Intranasal Bevacizumab for HHT-Related Epistaxis
Phase: PHASE4
Conditions: HHT, Hereditary Hemorrhagic Telangiectasia, Epistaxis, Nose Bleeds, Nasal Bleeding
Sponsor: Stanford University

Intranasal Bevacizumab for HHT-Related Epistaxis 
Study Protocol and Statistical Analysis Plan 
NCT02389959 
 August 19, 2014 

 
Principal Investigator/Program Director (Last, first, middle): Clark, Amelia K.  
 
1 
Research Strategy 
RESEARCH  STRATEGY 
 
A Randomized Controlled Trial of Bevacizumab for HHT-Related Epistaxis 
 
SIGNIFICANCE 
 
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder 
characterized by systemic vascular malformations that result from mutations of the ENG gene, which 
encodes for factors in the vascular endothelial growth factor (VEGF) pathway. HHT is diagnosed by 
the Curacao Criteria including the presence of epistaxis; telangiectasias or vascular malformations in 
the lungs, liver, or nervous system; and a positive family history involving a first-degree relative1.  One 
of the most common presentations of this disease is recurrent and profound epistaxis, with many 
patients reporting more than 4 epistaxis episodes in a day, many lasting up to an hour.  HHT-related 
epistaxis often results in severe anemia requiring intravenous iron and repeated blood transfusions, 
and also carries significant psychosocial disability relating to impaired quality of life and work 
absenteeism.  Multiple approaches to treatment have been described, including electrocautery, laser 
treatment, embolization, septodermoplasty, and as a last resort, Young’s procedure, involving closure 
of the nasal vestibule2. These approaches are largely palliative, with variable effectiveness, and 
almost always require repeated procedures for chronic management of bleeding3.  There is a great 
need for the development of new treatment options for reducing the medical morbidity and quality of 
life impairment associated with refractory epistaxis in HHT. 
 
Recently there has been promising data suggesting that inhibition of angiogenesis may be an 
effective strategy for managing HHT-related bleeding.  Circulating concentrations of VEGF are 
significantly elevated in HHT, making VEGF an attractive therapeutic target4.  Preliminary studies 
suggest that bevacizumab, a recombinant monoclonal antibody that inhibits the biologic activity of 
VEGF, can significantly improve epistaxis severity when topically applied, locally injected, or 
intravenously administered5. However, these early pilot studies of bevacizumab have been limited 
exclusively to retrospective case series.  As yet, there has been no prospective double-blind placebo 
controlled trial to establish the role of bevacizumab in the treatment of HHT-related epistaxis.   
 
INNOVATION 
 
The Stanford Sinus Center is a tertiary referral center for advanced rhinologic care, with a catchment 
area that is focused on northern California (population 13 million), but also includes southern 
California, Nevada, southern Oregon and Hawaii. The clinical volume of the center encompasses 
approximately 6000 clinic visits and 600 operations per year.  Included in the patient population is a 
robust base of HHT patients who return to Stanford regularly for surgical management of epistaxis.  
Dr. Hwang, Director of the Sinus Center, has an active interest in HHT; he has been a guest speaker 
at the national HHT patient conference and has published on surgical techniques for HHT-related 
epistaxis.  Complemented by our team of dedicated research fellows and resources for clinical 
research support available through the Stanford School of Medicine, the Sinus Center is poised to 
carry out the first randomized, double-blind, placebo-controlled clinical trial of bevacizumab injection 
versus saline control for the management of HHT-related epistaxis, by which we hope to shift the 
current clinical practice paradigms in treating this debilitating disease. 
 

 
Pri n ci p al I n v e sti g at or/ Pr o gr a m Dir e ct or ( L a st, fir st, mi d dl e):  Cl ar k, A m eli a K.  
 
