Clinical trial NCT03910244
Conditions: Telangiectasia, Hereditary Hemorrhagic
Keywords: Epistaxis pomalidomide blood transfusion
Sponsor: The Cleveland Clinic
Start date: 2019-10-17; Completion date: 2023-09-08
Enrollment: 145 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase II placebo-controlled double-blind study of pomalidomide in patients with hereditary hemorrhagic telangiectasia (HHT) with moderate to severe epistaxis who have anemia and/or require parenteral iron infusions or blood transfusions. A total of 159 patients will be randomized 2:1 to treatment with oral pomalidomide or matching placebo for 24 weeks. Mean change from baseline to 24 weeks in the Epistaxis Severity Score (ESS) will be compared between treatment groups to determine pomalidomide efficacy.

Detailed description:
HHT is associated with substantial morbidity, leading to a reduced quality of life, decreased rate of employment and a high incidence of depression. There currently exists no medical therapy recognized as consistently efficacious in HHT. Reports of the efficacy of thalidomide in HHT, as well as interim results of a pilot trial of pomalidomide in HHT provide evidence of efficacy with minimal toxicity. The favorable efficacy:toxicity ratio of pomalidomide suggest that it may benefit patients with HHT.

This study is designed as a Phase II placebo-controlled double-blind study of pomalidomide in HHT patients with moderate to severe epistaxis who have anemia and/or require parenteral iron infusions or blood transfusions. A total of 159 patients will be randomized 2:1 to treatment with oral pomalidomide or matching placebo for 24 weeks.

Primary Objective: To determine efficacy of pomalidomide compared to placebo for the reduction in severity of epistaxis after 24 weeks of treatment.

Secondary Objectives: To determine the safety and tolerability of pomalidomide for the treatment of HHT; to determine if pomalidomide treatment improves quality of life in HHT; to determine whether a continued response to pomalidomide is evident 4 weeks after treatment discontinuation; to develop a biorepository for future studies to define biomarkers predictive of pomalidomide response and allow investigations into the biology of HHT and mechanisms of pomalidomide.

Arms: arm 1: Oral Pomalidomide will be provided as a capsule at 4 mg/day dose. There will be 6 treatment cycles of 28 days (4 weeks) each. Total treatment phase duration will be 24 weeks. arm 2: A placebo matching the study drug will be provided as a capsule. There will be 6 treatment cycles of 28 days (4 weeks) each. Total treatment phase duration will be 24 weeks.
Interventions: intervention 1: Pomalidomide Oral Product intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Pomalidomide, a third generation derivative of thalidomide, given orally at a starting dose of 4 mg/day for days 1-28 of six 28-day cycles. The dose may be reduced to 3 or 2 mg/day based on specific adverse event (AE) criteria. intervention 2: Matching placebo will be given.

Protocol documents:
ICF_002.pdf: 
PATH
Pomalidornide for
Treatment of Bleeding
the
in HHT
POMALIDOMIDE FOR THE TREATMENT OF
BLEEDING IN HEREDITARY HEMORRHAGIC
TELANGIECTASIA
NCT039 10244
Protocol 133646-2
Part 1 Master Consent
Version 2.9, October 25,2022


CCF IRB #: l8-1098
Approval
Expiration
Date:712612023
Date:7125/2024
Consent to Participate in a Research Study
PART 1: Master Consent
Study Title: 
PATH-HHT: Pomalidomide for the Treatment of Bleeding in Hereditary
Hemorrhagic Telangiectasia (HHT)
IND Sponsor and Grant 
Keith McCrae, MD
Holder:
Funding Source: 
National Heart, Lung, and Blood lnstitute
You ore being invited to take part in a research study. This study is a multi-site study, meaning it
will take ploce at several different locdtions. Because this is a multi-site study this consent form
includes two pdrts, Part 7 of this consent form is the Master Consent and includes information that
applies to all study sites. Part 2 ol the consent form is the Study Site Information ond includes
inlormation specific to the study site where you dre being asked to enroll. Both pdrts together drc
the legal consent form and must be provided to you,
A research study is designed to answer specific questions about new ways to prevent, detect, and
treat disease. Being in a research study is different from being a patient. The purpose of this
document is to provide a written summary of the discussion and exchange of research information
you had with the research team. lt is also for use as a reference during the study.
