beta-blocker 
3. Current participation in other therapeutic trial for HHT 
4. Current pregnancy or breastfeeding. 
Treatment 
Agent: 
Timolol Maleate Ophthalmic Solution USP 0.5% 
Dosage, schedule, route of 
administration: 
Topical timolol maleate 0.5% drops vs. placebo saline drops 
One drop applied twice daily for 12 weeks (84 days) or until 
disappearance of lesions. 
Study drops will be applied to 4 cutaneous telangiectasias per 
patient (timolol drops for 3 telangiectasia per patient and placebo 
drops to 1 telangiectasia per patient) using an eye dropper.   
Safety Issues: 
In clinical trials, Timolol maleate ophthalmic solution was generally 
well tolerated and produced fewer and less severe side effects than 
either pilocarpine or epinephrine. Bradycardia was reported with 
timolol maleate ophthalmic solution. At trough (12 hours post-dose), 
the mean reduction was 3.6 beats/minute. At two hours post-dose, 
the mean reduction in heart rate was 5 beats/minute. Timolol 
maleate ophthalmic solution has also been used in patients with 
glaucoma wearing conventional hard contact lenses, and has 
generally been well tolerated. 


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Primary Outcome Measures: 
Mean reduction in lesion area (compared with baseline 
measurement) of treated telangiectasia 
Secondary Outcome 
Measures: 
1. From Tissue: Descriptive changes in histopathology in 
baseline vs. treated lesions, vessel density and distribution 
of capillaries, arterioles and venules.  
2. From speckle variance OCT: Changes in lesion area, blood 
flow velocity and volume flow rates (treated vs. baseline/ 
placebo). 
3. Serum angiogenic markers (Aushon Blood-based 
Biomarkers in Clinical Research kit, analyzing 5- angiogenic 
biomarkers): Endoglin, BMP-9, VEGF+, TGF-beta1, TSP-1 
at baseline and 84 days.   
4. Stability of area of untreated telangiectasias over the 84 day 
period (placebo group) 
Statistical Considerations 
(sample size and analysis 
plan): 
This is a small proof of concept pilot study of 10 patients from St. 
Michael’s Hospital who have Hereditary Hemorrhagic Telangiectasia 
(HHT) and have at least 5 typical telangiectasias on their hands or 
face, during a 3 month period.  
 
Standard descriptive statistics will be used for reporting primary and 
secondary outcomes.   
 
Reduction in telangiectasia area:  Will analyze log area using a 
mixed linear regression model with predictors of time, treated/not 
and the interaction of time and treated/not (which compares the 
percent reduction in lesion area between treated and untreated 
lesions). The mixed model would include random effects for 
participant, lesion within participant and the change over time.  
Same analyses would be used for OCT variables.  
Sponsors (federal, state, 
foundation and industry 
support): 
National Institute of Health 
 
 
1.1 Overview 
Hereditary hemorrhagic telangiectasia (HHT) is a hereditary vascular condition 
characterized by the development of abnormal connections between arteries and veins 
throughout the body, called vascular malformations. These abnormal blood vessels are 
referred to as arteriovenous malformations (AVM) if they are large and telangiectasias if 
they are small.   
 
Telangiectasias develop due to irregular growth of blood vessels. Anti-angiogenic 
therapy, such as the study medication Apo-timop, curbs the growth of new blood 
vessels. Apo-timop is included in a class of medications called beta-blockers. Anti-
angiogenic therapies exert their beneficial effects in a number of ways: by disabling the 
agents that activate and promote cell growth, or by directly blocking the growing blood 
vessel cells.10 adults with Hereditary Hemorrhagic Telangiectasia (HHT) and have at 
least 5 typical telangiectasias on their hands or face from the Toronto HHT Centre at St. 
Michael’s Hospital in Toronto, Canada will be eligible for this study. 


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The purpose of this study is to prove that using an anti-angiogenic therapy (a therapy 
that inhibits or prevents the growth of new blood vessels) will lead to a shrinkage of 
telangiectasis in HHT patients.  
 
The research team has extensive experience in HHT in general (Marie Faughnan, 
Michelle Letarte, clinical research (Marie Faughnan, William Young), cutaneous HHT 
(Anne Curtis) and anti-angiogenic therapy (Michelle Letarte, Peter Kertes). Anne Curtis 
is a dermatologist with extensive expertise in HHT; she will collect tissue (perform the 
telangiectasia biopsies).  Henry Jakubovic is a dermato-pathologist who will oversee 
tissue preparation and perform histopathology review. Victor X. D Yang is a biomedical 
engineering scientist with combined biophotonics research and neurosurgical training.  
He has a clinical interest in cerebral vascular diseases and experience using optical 
coherence tomography (OCT) in HHT cutaneous lesions [1], the only published 
experience of this type. Michelle Letarte is a leading basic scientist in mechanisms of 
disease in HHT. 
 
We hope that this study will provide proof of this concept and might lead to the 
development and study of anti-angiogenic therapies to improve the lives of individuals 
with vascular malformations. 
 
Topical timolol maleate 0.5% drops or placebo saline drops will be applied to 4 
telangiectasias on the subjects’ hand, twice daily for 12 weeks (84 days) or until 
disappearance of lesions (timolol drops for 3 telangiectasia per patient and placebo 
drops to 1 telangiectasia per patient).    
 
2.0 Specific Aims (Hypothesis and Objectives) 
Rationale:  
The goal of the study is to demonstrate that an antiangiogenic agent can lead to 
regression of a vascular malformation in humans with HHT.  To date the evidence for 
anti-angiogenic effectiveness in HHT remains largely in animal arteriovenous 
malformation (AVM) models.  In humans, there are case reports and small case series 
showing improvement in complex clinical outcomes (severe chronic bleeding, heart 
failure) using systemic (intravenous) antiangiogenic therapy, without demonstrating 
regression of AVMs per se.  Though this is promising and these are important clinical 
outcomes, the mechanism for the clinical improvement remains unknown and it remains 
uncertain whether antiangiogenic therapy can lead to AVM regression in human HHT. 
 
The current study aims to address these unanswered questions by studying, in humans, 
lesions that are accessible to direct (topical) therapy, given their superficial skin 
location, and that are likely to be most responsive to therapy.  We believe that skin 
telangiectasia are more likely to be responsive to therapy given that they are smaller, 
likely “earlier” vascular malformations, and more dynamic in patients.  People with HHT 
develop new telangiectasia as they advance through life.  The development of new 
(large) organ AVMs however, are rarely seen in adults with HHT.  As such we have 


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chosen to treat skin telangiectasia in this study.  Using a topical therapy also allows us 
to treat only the lesions and local surrounding tissues, therefore minimizing exposure to 
the drug, as compared to treating with a systemic agent. 
 
The outcomes of this study should have two major implications.  First, if the pilot study 
outcome is positive, then we propose to study timolol (and potentially other beta-
blockers) as a systemic agent in a clinical trial to regress brain AVMs in HHT.  Second, 
we can use this topical study design to test other agents of interest (bevacizumab, 
pazopanib, thalidomide derivatives, antioxidants, etc.) for regression of vascular 
malformations in HHT.  If the study process and outcome measures are feasible, then 
this topical drug screening study design can be used for testing other agents, regardless 
of whether the pilot study outcome is positive.  In addition, we plan to use results from 
the study of other future screened agents to guide clinical trials of these agents in brain 
AVMs in HHT.   
 