2 
R e s e ar c h Str at e g y 
A P P R O A C H  
 
Pr eli mi n ar y D at a 
 
S e v er al r etr o s p e cti v e st u di e s i n t h e r e c e nt lit er at ur e h a v e d e m o n str at e d t h at t h e u s e of b e v a ci z u m a b 
a s a n a dj u n ct t o el e ctr o c a ut er y or l a s er tr e at m e nt f or e pi st a xi s r el at e d t o H H T i s a s s o ci at e d wit h 
a d diti o n al b e n efit i n r e d u ci n g e pi st a xi s s y m pt o m s 6 .  W h e n c o m p ar e d t o a gr o u p of p ati e nt s w h o 
r e c ei v e d l a s er tr e at m e nt al o n e, t h e gr o u p w h o r e c ei v e d b e v a ci z u m a b i n a d diti o n t o l a s er tr e at m e nt 
h a d a r e d u cti o n i n t h e fr e q u e n c y of e pi st a xi s, n u m b er of bl o o d tr a n sf u si o n s, di s a bilit y, a n d eff e ct o n 
s o ci al lif e 7 .  T h er e i s g o o d e vi d e n c e t o s u p p ort t h at i ntr a n a s al u s e of l o w- d o s e b e v a ci z u m a b i s al s o 
s a f e.  S y st e mi c u s e of b e v a ci z u m a b a s a tr e at m e nt f or m et a st ati c c a n c er u si n g d o s e s of u p t o 5 t o 
1 5 m g/ k g h a s b e e n a s s o ci at e d wit h s eri o u s si d e eff e ct s 8 .  H o w e v er, b e v a ci z u m a b h a s b e e n u s e d 
e xt e n si v el y i n o p ht h al m ol o g y i n l o w d o s e s t o tr e at n e o v a s c ul ari z ati o n wit h l o w c o m pli c ati o n r at e s o n 
t h e or d er of 0. 2 1 % or l e s s9 .  I n a c h art r e vi e w of 5 8 p ati e nt s w h o r e c ei v e d b e v a ci z u m a b b y i ntr a n a s al 
s u b m u c o s al i nj e cti o n or t o pi c al s pr a y, fi v e p ati e nt s s u st ai n e d s e pt al p erf or ati o n. T h e a ut h or s n ot e t h at 
t h e tr e at m e nt pr ot o c ol w a s c h a n g e d s u c h t h at i nj e cti o n t o t h e c artil a gi n o u s s e pt u m w a s a v oi d e d, a n d 
aft er t hi s n o f urt h er s e pt al p erf or ati o n s w er e i d e ntifi e d 1 0 .   
 
S u b s e q u e ntl y, a st u d y fr o m 2 0 1 2 d e v el o p e d a st a n d ar di z e d i nj e cti o n pr ot o c ol f or b e v a ci z u m a b 
tr e at m e nt b a s e d o n t h e v a s c ul ar a n at o m y of t h e n o s e wit h att e nti o n t o a v oi di n g i nj e cti o n of t h e 
c artil a gi n o u s s e pt u m 1 1 .  T hi s i nj e cti o n pr ot o c ol u s e d 1 0 0 m g of b e v a ci z u m a b i nj e ct e d s u b m u c o s all y, 
( 5 0 m g p er si d e), i nt o f o ur l o c ati o n s wit hi n t h e n o s e: t h e s p h e n o p al ati n e ar e a, t h e u p p er p art of t h e 
b o n y s e pt u m, t h e u p p er p art of t h e l at er al n a s al w all, a n d t h e a nt eri or p art of t h e n a s al fl o or.  T hi s 
st u d y f o u n d a si g nifi c a nt i m pr o v e m e nt i n t h e p o st-tr e at m e nt e pi st a xi s fr e q u e n c y a n d s e v erit y f or t h e 8 
p ati e nt s e nr oll e d i n t h e st u d y, b ut wit h o ut a c o ntr ol gr o u p f or c o m p ari s o n; n o i n ci d e nt s of s e pt al 
p erf or ati o n w er e n ot e d.  
 
E x p eri m e nt al Pl a n 
 
S p e cifi c Ai m 1: D et er mi n e if i ntr a n a s al b e v a ci z u m a b i nj e cti o n d e cr e a s e s e pi st a xi s fr e q u e n c y 
a n d s e v erit y c o m p ar e d t o pl a c e b o w h e n u s e d i n c o nj u n cti o n wit h el e ctr o c a ut er y f or p ati e nt s 
wit h H H T  
 
R ati o n al e a n d H y p ot h e si s 
B a s e d o n e xi sti n g l e v el 4 
e vi d e n c e t h at s u g g e st s t h at 
b e v a ci z u m a b i nj e cti o n i s 
b e n efi ci al i n t h e m a n a g e m e nt of 
H H T -r el at e d e pi st a xi s, w e 
h y p ot h e si z e t h at p ati e nt s w h o 
r e c ei v e i ntr a n a s al i nj e cti o n wit h 
b e v a ci z u m a b at t h e ti m e of 
el e ctr o c a ut er y tr e at m e nt will h a v e 
a n i m pr o v e m e nt i n t h e fr e q u e n c y 
a n d s e v erit y of e pi st a xi s 
c o m p ar e d t o p ati e nt s w h o 
r e c ei v e i nj e cti o n of s ali n e c o ntr ol. 
 