KEY INFORMATION
The following is a short summary of this research study to help you decide whether or not to be a part
of this research study. More detailed information is included later on in this document.
What should I know about a research study?
o Someone will explain this research study to you.
o You can choose whether or not to take part.
e You can agree to take part and then later change your mind.
o Your decision whether or not to participate will not be held against you.
o You can ask allthe questions you want before you decide.
What is the ouroose. orocedures and duration of this studv?
We invite you to take part in a research study because you have been diagnosed with hereditary
hemorrhagic telangiectasia (HHT). The purpose of this study is to learn whether pomalidomide is
effective as a treatment for HHT.
After ensuring that you are eligible to participate in the study, you will be asked to complete 6 cycles
of pomalidomide treatment. At each of the 6 visits, the severity of your nosebleed will be calculated,
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blood samples will be collected and at severalof the visits you will be asked to complete a
questionnaire about how you feel.
Your participation in the study will last approximately 8 months, though you will be on active
treatment for only 6 months.
Some of the research visits may be conducted remotely, to accommodate for the ongoing COVID-19
pandemic. This means that the study visit may be completed using virtual software applications (such
as facetime, zoom, etc.) or a telephone call. More detailed information can be found under the section
labeled: 'lnformation on the Research'.
Whv misht vou choose not to oarticioate in this research studv?
Pomalidomide has been reported in some individuals to cause muscle cramps, constipation, and a
decrease in red blood cell, white blood cell and platelet counts. Additionally, the effect of
pomalidomide on a fetus is unknown and therefore safety precautions to avoid pregnancy would be
required.
More detailed information can be found under the section labeled: 'Risks'
Why might you choose to volunteer for this studv?
ln a pilot study, pomalidomide was shown to significantly decrease epistaxis and bleeding in patients
with HHT. Personally, you may or may not receive direct benefit from being in this study. However,
your participation in this study will help to obtain new information about developing effective therapy
for HHT.
More detailed information can be found underthe section labeled: 'Benefits'
What are mv other
if I do not take oart in this studv?
o The alternative to being in this study is to not take part.
More detailed information can be found underthe section labeled: 'Alternatives'
DETAILED INFORMATION
1, INFORMATION ON THE RESEARCH
Whv is the research studv beins done?
you are being asked to take part in this research study because you have hereditary hemorrhagic
telangiectasia (HHT) with nosebleeds (epistaxis) and have anemia or require periodic infusions of iron
or blood transfusion. The purpose of this study is to learn whether pomalidomide is safe and effective
as a treatment for HHT. Approximately 159 patients from about 15 sites (all in United States) will
participate in this studY.
CCF IRB #: 18-1098
Date:7/26/2023
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Pomalidomide is currently approved by the FDA for the treatment of refractory and relapsed multiple
myeloma, a disease caused by a type of cell in the bone marrow called plasma cells, which have
become cancerous. lt is not currently approved for treatment of HHT, though a small pilot study has
demonstrated that it has been helpful in reducing the frequency and severity of nosebleeds in HHT
patients. The use of pomalidomide in this study is investigational.
CCF IRB #: 18-1098
Date:7/26/2023
Date:712512024
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Figure 1: Study Design Schematic. After joining the study, you will be screened for your medical and
HHT history, undergo laboratory (iron studies, complete blood count, and complete metabolic panel)
testing, and have severity of your nosebleed calculated using the Epistaxis Severity Score (ESS) with 3-
month recall (i.e. over the previous three months). lf you are found to be eligible, you will be
randomized 2:1to pomalidomide or an identical-appearing placebo. ln addition, you will undergo
genetic testing for mutations in HHT-related genes to determine whether patients with specific
mutations respond better to pomalidomide (genetic testing is optional, and declining to undergo this
will not disqualify you from the study), complete quality of life (QOL) surveys, and ESS with 28 day
recall. you will come for your study visits once every 4 weeks for 24 weeks, which is six 4-week cycles
of therapy. Study drug will be stopped after the 24 week end-of-treatment visit. You will be seen
once more 4 weeks after stopping study drug to find out if you continue to show response 4 weeks
after stopping study drug. You will also record the duration of each nosebleed event during the 4-
week periods between screening and baseline before starting study drug, weeks 8-12 and weeks 20-
24 after starting study drug, and 4 weeks after study drug is stopped.