Hypothesis:  Topical anti-angiogenic therapy will lead to regression of cutaneous 
telangiectasia in patients with Hereditary Hemorrhagic Telangiectasia (HHT). 
 
Specific Hypothesis: Topical timolol (beta-blocker) therapy will lead to regression of skin 
telangiectasia in patients with HHT. 
 
3.0 Background 
Telangiectasias develop due to dysregulated angiogenesis in patients with HHT.  There 
is evidence in some HHT mouse models that anti-angiogenic therapy can lead to 
regression of experimental vascular malformations (VMs).  In addition, there are case 
reports of chronic bleeding and VM-related shunting regressing in HHT patients treated 
with anti-angiogenic therapy for other indications.  We expect that anti-angiogenic 
therapy will lead to regression of VMs in HHT patients, with the smallest VMs 
(telangiectasia) likely to be most responsive to therapy.  We propose to prove this 
concept in easily accessible cutaneous telangiectasia by treating with a topical beta-
blocker, with known anti-angiogenic properties.  If the concept is proven, this may lead 
to new therapies for VMs in HHT and improvement in quality of life, morbidity (chronic 
bleeding, heart failure and stroke) and mortality. 
 
HHT is due to mutations in endoglin (ENG; HHT1) or activin receptor-like kinase 1(ALK1 
or ACVRL1; HHT2). These two genes code for receptors for BMP9 and TGF-beta, 
which are known to play a role in the regulation of angiogenesis. The underlying 
mechanism of HHT is haploinsufficiency, implying that it is the 50% reduction in the 
functional amount of these proteins that is responsible for disease initiation.  This 
reduction in functional endoglin or ALK-1 predisposes vessels to stress such as 
increased blood flow, inflammation or injury, leading to vascular remodeling and VMs. 
While ALK-1 conditional knockout mice (cKO; where ALK1 is deleted in endothelial 
cells) develop VMs in multiple visceral organs, secondary insults like wounding are 
necessary to induce sub-dermal vessels to form de novo VMs. It was subsequently 
shown that either induction of inflammation or angiogenesis, using LPS or VEGF 


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respectively, could recapitulate the wound response and generate VMs. Treatment with 
neutralizing antibodies to VEGF led to significant blunting of both inflammation and 
angiogenesis and prevented wound-induced VMs[2].    
 
Though interest is growing in the concept of anti-angiogenic therapy for HHT, there are 
no published controlled clinical trials of antiangiogenic therapies in HHT patients to date.  
There are however isolated case reports [3-5]  and small series of reduced bleeding and 
shunting [6, 7] in HHT patients treated with either bevacizumab or thalidomide, both 
antiangiogenic therapies.  In addition, there is an isolated case report of treatment with 
intranasal topical bevacizumab demonstrating regression of nasal telangiectasia[8, 9]  
and very recently an isolated case of nasal mucosal topical treatment with timolol with 
reported reduction in epistaxis in an HHT patient[10]. 
 
Recent clinical and cellular reports suggest that beta-blockers should also be 
considered as potential therapeutic agents given their anti-angiogenic properties.  There 
are no published cases or studies to date of the use of beta-blockers therapy for HHT 
lesions, though there is growing case report[11] and small case series evidence[12-14] 
of effectiveness of topical beta-blocker in cases with other cutaneous VMs, such as 
infantile hemangiomas, in which these lesions regressed within weeks. Propanolol, a 
non-selective beta-adrenergic blocking drug, was recently shown to control the growth 
of hemangiomas.  A recent study reported that propranolol inhibited the growth of 
endothelial cells in culture through G0/G1 cell cycle arrest; it also blocked the migration 
and differentiation of endothelial cells into capillary-like structures. Propanolol inhibited 
VEGF receptors downstream signaling, including MMP2 metallo-protease activation, 
which participates in vascular remodeling [15]. These data suggest that propranolol not 
only blocks adrenergic receptors but can interfere with VEGF receptor mediated 
pathways, therefore interfering with angiogenesis. A recent study indicated that 
propranolol was protective against retinal angiogenesis in an oxygen-induced mouse 
retinopathy model [16].  
 
Our goal is to prove the concept that anti-angiogenic therapy in HHT can cause 
regression of VMs.  Topical beta-blocker is a particularly interesting agent for this proof 
of concept pilot study, for a number of reasons.  First, as noted above, there is some 
clinical evidence of effectiveness for regression of VMs in other disorders and there are 
plausible biological mechanisms.  Second, it appears to be a low risk therapy.  There is 
50% bioavailability with mucosal application but cutaneous cases treated to date have 
had no systemic side effects (systemic bioavailability unknown with cutaneous 
application, though likely very low), and in these reported cases treatment area was 
much larger than we propose here.   Third, the treatment is feasible in that it is 
available, inexpensive, easily applied topically, rapidly effective (days to weeks) allowing 
for a feasible study time line. 
 
4.0 Study Design and Methods 
Setting: Toronto HHT Centre, St Michael’s Hospital Toronto Canada.  
 


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Design: Double blind placebo-controlled, with randomization of lesions for treatment 
versus placebo.  
 
Randomization for assignment of telangiectasia: For each participant, the 5 
telangiectasia will be numbered (1-5) and then randomly assigned to: biopsy, 
timolol_biopsy, timolol, timolol, placebo.  The person measuring (mm measures and 
OCT) will remain blinded to the assignment.  
 
4.1 Inclusion Criteria 
1. Definite clinical or genetic diagnosis of HHT 
2. Known ENG or ALK1 mutation (personal or familial) 
3. Age>=18 years 
4. At least 5 typical (round/ovoid, not spider or linear) cutaneous telangiectasia (size 
range 2-5mm) on hands (not including lesions on over inter-phalangeal joints) or 
face. 
 
4.2 Exclusion Criteria 
1. Contraindication to systemic beta-blocker (severe asthma, severe COPD, sinus 
bradycardia, 2nd or 3rd degree AV block, overt heart failure, hypotension, 
allergy/intolerance/ hypersensitivity to timolol) 
2. Current treatment with systemic beta-blocker 
3. Current participation in other therapeutic trial for HHT 
4. Current pregnancy or breastfeeding. 
 
4.3 Recruitment of Participants 
Recruitment target: 10 patients.   
 
The Toronto HHT Clinic at St. Michael’s Hospital has approximately 300 patients who 
would meet inclusion criteria, of whom only approximately 10% would have exclusion 
criteria. Patients will be screened for eligibility from our St. Michael’s Hospital HHT 
Database. Participants in our HHT Database have agreed to be screened and 
contacted for the studies for which they are eligible.  
 
4.4 Retention Strategies 
Subjects are seen or called weekly for monitoring and will be reminded of their next 
visit. At the baseline visit all visit dates are arranged. 
 