F i g ur e 1. Tri al D e si g n. S ur v e y s will b e a d mi ni st er e d at b a s eli n e, a s w ell 
a s 1 m o nt h, 2 m o nt h s, 4 m o nt h s, a n d  6 m o nt h s aft er bli n d e d i nj e cti o n of 
dr u g v er s u s c o ntr ol.
r a n d o miz a o n
E nr oll m e nt &
C o ns e nt
Bl e e di n g
S urv e ys
Bl e e di n g
S ur v eys
Bl e e di n g
S urv e ys
Bl e e di n g
S ur v e ys
t = 0
1 m o nt h
2 m o nt hs
6 m o nt hs
Pr e- o p Visit
T o O R f or
C a ut er y
I ntr a n as al
B e v aciz u m a b
I nj ec o n
I ntr a n as al
S ali n e
I nj ec o n
Bl e e di n g
S urv e ys
4 m o nt hs
 

 
Principal Investigator/Program Director (Last, first, middle): Clark, Amelia K.  
 
3 
Research Strategy 
 
 
Approach 
Patients to be included in this study are those who have a diagnosis of HHT confirmed by the 
Curacao Criteria, who are to undergo treatment with electrocautery in the operating room under 
endoscopic visualization, and who are at least 18 years of age.  Patients will be excluded if they have 
had any new treatments for their epistaxis within the 8 weeks prior to starting the trial, or if the patient 
is a minor or is pregnant. After informed consent is obtained, patients will be randomized to either 
bevacizumab injection or saline control.  The Stanford Hospital Investigational Pharmacy will perform 
all randomization, drug storage and management, as well as mixing and packaging for double-blinded 
injection of bevacizumab or saline control.  Patients enrolled in the study will undergo standard-of-
care bipolar electrocautery of nasal telangiectasias in the Stanford Ambulatory Surgery Center 
operating room.  At the time of electrocautery, patients will receive intranasal injection of either study 
drug or saline control.  The surgeon performing the injection will be blinded to whether injection is 
composed of bevacizumab or saline control.  Bevacizumab will be mixed by the Stanford Hospital 
Pharmacy to a total dose of 100mg in 4mL, and 50mg (2mL) will be injected into each side of the 
nose.  Injections will be performed according to the standardized four-point injection protocol 
(0.5mL/site) based on the vascular anatomy of the nose published in 2012 by Dheyauldeen et al13.  In 
accordance with this protocol, care will be taken to avoid injection of the cartilaginous nasal septum to 
avoid the risk of nasal septal perforation.  At the pre-operative appointment and then again following 
operative electrocautery with injection, patients will be followed with serial surveys regarding their 
epistaxis symptoms administered at 1 month, 2 months, 4 months, and 6 months post-injection 
(Figure 1).  The time points selected for this 
analysis were based upon the study by 
Karnezis et al., which followed Epistaxis 
Severity Scores on a monthly basis up to one 
year after submucosal injection of 
bevacizumab12. 
 
The majority of studies of HHT-related 
epistaxis use the Epistaxis Severity Score 
(ESS) as a standardized and reproducible 
outcome measure for control of epistaxis13.  
This validated measure was developed by a 
panel of HHT care providers and a focus group 
of patients to determine the factors that best 
correlate with epistaxis severity.  It is 
composed of six factors that are independent 
predictors of self-described epistaxis severity, 
each one weighted by coefficients from the 
model derived (Figure 2).  In order to more 
accurately capture the change in epistaxis 
symptoms over time at each of the data points 
proposed in this study, we will modify the ESS 
questions slightly to focus on the symptoms 
experienced over the preceding month (for 
example, instead of asking “have you ever 
sought medical attention for nose bleeding?” 
our questionnaire will be modified to ask “have you sought medical attention for nose bleeding within 
Figure 2. Epistaxis Severity Score. Comprised of 6 
independent predictors of epistaxis severity. (From 
Hoag et al., 2010) 

 
Principal Investigator/Program Director (Last, first, middle): Clark, Amelia K.  
 
4 
Research Strategy 
the last month?”). 
 
Statistical Considerations 
The primary endpoint of this study is to determine if there is a significant difference in the change in 
Epistaxis Severity Score in the bevacizumab group compared to the group who received injection of 
saline control.  Based on previously published data, a reasonable therapeutic target is a difference in 
the change in ESS score between groups of 2 points on the ESS scale.  In order to have 80% power 
at this target, we will require 17 informative patients per arm of this trial.  To account for loss to follow-
up and other unforeseen attrition, we propose to study 20 patients in the bevacizumab group and 20 
patients in the saline control group for a total accrual goal of 40 patients.  This estimate is in fact 
based on a conservative power calculation as it is based on anticipating a standard deviation within 
the ESS scoring system of 2, however other published data within the literature suggests that a more 
likely standard deviation of 1 can be achieved with the ESS grading scale.  A two-sample t-test power 
calculation was used to perform this power analysis.  
 