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What is involved if vou decide to take part in this research studv?
lf you take part in this study, you will be asked to come to the doctor's office or clinic for your visits.
The totaltime in this study will be for a maximum of 8-9 months, and you will be treated with either
pomalidomide or placebo for 6 of those months. A placebo is a pillthat looks exactly like
pomalidomide but does not contain any active ingredients. You will not know whether you are taking
pomalidomide or placebo. However, the study is designed with a 2:1 randomization, meaning that two
of every three patients will receive pomalidomide; i.e., you have a 66.6% chance of being randomized
to receive pomalidomide. After completing therapy, you will be followed for another 4 weeks to see if
your response, if present, continues after study drug is stopped. An outline of the study is shown in
Figure 1.
Screenine (SC)
lf you agree to take part in this study, after you sign this document, you will be asked to begin the
screeningprocesstofindoutifyoumeetallstudyentrycriteria. 
lfappropriate,thescreeningvisit
may be conducted remotely. At the screening visit, all information related to your medical history and
currenthealthstatuswillbecollected. Pleaseletyourstudydoctorknowallofyourpresentandpast
health history, as well as allergies and any medication you are taking, including over-the-counter
medications, vitamins, herbal, homeopathic or holistic. This is important because a possible
interaction of pomalidomide with some medications, vitamins, and remedies may still be unknown.
The procedures below will be performed at the screening visit:
o A detailed physical exam
o Medicaland disease history
o Review of current medications
o An epistaxis severity score (ESS), which will measure the severity of your nosebleeds over the
previous three months.
r 
Blood counts and tests (complete blood count, blood clottingtests, iron studies, serum
chemistries including tests of liver and kidney function)
r 
Pregnancy test for females of child bearing potential in accordance with the REMS schedule
o Blood sample for storage in a biorepository (blood samples will be used to identify blood
markers that predict response to pomalidomide and provide new information about the
mechanisms by which HHT causes bleeding)
o Determine need for intravenous iron therapy based on results of iron studies.
o Provide you with instructions for recording duration of nosebleeds (epistaxis duration)
between screening and the next baseline/randomization visit.
It is recommended that you use an app on your smartphone to record information on your nosebleed
events. This app will securely transfer the information you record directly to the site that coordinates
the data for this study. The study team will help you with set-up and can answer any other questions
or concern regarding use of the phone app. lf you are unable to use the phone app, you will be
provided with a paper diary to record your nosebleed events.
CCF IRB #: 18-1098
Date:7126/2023
Date:7/25/2024
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Randomization (BL)
The randomization visit will be conducted between 28 and 55 days (approximately) after your
screening visit. You will be scheduled for a randomization visit only if you meet allthe study entry
criteria. The randomization will be 2:1, meaning that you will have two chances out of three to
receive the active drug. Neither you, your doctor, nor any of the study personnel will know, or be able
to tell whether you a re receiving poma lidomide or placebo until the end of the study. lf you were to
develop a serious side effect during the study, and if your study doctor thinks it is necessary, we will
find out whether you were taking pomalidomide or placebo. We will then determine if your side
effects could be related to pomalidomide and thereby provide more specific treatment.
At this randomization visit, the following procedures will be performed:
o A phYsical exam
o Review of current medications and other medical events that may have occurred after the
screening visit
o Blood counts and tests (complete blood count, complete metabolic panel, iron studies)
r 
Pregnancy test for females of child bearing potential in accordance with the REMS schedule
o Blood sample (optional) for storage in a biorepository
o Genetic testing to determine whether you have one of the known genetic mutations
associated with HHT. lf you have already had genetic testing performed as part of routine
clinical care, we will not repeat this testing. lf you have previously undergone genetic testing
for HHT and are known to have a mutation in SMAD4 gene, you will not be eligible for the
study unless you have had a colonoscopy with normal (negative) results or no more than 5
small colonic polyps completely removed within the preceding 18 months. However, if you are
enrolled in the study prior to the completion of genetic testing and are later found to have a
SMAD4 mutation, you will be allowed to continue in the study.
o Collection of epistaxis duration diary that records duration of each nosebleed event over the
previous 28 days
o ESS score with a 28-day recall period.
o Quality of life (QOL) questionnaire, which asks questions about your activities and
social/emotional impact due to the severity of your nosebleeds
o Study drug dispensation
Because pomalidomide is regulated by Celgene's POMALYST-REMS (risk evaluation and mitigation
strategies) program, it is important that female study subjects of child bearing potential have two
negative pregnancy tests before drug initiation. The first pregnancy test would be 10-14 days before
study drug order and the second pregnancy test would be within 24 hours before study drug order.