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4.5 Data Elements 
Outcomes: 
Primary:  Mean reduction in lesion area (compared with baseline measurement) of 
treated telangiectasia. 
Secondary: 
1. From Tissue: Descriptive changes in histopathology in baseline vs treated 
lesions, vessel density and distribution of capillaries, arterioles and venules. 
2. From speckle variance OCT: Changes in lesion area, blood flow velocity and 
volume flow rates (treated vs baseline/ placebo). 
3. Serum angiogenic markers (Aushon Blood-based Biomarkers in Clinical 
Research kit, analyzing 5- angiogenic biomarkers): Endoglin, BMP-9, VEGF+, 
TGF-beta1, TSP-1 at baseline and 84 days.   
4. Stability of area of untreated telangiectasias over the 84 day period (placebo 
group) 
Measurements:  
1. Data collection of eligibility information, demographics and concomitant 
medications 
 
2. Telangiectasia size: 
a. Baseline measurement:   with mm graded calipers, in largest diameter, of 
all 5 telangiectasia (targeted for treatment, placebo and tissue) 
b. Post-treatment/placebo (days #14, 28, 56, 84) measurement:  with mm 
graded calipers, in largest diameter, for  4 telangiectasia (3 treated/1 
placebo) 
3. Speckle Variance Optical Coherence Tomography (OCT) Vasculature 
Measurements: 
A Fourier domain mode locking (FDML) swept source optical coherence 
tomography (SS-OCT) system is used to obtain the OCT measurements. This 
system uses a 43–67 kHz FDML fiber-ring laser source incorporating a polygon-
based tunable filter with a sweeping range of 112 nm centered at 1310 nm, −6 
dB ranging depth of 6 mm in air (corresponding to a coherence length of 12 mm), 
axial resolution of ~ 8 um in tissue, and average output power of 48 mW. The 
total cavity length used in FDML the laser ranges from 3.3 to 4.5 km. A fiber 
Bragg grating provides the A-scan trigger.  Inter-frame speckle variance images 
of the structural OCT intensity are calculated across B-mode images. [17] 
a. Baseline measurements (Day #0) in all 5 telangiectasia: 3-dimensional 
structural (3mmx3mmx3mm), Doppler, and speckle variance OCT 


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(SVOCT) imaging[17].  Derived parameters include vascular volume, 
vessel diameter distribution, velocity and volume flow rate 
b. Post-treatment/placebo (days #14, 28, 56, 84) measurement for 4 
telangiectasia (3 treated/1 placebo): 3-dimensional structural, Doppler, 
and SVOCT imaging.  Derived parameters include vascular volume, 
vessel diameter distribution, velocity and volume flow rate. 
4. Tissue sampling: 
a. Baseline: Excisional 3mm punch biopsy of 1 cutaneous telangiectasia 
(day #0, untreated), after local injection with lidocaine-epineprhine. 
b. Post-treatment  (at 50% reduction of one lesion or day #84, whichever 
comes first): Excisional 3mm punch biopsy of 1 timolol-treated cutaneous 
telangiectasia (randomly selected amongst timolol treated),  after 
measurement, and after local injection with lidocaine-epineprhine 
c. Preparation: Tissue will be fixed in 10% buffered formalin and stained for 
H&E stain, PAS stain, smooth muscle cell actin and CD31.  Four sections 
(slides) per sample will be prepared, using standard techniques.   
d. Tissue analysis:  All measurements (vessel densities) will be reported as 
mean per section and reviewed by two independent pathologists.  
 
4.6 Schedule of Events 
 
Baseline 
Day 14 
Day 28 
Day 56 
Day 84 
Data collection (eligibility 
information, demographics) 
x 
 
 
 
 
Data collection (concomitant 
medications) 
x 
x 
x 
x 
x 
Measurements (calipers) 
x 
x 
x 
x 
x 
Photos of 5 telangiectasias 
x 
 
 
 
 
Photos of 4 treated telangiectasias 
 
 
 
 
x 
OCT 
x 
x 
x 
x 
x 
Urine Pregnancy Test 
x 
 
 
 
 
Serum angiogenic markers 
x 
 
 
 
x 
Resect (biopsy) telangiectasis that 
will not be treated 
+ 3 days* 
x 
 
 
 
 
Resect (biopsy) a randomly 
selected timolol treated 
telangiectasia 
 
 
 
 
+ 3 days* 
x 
(or at 
50% size 
reduction) 
Monitoring for adverse outcomes 
 
x** 
x 
x 
x 
*Flexibility needed for booking biopsies 
**In addition to weekly calls in between visits 
 


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5.0 Data and Safety Monitoring Plan 
The study protocol will be reviewed and approved by the National Institutes of Health 
(NIH) before submission to individual center IRB/REBs for approval.  Participant 
enrollment may only begin with IRB/REB approved consent forms.  
 
This is an interventional pilot study that meets the federal definition of low risk. 
 
Monitoring for local adverse outcomes (rash, pain, bleeding of telangiectasia) and 
systemic adverse outcomes (hypotension, bradycardia, drowsiness, bronchospasm) by 
clinical assessment will occur at days #14, 28, 56, 84 and also by telephone contact 
weekly.  Participants will also be able to reach a study coordinator or investigator if they 
have concerning symptoms at other times, by pager.  If there are uncomfortable or 
concerning side effects, the study investigator will stop the study treatment and manage 
as medically appropriate. 
 
Adverse events will be reported to Health Canada, St. Michael’s Research Ethics 
Board, and the RDCRN. (See section 5.4 for more information on reporting 
responsibilities.) 
 
The Study Chair will appoint an NINDS approved Independent Medical Monitor (IMM) to 
review all reported adverse events that are serious, unexpected, and 
possibly/probably/definitely related to the study intervention in real time. 
 
The IMM will also review cumulative adverse events. The frequency of review of 
cumulative AEs will be determined by the IMM in conjunction with the Study Chair and 
will occur at least once every 12 months. The IMM will then evaluate whether the 
protocol or informed consent document requires revision based on the reports. 
 
5.1 Study Oversight 
The Study Chair has primary oversight responsibility of this clinical trial. The Brain 
Vascular Malformation Consortium will review accrual, patterns and frequencies of all 
adverse events, and protocol compliance at least every 6 months.  
 
The site’s Principal Investigator and her research team (co-Investigators, research 
nurses, clinical trial coordinators, and data managers) are responsible for identifying 
adverse events. Aggregate report- detailed by severity, attribution (expected or 
unexpected), and relationship to the study drug/study procedures – will be available 
from the Rare Diseases Clinical Research Network (RDCRN) Data Management and 
Coordinating Center (DMCC) for site review.  Adverse events will be reviewed weekly 
by the research team.   A separate report detailing protocol compliance will also be 
available from the DMCC for site review on a monthly basis.  


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HHT Topical Pilot 
 
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NCT # 01752049 
 
Page 12 of 25 
5.2 Definitions and Standards 
The Rare Diseases Clinical Research Network defines an adverse event as:  “…an 
unfavorable and unintended sign, symptom or disease associated with a participant’s 
participation in a Rare Diseases Clinical Research Network study.” 
 
Serious adverse events include those events that:  “result in death; are life-threatening; 
require inpatient hospitalization or prolongation of existing hospitalization; create 
persistent or significant disability/incapacity, or a congenital anomaly/birth defects.”  
 
An unexpected adverse event is defined as any adverse experience…the specificity or 
severity of which is not consistent with the risks of information described in the protocol.  
 