Expected Results 
Our primary goal is to determine if intranasal bevacizumab injection as an adjunct to operative 
electrocautery provides any additional benefit in the management of epistaxis frequency or severity or 
need for repeated interventions in patients with HHT, as measured by the ESS scoring system. We 
expect that patients treated with bevacizumab will have a significantly greater reduction in their ESS 
grading than patients injected with the saline control when comparing pre-and post-injection ESS 
grades.  We anticipate that differences in epistaxis symptoms between the two groups may be difficult 
to discriminate at the 1 month time point, as both groups will likely show an improvement in their 
epistaxis related to the operative electrocautery at this early time point, however based on the time 
points in the Karnezis trial the 1 month time point will allow us to establish a new post-operative 
baseline for epistaxis symptoms.  We would anticipate significant differences to manifest at the 2 
month, 4 month, and 6 month time points.  Data will be analyzed using an ANCOVA model, testing for 
the change in the two arms while allowing appropriate adjustment for the baseline value.  
 
Potential Problems and Alternative Approaches 
A the study proceeds, we anticipate the possible need to administer ESS surveys at additional time 
points to optimize our understanding of the contribution of bevacizumab injection with electrocautery 
on epistaxis symptoms over time.  The selected time points were based upon data available from the 
aforementioned Karnezis study which administered ESS surveys monthly after bevacizumab9.  
However, because this retrospective analysis did not include a control arm it is difficult to predict at 
what time point we will see the maximum spread in the change of ESS will be seen when comparing 
the drug intervention versus saline control group.  
 
Specific Aim 2: Determine if intranasal bevacizumab injection results in a greater improvement 
in quality of life compared to placebo when used in conjunction with electrocautery for 
patients with HHT 
 
Rationale and Hypothesis 
Given the known negative impact of recurrent refractory epistaxis on quality of life in patients with 
HHT, we hypothesize that patients who undergo blinded intranasal injection with bevacizumab will 
demonstrate improved post-operative quality of life and health status scores than patients who 
receive injection with saline control. 
 
Approach 

 
Principal Investigator/Program Director (Last, first, middle): Clark, Amelia K.  
 
5 
Research Strategy 
We will assess global health outcomes and quality of life using the Short Form-36 (SF-36) Health 
Status Questionnaire.  This short survey is a validated health status survey that was developed out of 
two large epidemiological studies, the Health Insurance experiment, and the Medical Outcomes 
Study, and has been reliably used in a number of chronic disease states14.  This survey was further 
validated in its ability to measure the health of patients with epistaxis due to HHT by Lennox et al. in 
2005, who demonstrated the utility of SF-36 as an outcome measure in assessing efficacy of 
treatment of HHT-related epistaxis15.   
 
Patients enrolled in this study will complete the SF-36 surveys in conjunction with the ESS surveys at 
baseline (pre-operative), 1 month post- treatment, 2 months post-treatment, 4 months post-treatment, 
and 6 months post-treatment.  The SF-36 queries various quality of life parameters experienced by 
the patient over the preceding four-week period, which will align well with the 4-week symptom 
window of our modified ESS survey results for purposes of outcomes analysis.  
 
Expected Results 
We expect that health status scores will improve in all patients after operative electrocautery 
treatment of telangiectasias.  However we expect to see a greater magnitude of improvement and 
possibly a prolonged quality of life benefit in the group of patients randomized to receive 
bevacizumab injection versus those who receive injection of saline control.  Data will be analyzed 
using an ANCOVA model, testing for the change in the two arms but adjusting for the baseline value.  
 
Potential Problems and Alternative Approaches 
Patients in the study may experience concurrent HHT-related complications in other organ systems 
such as pulmonary AV malformations, hepatic involvement, or gastrointestinal bleeding, which can 
adversely affect global quality of life and health status.  In such circumstances, the SF-36 may be less 
sensitive for detecting changes in quality of life and health status specific to the treatment for 
epistaxis.  A newly introduced adjunctive survey which focuses on epistaxis-specific quality of life 
items may be administered as a complement to the SF-36 if the results of the SF-36 alone are not 
sensitive enough to detect a change16. 
 
Specific Aim 3: Determine the cost-effectiveness of intranasal bevacizumab injection 
compared to placebo when used in conjunction with electrocautery 
 
Rationale and Hypothesis 
In a time of increasing health care expenditure, there is growing concern pertaining to the fiscal 
sustainability of the US health care system.  In 2009, the USA spent an estimated $7,960 per capita 
on heath care with approximately 17.4% of its GDP and spending is increasing on average of 4% per 
year17.  This data emphasizes the importance of critically evaluating the delivery of both current and 
future interventions in order to ensure resource allocation is cost-effective. 
 