Pregnancy testing must occur weekly during the first four weeks of use. For subsequent treatment
cycles pregnancy testing will occur once every 4 weeks if menses are regular and once every 2 weeks if
menses are irregular.
you will only receive one bottle of study drug that has enough supply for only one cycle of treatment,
which is 28 days (4 weeks). You willtake your assigned treatment (pomalidomide/placebo) at a dose
of 4 mg/day (one capsule), every day with water on an empty stomach. Study drug capsules should be
swallowed whole, and should not be broken, chewed or opened. You should not eat food for at least
2 hours before or after you take study drug. lf you miss a dose of study drug, it should be taken as
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soon as possible on the same day. lf you missed it for the entire day, it should not be made up the
next day. lf you take more than the prescribed dose of study drug, please seek emergency medical
care if needed, and contact study staff immediately.
lf you have any side effects, you should immediately inform your study doctor. Your doctor will
evaluate your symptoms and decide whether it would be appropriate to continue with study drug,
reduce your daily dose, or discontinue study drug. You should not make these decisions by yourself,
as it may not be safe for you to change dosage or stop study drug without consulting with your study
doctor.
You should never share your medication with another person. You need to return all unused
medication to your study doctor at the end of treatment or if you discontinue study medication before
the study ends.
Treatment Visits (C1-C6)
The treatment study visits will occur every 4 weeks, at the end of each cycle. There will be a total of 6
treatment cycles, starting from the baseline visit. Study drug for the next cycle of treatment will be
given during your monthly study visits. For every treatment cycle, female subjects of child bearing
potential must have a negative pregnancy test to receive study drug.
For scheduling convenience, you have a window of up to 5 days after your last study drug dose to
schedule your next visit and get study drug for the next treatment cycle. lt is acceptable to have a gap
(where you do not take study drug) of up to 5 days in between your treatment cycles. This will not
affect your treatment response. lf appropriate, study visits at the end of treatment cycles L, 2,3, 4 and
5 may be conducted remotely. The visit at the end of treatment cycle 5 must be in-person. At each of
the treatment visits (C1-C6), you will be asked to bring the bottles (even if they are empty) so that
your study nurse/coordinator can count the pills and record your drug intake. ln case of remote visits,
you will be instructed to bring the bottles at the next in-person visit. Alternatively, your study
nurse/coordinator may request you to ship the empty bottle/bottle with remaining study drug to the
study site.
The following procedures will be performed at each treatment visit:
r 
Limited physical exam (Detailed physical exam at end of cycles 3 and 6)
o Review of current medications and other medical events that may have occurred since the
previous study visit
o Blood counts and tests
o Pregnancy test for females of child bearing potential in accordance with the REMS schedule
o ESS score with 28-day recall
o Blood sample (optional) for storage in a biorepository (end of cycles 3 and 5 only)
o Quality of life questionnaire (end of cycles 3 and 6 only)
. 
Collection of epistaxis duration diary (end of cycles 3 and 6 only)
r 
Study drug return and dispensation (no more study drug will be given at the end of cycle 6
visit, which marks completion of all 5 treatment cycles)
CCF IRB #: l8-1098
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DaIe:7125/2024
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End of studv visit (Eos)
The last study visit will be 4 weeks after completing the 6th treatment cycle visit (C6) and this may also
be completed remotely. The main reason for this visit is to monitor your nosebleeds and determine
whether the effects of pomalidomide on your nosebleeds continues even after the drug is stopped.