Expected adverse events are those that are identified in the research protocol as having 
been previously associated with or having the potential to arise as a consequence of 
participation in the study 
 
All reported adverse events will be classified using the current version of the Common 
Terminology Criteria for Adverse Events (CTCAE) developed and maintained by CTEP 
at National Cancer Institute. 
 
5.3 Expected/Known Risks/Discomforts/Adverse Events Associated 
with Study Intervention and Procedures: Definition of Expected 
Adverse Events 
Timolol maleate ophthalmic solution (Apo-Timolol) is usually well tolerated when applied 
to the eye. As with many topically applied ophthalmic drugs, this drug is absorbed 
systemically when applied mucosally. Though systemic bioavailability is unknown with 
cutaneous application, it is likely very low.  In addition, there has been no clinic 
evidence to date of systemic absorption in reported cutaneous treatment cases to date, 
and treatment area was much larger in these cases than we propose here. As this is a 
small pilot study and we have very limited resources, we will not attempt these assays 
until the next larger study. 
 
The same adverse reactions found with systemic administration of beta-adrenergic 
blocking agents may occur with topical cutaneous administration. Possible risks and 
discomforts are detailed below; however, there may be other risks and side effects that 
are not yet known.    
 
As this is a pilot study we are not aware of any risks associated with Apo-timop applied 
topically to the skin. Our goal is to prove the concept that anti-angiogenic therapy in 
HHT can cause regression of VMs.  Topical beta-blocker is a particularly interesting 
agent for this proof of concept pilot study, for a number of reasons.  First, as noted 
above, there is some clinical evidence of effectiveness for regression of VMs in other 
disorders and there are plausible biological mechanisms.  Second, it appears to be a 
low risk therapy.   


RDCRN Protocol # 6207      
HHT Topical Pilot 
 
Version Date: 01May14 
 
NCT # 01752049 
 
Page 13 of 25 
 
There is 50% bioavailability with mucosal application but cutaneous cases treated to 
date have had no systemic side effects (systemic bioavailability unknown with 
cutaneous application, though likely very low), and in these reported cases treatment 
area was much larger than we propose here.  
 
The following sections are cited from the Product Monograph: 
 
“WARNINGS AND PRECAUTIONS  
General 
As with other topically applied ophthalmic drugs, this drug may be absorbed 
systemically. The same adverse reactions reported with systemic beta-adrenergic 
blocking agents may occur with topical administration. Timolol maleate ophthalmic 
solution should be used with caution in patients subject to spontaneous hypoglycemia 
or in diabetic patients (especially those with labile diabetes) who are receiving insulin or 
oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and 
symptoms of acute hypoglycemia.In patients with angle-closure glaucoma, the 
immediate objective of treatment is to reopen the angle. This requires constricting the 
pupil with a miotic. Timolol maleate has little or no effect on the pupil. When timolol 
maleate ophthalmic solution is used to reduce elevated intraocular pressure in angle-
closure glaucoma they should be used with a miotic and not alone. Cardiac failure 
should be adequately controlled before beginning therapy with timolol maleate 
ophthalmic solution. In patients with a history of severe cardiac disease, signs of cardiac 
failure should be watched for and pulse rates should be checked. Respiratory reactions 
and cardiac reactions, including death due to bronchospasm in patients with asthma 
and rarely death in association with cardiac failure, have been reported following 
administration of timolol maleate ophthalmic solutions. Because of the potential effects 
of beta-adrenergic blocking agents on blood pressure and pulse, these agents should 
be used with caution in patient with cerebrovascular insufficiency. If signs or symptoms 
suggesting reduced cerebral blood flow develop following initiation of therapy with 
timolol maleate ophthalmic solution, alternative therapy should be considered. 
Endocrine and Metabolism 
Thyrotoxicosis 
β-adrenergic blocking agents may mask certain clinical signs of hyperthyroidism (e.g., 
tachycardia). Patients suspected of developing thyrotoxicosis should be managed 
carefully to avoid abrupt withdrawal of β-adrenergic blocking agents which might 
precipitate a thyroid storm. 
Immune 
Risk from Anaphylactic Reaction 
While taking beta blockers, patients with a history of atopy or a history of severe 
anaphylactic reaction to a variety of allergens may be more reactive to repeated 
challenge with such allergens,either accidental, diagnostic, or therapeutic. These 
patients may be more resistant to treatment of anaphylactic reactions with the usual 
doses of epinephrine since timolol may blunt the beta agonist effect of epinephrine. In 
such cases, alternatives to epinephrine should be considered. 
Ophthalmologic 


RDCRN Protocol # 6207      
HHT Topical Pilot 
 
Version Date: 01May14 
 
NCT # 01752049 
 
Page 14 of 25 
Choroidal Detachment 
Choroidal detachment has been reported with administration of aqueous suppressant 
therapy (e.g., timolol, acetazolamide or combination) after filtration procedures. 
Management of eyes with chronic or recurrent choroidal detachment should include 
stopping all forms of aqueous suppressant therapy and treating endogenous 
inflammation vigorously. As with the use of other antiglaucoma drugs, diminished 
responsiveness to timolol maleate ophthalmic solution after prolonged therapy has been 
reported in some patients. However, in clinical studies in which 164 patients have been 
followed for at least 3 years, no significant difference in mean intra ocular pressure has 
been observed after initial stabilization. 
Contact Lenses 
The preservative in APO- TIMOP ophthalmic solution is benzalkonium chloride. This 
preservative is a quaternary ammonium compound that may be absorbed by soft 
contact lenses. Therefore, APO-TIMOP ophthalmic solution should not be administered 
while wearing soft contact lenses. The contact lenses should be removed before 
application of the drops and not be reinserted earlier than 15 minutes after use. 
Neurologic 
Muscle Weakness 
β-adrenergic blockade has been reported to increase muscle weakness consistent with 
certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). 
Timolol has been reported rarely to increase muscle weakness in some patients with 
myasthenic symptoms. 
Peri-Operative Considerations 
Major Surgery 
The necessity or desirability of withdrawal of β-adrenergic blocking agents prior to major 
surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the 
heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the 
risk of general anesthesia in surgical procedures. Some patients receiving beta-
adrenergic blocking agents have experienced protracted severe hypotension during 
anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. 
For these reasons, in patients undergoing elective surgery, some authorities 
recommend gradual withdrawal of beta-adrenergic blocking agents. If necessary during 
surgery, the effects of β-adrenergic blocking agents may be reversed by sufficient doses 
of such agonists as isoproterenol, dopamine, dobutamine or levarterenol. 
Special Populations 
Pregnant Women: 
Timolol maleate ophthalmic solution has not been studied in human pregnancy. The use 
of timolol maleate ophthalmic solution requires that the anticipated benefit be weighed 
against possible hazards. 
Nursing Women: 
Timolol is detectable in human milk. Because of the potential for serious adverse 
reactions from timolol in nursing infants, a decision should be made whether to 
discontinue nursing or to discontinue the drug, taking into account the importance of the 
drug to the mother. 
Pediatrics: 
Safety and effectiveness in children have not been established.” 