One hundred milligrams of bevacizumab costs approximately $600 as a wholesale acquisition18, but 
the indirect cost of recurrent epistaxis in terms of patient productivity can lead to significant economic 
losses to society.  Frequent epistaxis related to HHT is itself disabling, worsened by the additional 
costs of repeated operating room fees, anesthesia costs, recurrent blood transfusions and 
intravenous iron treatments, and repeated emergency room visits.  We hypothesize that patients who 
undergo blinded intranasal injection with bevacizumab with have lower post-operative epistaxis-
related costs (both direct and indirect) than patients who receive injection of saline control.  We also 
hypothesize that the incremental cost effectiveness ratio (ICER) of bevacizumab injection will be 

 
Principal Investigator/Program Director (Last, first, middle): Clark, Amelia K.  
 
6 
Research Strategy 
considered cost effective compared to saline injection based on a willingness to pay threshold of 
$50,000 per quality adjusted life year (QALY).  
 
Approach 
The economic evaluations will take the societal perspective.  Direct cost collection and estimation will 
follow the three steps outlined by Smith and Rudmik19.  Indirect costs will be estimated using the 
human capital approach for defining productivity costs.  Productivity costs will include both 
presenteeism and absenteeism.  Absenteeism will be quantified using the Quantity and Quality 
Questionnaire20.   Based on current recall recommendations, absenteeism will be quantified by asking 
both the number of full work days missed and the number of work hours missed due to HHT-related 
epistaxis in the last 3 months16-18.  All cost related questionnaires will be completed at baseline and 6 
months post-injection.  Lost productive time will be assessed by measurement of per-person work 
days lost due to epistaxis, as well as measurement of lost productivity time due to disease-related 
reduced work performance.  Household productivity loss will be evaluated by asking patients how 
much time is used at home to care for epistaxis each day.  This lost productive time can then be 
monetized based upon median annual income data and used to approximate the productivity cost to 
society.  
 
The primary outcome for our CEA will be the cost per QALY.  The QALY is based off the patients’ 
preference for being in a particular health state.  This preference is equal to a health state utility score 
and is ranked from 0.0= “death” to 1.0= “perfect health”.  For this economic evaluation, the utility 
scores will be obtained using the SF-6D instrument.  The SF-6D is based on the general QoL 
instrument called the Short-Form 36 (SF-36) and Short form 12 (SF-12)21.  Health state utility scores 
(SF-6D) are derived from responses to 6 separate items indicated on both the SF-36 and SF-12 using 
a commercially available weighted algorithm derived by the Department of Health Economics and 
Decision Science at the University of Sheffield, Sheffield, United Kingdom22.  This algorithm 
application is compatible with most commercially available statistical software packages and was 
used to calculate standardized health state utility values from follow-up survey responses provided by 
each study subject.  The utility scoring system is based on standard gamble valuation technique 
performed in the United Kingdom general population. 
 
Expected Results 
We expect that patients who are randomized to receive bevacizumab injection at the time of operative 
electrocautery will have a significant reduction in both direct and indirect costs including paid work 
days missed, reduction in work performance, and household days lost to time spent caring for their 
epistaxis when compared to patients who are randomized to the saline-control injection group.  We 
hypothesize that injection of bevacizumab at the time of electrocautery will translate to a cost-
effective intervention compared to injection of saline for patients with HHT. 
 
Potential Problems and Alternative Approaches 
Our patient population seeking treatment at a tertiary medical center is likely to represent a selected 
cohort of individuals who may have more severe HHT manifestations.  As such, the productivity costs 
for these patients may be skewed higher.  Other limitations of performing an economic evaluation 
along side a RCT include challenges with calculating adequate power for the primary economic 
outcome.  Based on recommendation by Drummond et al23, we powered this study for the most 
important economic endpoint which is epistaxis symptom severity, since this outcome will likely drive 
the majority of health care resource consumption.  To prevent the inclusion of trial driven costs into 
the CEA, we will exclude any costs incurred as a result of being in the trial. 
 

 
Principal Investigator/Program Director (Last, first, middle): Clark, Amelia K.  
 
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Research Strategy 
 
 
 
 
 
 
REFERENCES 
 
                                            
1 Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic 
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Research Strategy 
                                                                                                                                                                  
18 Steinbrook R. The price of sight-ranibizumab, bevacizumab, and the treatment of macular 
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