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Version Date: 01May14 
 
NCT # 01752049 
 
Page 15 of 25 
 
 
Risks Related to Study Tests 
Blood Sample Collection:  When blood samples are taken from a vein, subjects may 
have discomfort or pain where the blood was taken.  Sometimes a person may become 
dizzy or faint when blood is taken.  There is also a risk of infection (rare), bleeding, 
redness or bruising at the skin puncture.  Bleeding and bruising can usually be reduced 
by putting pressure on the place where the blood was taken.  The chance of infection is 
lowered by using standard skin cleaning and sterile needles. 
 
Optical Coherence Tomography (OCT): This test will take approximately 30 minutes 
at each visit. The light used is near infrared at safe power level (significantly below the 
American National Standards Institute exposure level).  It will not cause heating or any 
sensation or any other known harmful effects.  OCT has been used for imaging the 
human retina during clinical visits. During imaging the patient is required to remain still 
intermittently.  There are no other inconvenience factors that we foresee. 
 
Biopsy: Subjects will have to travel to the Dr. Curtis’office at Bloor and Avenue Road 
for this procedure. They will need to schedule an extra 2 hours at 2 visits. 
Transportation will be arranged and paid for. The needle with the freezing causes a 
stinging or burning sensation for a few seconds, until the freezing takes hold. There is 
no pain during the remainder of the biopsy, because the area is frozen.  It is possible 
there may be bruising, which could last for 2 weeks.  There is a small risk of a local skin 
infection. This can be treated with an antibiotic cream, or occasionally requires 
antibiotics by mouth. There is likely to be a small scar at the site of the biopsy, which will 
be red initially, and will fade to pale over a few months to a year.  It is much less 
common to have a raised itchy scar, which could be injected with cortisone to help it 
flatten. 
 
5.4 Reporting Timeline 
 Within 24 hours (of learning of the event), investigators must report any reportable 
Serious Adverse Event (SAE) that: 
o 
Is considered life-threatening/disabling or results in death of subject 
-OR- 
o 
Is Unexpected/Unanticipated  
 Investigators must report all other reportable SAEs within 5 working days (of learning 
of the event). 
 All other (suspected) reportable AEs must be reported to the RDCRN within 20 
working days of the notification of the event or of the site becoming aware of the 
event. 
 
Local institutional reporting requirements to IRBs, any GCRC oversight committee and 
the FDA, if appropriate, remain the responsibility of the treating physician and the Study 
Chair. 
 


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Version Date: 01May14 
 
NCT # 01752049 
 
Page 16 of 25 
5.5 RDCRN Adverse Event Data Management System (AEDAMS) 
Upon entry of a serious adverse event, the DMCC created Adverse Event Data 
Management System (AEDAMS) will immediately notify the Study Chair, site PIs, the 
IMM, and any additional agencies (if applicable- industry sponsor, CTEP, etc.) of any 
reported adverse events via email.  
 
Serious adverse events: The IMM determines causality (definitely not related, probably 
not related, possibly related, probably related, definitely related) of the adverse event. 
The IMM may request further information if necessary and possibly request changes to 
the protocol or consent form as a consequence of the adverse event. A back-up 
notification system is in place so that any delays in review by the IMM beyond a 
specified period of time are forwarded to a secondary reviewer. The Adverse Event 
Data Management System (AEDAMS) maintains audit trails and stores data (and data 
updated) and communication related to any adverse event in the study.  
 
Non-serious expected adverse events: Except those listed above as immediately 
reportable, non-serious expected adverse events  that are reported to or observed by 
the investigator or a member of his/her research team will be submitted to the DMCC in 
a timely fashion (within 20 working days). The events will be presented in tabular form 
and given to the IMM on a bi-annual basis. Local site investigator is also required to 
fulfill all reporting requirements of their local institutions. 
 
The DMCC will post aggregate reports of all reported adverse events for site 
investigators and IRB/REBs. 
 
5.6 Study Discontinuation 
The NIH and local IRB/REBs (at their local site) have the authority to stop or suspend 
this trial at any time. This study may be suspended or closed if: 
 Accrual has been met 
 The study objectives have been met 
 The Study Chair / Study Investigators believe it is not safe for the study to 
continue 
 The NIH suspends or closes the trial 
 The FDA suspends or closes the trial 
 
5.7 Subject Discontinuation 
An intent to treat approach will be used. All data acquired prior to termination for the 
reasons outlined below will be included in the primary analysis unless patient withdraws 
consent. Every effort will be made to conduct a final study visit with the participant and 
participants will be followed clinically until, if applicable, all adverse events resolve.  
 
 Withdrawal of consent 
 Withdrawal by the participant 


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NCT # 01752049 
 
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 Withdrawal by the investigator due to the subject’s intolerance to timolol or non- 
compliance 
 Intercurrent illness or event that precludes further visits to the study site or ability 
to evaluate disease (e.g.-mental status change, large pleural effusion).  
 
5.8 Data Quality and Monitoring Measures 
 
 Data Monitoring: The research coordinator will identify missing or unclear data 
and generates a data query to the research team.  
 Data Delinquency Tracking: The research coordinator will monitor data 
delinquency on an ongoing basis.   
 
5.9 Quality Control: Study Related Procedures 
An extra patient will be recruited as a “lead-in” (or test run) phase for the OCT imaging 
and comparison of telangiectasia size caliper measurement, without drug administration 
or tissue sampling. The study chair presumes only one test patient will be sufficient. If 
this patient is eligible and willing to participate in the BVMC 6207 Research Study, the 
patient would be consented for the BVMC 6207 Research Study and the results of the 
test run imaging may be used for the BVMC 6207 Research Study.  
 
6.0 Statistical Considerations 
This is a small proof of concept pilot study of 10 patients from St. Michael’s Hospital 
who have Hereditary Hemorrhagic Telangiectasia (HHT) and have at least 5 typical 
telangiectasias on their hands or face, during a 3 month period.  
 
Sample Size: There is no justification for sample size. This is a small pilot study. If we 
can detect any effect then we will plan a future larger study, based on the results of this 
pilot. 
 
Standard descriptive statistics will be used for reporting primary and secondary 
outcomes.   
 
Reduction in telangiectasia area:   
We will analyze log area using a mixed linear regression model with predictors of time, 
treated/not and the interaction of time and treated/not (which compares the percent 
reduction in lesion area between treated and untreated lesions).  The mixed model 
would include random effects for participant, lesion within participant and the change 
over time.  Same analyses would be used for OCT variables.  
 
Definition of a significant reduction in lesion size: 
We have defined a successful outcome of therapy (a “go” decision) based on 
considering both clinical and statistical significance, as has been previously suggested 
[18] and to balance error rates.  If there is a statistically significant improvement in 


RDCRN Protocol # 6207      
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Version Date: 01May14 
 
NCT # 01752049 
 
Page 18 of 25 
lesion size at the usual level (=0.05, one-sided test) or if there is a clinically important 
improvement (at least a 20% reduction in lesion size) as well as borderline statistical 
significance (=0.10, one-sided test) we will consider this a successful outcome for 
timolol. 
 
7.0 Data Management 
Tissue samples will be analyzed and reviewed at St. Michael’s Hospital. Blood samples 
will be sent to Aushon for Serum angiogenic markers.  All results will be sent back to the 
research coordinators at St. Michael’s Hospital and will be entered into the 6207 data 
spreadsheets.  Data will be stored on a password protected computer in a locked room 
using unique identifiers. Identifying log will be kept separate from data at St. Michael’s 
Hospital.  De-identified data on spreadsheets will be sent to UCSF for analysis. The 
data will be electronically sent using encrypted communication links. Demographics 
data will be transferred to the DMCC monthly and all outcomes data will be transferred 
to the DMCC at the end of the study. 
 
All data will also be uploaded from site to DMCC by secure file transfer process (SFTP). 
 
All study data at the RDCRN Data Management and Coordinating Center will comply 
with all applicable guidelines regarding patient confidentiality and data integrity. 
 
7.1 Registration 
Registration of participants on this protocol will employ an interactive data system in 
which the clinical site will attest to the participant’s eligibility as per protocol criteria and 
obtain appropriate informed consent. IRB approval for the protocol must be on file at the 
DMCC before accrual can occur from the clinical site. 
 
The DMCC will use a system of coded identifiers to protect participant confidentiality 
and safety.  Each participant enrolled will be assigned a local identifier by the enrollment 
site.  This number can be a combination of the site identifier (location code) and a serial 
accession number.  Only the registering site will have access to the linkage between 
this number and the personal identifier of the subject.  When the participant is registered 
to participate in the study, using the DMCC provided web-based registration system, the 
system will assign a participant ID number.  Thus each participant will have two codes: 
the local one that can be used by the registering site to obtain personal identifiers and a 
second code assigned by the DMCC.  For all data transfers to the DMCC both numbers 
will be required to uniquely identify the subject.  In this fashion, it is possible to protect 
against data keying errors, digit transposition or other mistakes when identifying a 
participant for data entry since the numbers should match to properly identify the 
participant.  In this fashion, no personal identifiers would be accessible to the DMCC.  
 


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Version Date: 01May14 
 
NCT # 01752049 
 
Page 19 of 25 
7.2 Data Entry 
Tissue samples will be analyzed and reviewed at St. Michael’s Hospital. Blood samples 
will be sent to Aushon for Serum angiogenic markers.  All results will be sent back to the 
research coordinators at St. Michael’s Hospital and will be entered into the 6207 data 
spreadsheets. Data will be uploaded from site to DMCC by secure file transfer process 
(SFTP). 
 
8.0 Human Subjects 
8.1. GCP Statement 
This clinical trial will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki, and that are consistent with Good Clinical 
Practice and all applicable regulatory requirements. 
 
8.2. Risks 
Timolol maleate ophthalmic solution (Apo-Timolol) is usually well tolerated when applied 
to the eye. As with many topically applied ophthalmic drugs, this drug is absorbed 
systemically when applied mucosally. Though systemic bioavailability is unknown with 
cutaneous application, it is likely very low.  In addition, there has been no clinic 
evidence to date of systemic absorption in reported cutaneous treatment cases to date, 
and treatment area was much larger in these cases than we propose here. As this is a 
small pilot study and we have very limited resources, we will not attempt these assays 
until the next larger study. 
 
The same adverse reactions found with systemic administration of beta-adrenergic 
blocking agents may occur with topical cutaneous administration. Possible risks and 
discomforts are detailed below; however, there may be other risks and side effects that 
are not yet known.    
 
As this is a pilot study we are not aware of any risks associated with Apo-timop applied 
topically to the skin. Our goal is to prove the concept that anti-angiogenic therapy in 
HHT can cause regression of VMs.  Topical beta-blocker is a particularly interesting 
agent for this proof of concept pilot study, for a number of reasons.  First, as noted 
above, there is some clinical evidence of effectiveness for regression of VMs in other 
disorders and there are plausible biological mechanisms.  Second, it appears to be a 
low risk therapy.   
 
There is 50% bioavailability with mucosal application but cutaneous cases treated to 
date have had no systemic side effects (systemic bioavailability unknown with 
cutaneous application, though likely very low), and in these reported cases treatment 
area was much larger than we propose here.  
 
The following sections are cited from the Product Monograph attached to this 
submission: 


RDCRN Protocol # 6207      
HHT Topical Pilot 
 
Version Date: 01May14 
 
NCT # 01752049 
 
Page 20 of 25 
 
“WARNINGS AND PRECAUTIONS 
General 
As with other topically applied ophthalmic drugs, this drug may be absorbed 
systemically. The same adverse reactions reported with systemic beta-adrenergic 
blocking agents may occur with topical administration. Timolol maleate ophthalmic 
solution should be used with caution in patients subject to spontaneous hypoglycemia 
or in diabetic patients (especially those with labile diabetes) who are receiving insulin or 
oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and 
symptoms of acute hypoglycemia. In patients with angle-closure glaucoma, the 
immediate objective of treatment is to reopen the angle. This requires constricting the 
pupil with a miotic. Timolol maleate has little or no effect on the pupil. When timolol 
maleate ophthalmic solution is used to reduce elevated intraocular pressure in angle-
closure glaucoma they should be used with a miotic and not alone. Cardiac failure 
should be adequately controlled before beginning therapy with timolol maleate 
ophthalmic solution. In patients with a history of severe cardiac disease, signs of cardiac 
failure should be watched for and pulse rates should be checked. Respiratory reactions 
and cardiac reactions, including death due to bronchospasm in patients with asthma 
and rarely death in association with cardiac failure, have been reported following 
administration of timolol maleate ophthalmic solutions. Because of the potential effects 
of beta-adrenergic blocking agents on blood pressure and pulse, these agents should 
be used with caution in patient with cerebrovascular insufficiency. If signs or symptoms 
suggesting reduced cerebral blood flow develop following initiation of therapy with 
timolol maleate ophthalmic solution, alternative therapy should be considered. 
Endocrine and Metabolism 
Thyrotoxicosis 
β-adrenergic blocking agents may mask certain clinical signs of hyperthyroidism (e.g., 
tachycardia). Patients suspected of developing thyrotoxicosis should be managed 
carefully to avoid abrupt withdrawal of β-adrenergic blocking agents which might 
precipitate a thyroid storm. 
Immune 
Risk from Anaphylactic Reaction 
While taking beta blockers, patients with a history of atopy or a history of severe 
anaphylactic reaction to a variety of allergens may be more reactive to repeated 
challenge with such allergens,either accidental, diagnostic, or therapeutic. These 
patients may be more resistant to treatment of anaphylactic reactions with the usual 
doses of epinephrine since timolol may blunt the beta agonist effect of epinephrine. In 
such cases, alternatives to epinephrine should be considered. 
Ophthalmologic 
Choroidal Detachment 
Choroidal detachment has been reported with administration of aqueous suppressant 
therapy (e.g., timolol, acetazolamide or combination) after filtration procedures. 
Management of eyes with chronic or recurrent choroidal detachment should include 
stopping all forms of aqueous suppressant therapy and treating endogenous 
inflammation vigorously. As with the use of other antiglaucoma drugs, diminished 
responsiveness to timolol maleate ophthalmic solution after prolonged therapy has been 


RDCRN Protocol # 6207      
HHT Topical Pilot 
 
Version Date: 01May14 
 
NCT # 01752049 
 
Page 21 of 25 
reported in some patients. However, in clinical studies in which 164 patients have been 
followed for at least 3 years, no significant difference in mean intra ocular pressure has 
been observed after initial stabilization. 
Contact Lenses 
The preservative in APO- TIMOP ophthalmic solution is benzalkonium chloride. This 
preservative is a quaternary ammonium compound that may be absorbed by soft 
contact lenses. Therefore, APO-TIMOP ophthalmic solution should not be administered 
while wearing soft contact lenses. The contact lenses should be removed before 
application of the drops and not be reinserted earlier than 15 minutes after use. 
Neurologic 
Muscle Weakness 
β-adrenergic blockade has been reported to increase muscle weakness consistent with 
certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). 
Timolol has been reported rarely to increase muscle weakness in some patients with 
myasthenic symptoms. 
Peri-Operative Considerations 
Major Surgery 
The necessity or desirability of withdrawal of β-adrenergic blocking agents prior to major 
surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the 
heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the 
risk of general anesthesia in surgical procedures. Some patients receiving beta-
adrenergic blocking agents have experienced protracted severe hypotension during 
anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. 
For these reasons, in patients undergoing elective surgery, some authorities 
recommend gradual withdrawal of beta-adrenergic blocking agents. If necessary during 
surgery, the effects of β-adrenergic blocking agents may be reversed by sufficient doses 
of such agonists as isoproterenol, dopamine, dobutamine or levarterenol. 
Special Populations 
Pregnant Women: 
Timolol maleate ophthalmic solution has not been studied in human pregnancy. The use 
of timolol maleate ophthalmic solution requires that the anticipated benefit be weighed 
against possible hazards. 
Nursing Women: 
Timolol is detectable in human milk. Because of the potential for serious adverse 
reactions from timolol in nursing infants, a decision should be made whether to 
discontinue nursing or to discontinue the drug, taking into account the importance of the 
drug to the mother. 
Pediatrics: 
Safety and effectiveness in children have not been established. 
ADVERSE REACTIONS 
Clinical Trial Adverse Drug Reactions 
Because clinical trials are conducted under very specific conditions the adverse reaction 
rates observed in the clinical trials may not reflect the rates observed in practice and 
should not be compared to the rates in the clinical trials of another drug. Adverse drug 
reaction information from clinical trials is useful for identifying drug-related adverse 
events and for approximating rates. Timolol maleate ophthalmic solution is usually well 


RDCRN Protocol # 6207      
HHT Topical Pilot 
 
Version Date: 01May14 
 
NCT # 01752049 
 
Page 22 of 25 
tolerated. The following adverse reactions have been reported with ocular 
administration of this or other timolol maleate formulations, either in clinical trials or 
since the drug has been marketed. 
Body as a Whole 
Headache, asthenia, fatigue, chest pain. 
Cardiovascular 
Aggravation or precipitation of certain cardiovascular pulmonary and other disorders 
presumably related to effects of systemic beta blockade has been reported (see 
CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS). These include 
bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, 
cerebral ischemia, palpitation, cardiac arrest, congestive heart failure, edema, 
claudication, Raynaud’s phenomenon, cold hands and feet and in insulin-dependent 
diabetics masked symptoms of hypoglycemia have been reported rarely. Nausea, 
diarrhea, dyspepsia, dry mouth. 
Hypersensitivity 
Signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, 
localized and generalized rash. 
Immunologic 
Systemic lupus erythematosus. 
Integumentary 
Alopecia, psoriasiform rash or exacerbation of psoriasis. 
Nervous System/Psychiatric 
Dizziness, depression, insomnia, nightmares, memory loss, increase in signs and 
symptoms of myasthenia gravis, paresthesia. 
Respiratory 
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), 
respiratory failure, dyspnea, cough. 
Special Senses 
Signs and symptoms of ocular irritation: including burning and stinging, conjunctivitis, 
blepharitis, keratitis, decreased corneal sensitivity, and dry eyes. Visual disturbances: 
including refractive changes (due to withdrawal of miotic therapy in some cases), 
diplopia, ptosis, and choroidal detachment following filtration surgery (see WARNINGS 
AND PRECAUTIONS). Tinnitus. 
Urogential 
Decreased libido, Peyronie’s disease. 
Causal Relationship Unknown 
The following adverse reactions have been reported but a causal relationship to therapy 
with timolol maleate ophthalmic solution has not been established: aphakic cystoid 
macular edema, nasal congestion, anorexia, CNS effects (e.g., behavioral changes 
including confusion, hallucinations, anxiety, disorientation, nervousness, somnolence, 
and other psychic disturbances), hypertension, retroperitoneal fibrosis and 
pseudopemphigoid. 
Potential Adverse Reactions 
Adverse reactions reported in clinical experience with systemic timolol maleate may be 
considered potential side effects of ophthalmic timolol maleate.” 
 


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NCT # 01752049 
 
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Risks Related to Study Tests 
Blood Sample Collection:  When blood samples are taken from a vein, subjects may 
have discomfort or pain where the blood was taken.  Sometimes a person may become 
dizzy or faint when blood is taken.  There is also a risk of infection (rare), bleeding, 
redness or bruising at the skin puncture.  Bleeding and bruising can usually be reduced 
by putting pressure on the place where the blood was taken.  The chance of infection is 
lowered by using standard skin cleaning and sterile needles. 
 
Optical Coherence Tomography (OCT) 
This test will take approximately 30 minutes at each visit. 
Subjects will travel by taxi to and from Sunnybrook Hospital for OCT imaging.  
This could amount to 1-2 extra hours due to travelling time. 
The light used is near infrared at safe power level (significantly below the American 
National Standards Institute exposure level).  It will not cause heating or any sensation 
or any other known harmful effects.  OCT has been used for imaging the human retina 
during clinical visits. During imaging the patient is required to remain still intermittently.  
There are no other inconvenience factors that we foresee. 
 
Biopsy 
Subjects will have to travel to the Bloor and Avenue Road for this procedure. They will 
need to schedule an extra 2 hours at 2 visits. Transportation will be arranged and paid 
for.The needle with the freezing causes a stinging or burning sensation for a few 
seconds, until the freezing takes hold. There is no pain during the remainder of the 
biopsy, because the area is frozen.  It is possible there may be bruising, which could 
last for 2 weeks.  There is a small risk of a local skin infection. This can be treated with 
an antibiotic cream, or occasionally requires antibiotics by mouth. There is likely to be a 
small scar at the site of the biopsy, which will be red initially, and will fade to pale over a 
few months to a year.  It is much less common to have a raised itchy scar, which could 
be injected with cortisone to help it flatten. Subjects may opt not to include 
telangiectasia located on their face if they so prefer to avoid facial scarring or the palms 
of their hands as it may be somewhat more painful. 
 
8.3 Benefits 
Subjects will not benefit directly from inclusion in this study. However, we hope that at 
the end of this pilot study, researchers will be in a better position to propose therapies 
and studies that may help reduce vascular malformations in individuals with HHT. 
 
8.4 Recruitment  
Approximately 300 HHT Database cases will be reviewed for eligibility. Subjects 
enrolled in our HHT Database have consented to be screened for study eligibility. All 
eligible patients will be approached: there will be no internal bias. There is no proposed 
exclusion of any sex/gender or racial/ethnic group. 
 


RDCRN Protocol # 6207      
HHT Topical Pilot 
 
Version Date: 01May14 
 
NCT # 01752049 
 
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8.5 Written Informed Consent 
Written informed consent will be obtained from each participant before any study-
specific procedures or assessments are done and after the aims, methods, anticipated 
benefits, and potential hazards are explained.  The participant’s willingness to 
participate in the study will be documented in writing in a consent form, which will be 
signed by the participant with the date of that signature indicated.  The investigator will 
keep the original consent forms and signed copies will be given to the participants.  It 
will also be explained to the participants that they are free to refuse entry into the study 
and free to withdraw from the study at any time without prejudice to future treatment.  
Written and/or oral information about the study in a language understandable by the 
participant will be given to all participants. 
 
8.6 Process of Consent   
Contact will be made by phone or in clinic by the research coordinator who is usually 
familiar with her/him from being recruited for the database. In most cases the treating 
physician (PI) would mention the patient’s potential eligibility for the study and ask if 
delegated staff could contact them. However all patients have shown research interest 
by consenting to be on our HHT Database. 
 
Obtaining Informed Consent: 
 Patient is approached in Clinic or by phone. 
o Study Coordinator (RC) will explain the information of the written informed 
consent to the patient. 
o Patient will be asked several times if he/she understood details of the study and 
if he or she has questions about it. 
o Patient will be offered extra time to read, consider discuss the study. 
o If participant would like more time to think about his/her participation he/she will 
be offered an unsigned consent form to take home and study and a plan will be 
made for a follow-up conversation in clinic or by phone. 
o Patient will be asked if he/she would agree to participate in this study. 
o Patient will sign informed consent in clinic before starting any study procedures. 
o Patient will receive a signed copy of consent. 
If patient does not consent to having this conversation he/she will be thanked for 
their time. 
In all cases, patients will be given as much time as they like to make their decision. 
 


RDCRN Protocol # 6207      
HHT Topical Pilot 
 
Version Date: 01May14 
 
NCT # 01752049 
 
Page 25 of 25 
9.0 References 
1. 
Tang, S.J., et al., In vivo Doppler optical coherence tomography of mucocutaneous 
telangiectases in hereditary hemorrhagic telangiectasia. Gastrointest Endosc, 2003. 
58(4): p. 591-8. 
2. 
Han, C. and S.P. Oh, Preclinical Assessment of VEGF blockades for inhibition of 
arteriovenous malformation in a mouse model for HHT (abstract)  Hematology 
Conference Reports, 2011. 3(S2): p. D16. 
3. 
Suppressa, P., A. Liso, and C. Sabba, Low dose intravenous bevacizumab for the 
treatment of anaemia in hereditary haemorrhagic telangiectasia. Br J Haematol. 152(4): 
p. 365. 
4. 
Bose, P., J.L. Holter, and G.B. Selby, Bevacizumab in hereditary hemorrhagic 
telangiectasia. N Engl J Med, 2009. 360(20): p. 2143-4. 
5. 
Flieger, D., S. Hainke, and W. Fischbach, Dramatic improvement in hereditary 
hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor 
(VEGF) antagonist bevacizumab. Ann Hematol, 2006. 85(9): p. 631-2. 
6. 
Simonds, J., et al., The effect of bevacizumab (Avastin) treatment on epistaxis in 
hereditary hemorrhagic telangiectasia. Laryngoscope, 2009. 119(5): p. 988-92. 
7. 
Dupuis-Girod, S., et al., Bevacizumab in patients with hereditary hemorrhagic 
telangiectasia and severe hepatic vascular malformations and high cardiac output. 
JAMA. 307(9): p. 948-55. 
8. 
Davidson, T.M., S.E. Olitsky, and J.L. Wei, Hereditary hemorrhagic 
telangiectasia/avastin. Laryngoscope. 120(2): p. 432-5. 
9. 
Karnezis, T.T. and T.M. Davidson, Treatment of hereditary hemorrhagic telangiectasia 
with submucosal and topical bevacizumab therapy. Laryngoscope. 122(3): p. 495-7. 
10. 
Olitsky, S.E., Topical timolol for the treatment of epistaxis in hereditary hemorrhagic 
telangiectasia. Am J Otolarygol, 2011. 
11. 
Guo, S. and N. Ni, Topical treatment for capillary hemangioma of the eyelid using beta-
blocker solution. Arch Ophthalmol. 128(2): p. 255-6. 
12. 
Leaute-Labreze, C., et al., Propranolol for severe hemangiomas of infancy. N Engl J 
Med, 2008. 358(24): p. 2649-51. 
13. 
Ni, N., et al., Topical timolol for periocular hemangioma: report of further study. Arch 
Ophthalmol. 129(3): p. 377-9. 
14. 
Pope, E. and A. Chakkittakandiyil, Topical timolol gel for infantile hemangiomas: a pilot 
study. Arch Dermatol. 146(5): p. 564-5. 
15. 
Lamy, S., et al., Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, 
migration, and differentiation of endothelial cells. Vascul Pharmacol. 53(5-6): p. 200-8. 
16. 
Ristori, C., et al., Role of the adrenergic system in a mouse model of oxygen-induced 
retinopathy: antiangiogenic effects of beta-adrenoreceptor blockade. Invest Ophthalmol 
Vis Sci. 52(1): p. 155-70. 
17. 
Mariampillai, A., et al., Optimized speckle variance OCT imaging of microvasculature. 
Opt Lett. 35(8): p. 1257-9. 
18. 
Chuang-Stein, C., et al., A Quantitative Approach for Making Go/No-Go Decisions in 
Drug Development. . Drug Information Journal, 2011. 45: p. 187. 
 


NCT # 01752049 
 
Rare Diseases Clinical Research Network 
Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of Concept  
Brain Vascular Malformation Consortium 
PI: Marie E. Faughnan MD MSc FRCPC 
 
Statistical Considerations 
This is a small proof of concept pilot study of 10 patients from St. Michael’s Hospital 
who have Hereditary Hemorrhagic Telangiectasia (HHT) and have at least 5 typical 
telangiectasias on their hands or face, during a 3 month period.  
 
Sample Size: There is no justification for sample size. This is a small pilot study. If we 
can detect any effect then we will plan a future larger study, based on the results of this 
pilot. 
 
Standard descriptive statistics will be used for reporting primary and secondary 
outcomes.   
 
Reduction in telangiectasia area:   
We will analyze log area using a mixed linear regression model with predictors of time, 
treated/not and the interaction of time and treated/not (which compares the percent 
reduction in lesion area between treated and untreated lesions).  The mixed model 
would include random effects for participant, lesion within participant and the change 
over time.  Same analyses would be used for OCT variables.  
 
Definition of a significant reduction in lesion size: 
We have defined a successful outcome of therapy (a “go” decision) based on 
considering both clinical and statistical significance, as has been previously suggested 
and to balance error rates.  If there is a statistically significant improvement in lesion 
size at the usual level (=0.05, one-sided test) or if there is a clinically important 
improvement (at least a 20% reduction in lesion size) as well as borderline statistical 
significance (=0.10, one-sided test) we will consider this a successful outcome for 
timolol.