The following procedures will be performed:
o A detailed physical exam
o Review of current medications and other medical events that may have occurred since the last
study visit
o Blood counts and tests
o Blood sample (optional) for storage in a biorepository
o ESS score with a 4-week recall
o Quality of life questionnaires
r 
Collection of epistaxis duration diary
Studv Drus Discontinuation and Earlv Termination Visit (ET)
lf there are any safety concerns your study doctor may ask you to temporarily stop study medication;
when it is found to be safe you may be asked to restart study drug. You will continue with study visits
on the same schedule even when you are not taking study medication.
lf you have been asked to permanently stop taking study drug for safety reasons or if you choose to
stop due to personal reasons, you will be asked to complete the study visit associated with your
current treatment cycle and come in for one last study visit (EOS visit as described above) 4 weeks
later.
lf you choose to withdraw consent from study participation prior to completion, study drug will be
stopped and you will be asked to come in for an early termination visit and return all unused study
drug at this visit. ln addition, the following procedures will be performed:
r 
A detailed physical exam
o Review of current medications and other medical events that may have occurred
o Blood counts and tests
o Pregnancy test for females of child bearing potential if study medication was taken after the
last pregnancytest that was performed
o Blood sample (optional) for storage in a biorepository
o ESS score with 28-day recall
o Quality of life questionnaires
o Collection of epistaxis duration diary if dispensed for the previous visit
Restricted Med ications
While you are participating in this research study, you will not be able to take certain medications,
such as:
a
Octreotide (Sandostatin)
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o Bevacizumab (Avastin) or within six weeks prior to starting the study
o Pazopanib (Votrient) or within six weeks prior to starting the study
o You may not initiate treatment with epsilon aminocaproic acid (Amicar) or tranexamic acid
(cyclokapron) during the study. However, if you were taking one of these drugs at the time of
screening you may continue to take it at the same dose during the study but may not change
the dose during pomalidomide treatment.
o You may not initiate treatment with nasal sprays of epsilon aminocaproic acid (Amicar),
tranexamic acid (cyclokapron) or timolol (blocadren) or propanolol (lnderal). However, if you
were taking either of these drugs at the time of screening you may continue to take the drug
during the study but may not change the dose during pomalidomide treatment.
r 
Erythropoetic agents may increase the risk of blood clots and should be avoided.
r 
Certain drugs such as ciprofloxacin may increase pomalidomide levels and should be avoided.
Fluvoxamine, and fluvoxamine with ketoconazole taken together with pomalidomide may
increase levels of pomalidomide and should be avoided.
o Certain drugs such as carbamazepine may cause your body to break down pomalidomide
more quickly and thus reduce its therapeutic effect and should not be taken during this study.
o Oral contraceptives which contain combination of estrogens and/or progestins may affect the
activity of HHT and also increase thrombotic risk and should be avoided. A Mirena IUD has
minimalthrombotic risk and is acceptable.
o Nasal estriol is allowed if you were using this agent before starting the study and do not
change the dose during the study. You may not initiate treatment with nasal estriol during
the study.
Your doctor and research nurse will review all your medications with you before you start the study.
Please ask your nurse or doctor if you are concerned about any medication you are currently taking
before you start the study.
Genetic Testing
Blood or saliva samples to test whether there are alterations in the HHT-related genes are requested
This would be a one-time sample collection at the Randomization (BL) visit. lt is not mandatory to
undergo genetic testing to participate in this study although the results of this testing may assist in
predicting which patients will respond to pomalidomide in the future'
lf you have had prior genetic testing for the three well-established HHT genes (ENG, ACVRL1 and
SMAD4) and if those results would be made available for this study, we will not need any further
samples for genetic testing. lf you have not had genetic testing and agree to provide samples, genetic
testing will be performed at Ambry Genetics using the HHTNEXT panel that includes ENG, ACVRL1 and
SMAD4 as well as 3 additional genes (EPHB4, GDF2, and RASAI)that may also be related to HHT.
Results of the genetic tests will be shared with you. There is no additional cost for testing six genes
rather than the standard three genes given that the HHTNEXT panel is designed to assess all six of the
genes.
Since genetic testing may help to identify certain individuals with a higher likelihood of responding to
pomalidomide in the future, we encourage all study participants to provide samples for genetic
testing, though this is not required for participation in the study. Please checkthe appropriate box
below if you are willing (or not willing) to provide samples for genetic testing.
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E Yes, I agree to provide samples
! No, I do not agree to provide samples
Biorepositorv
We request biorepository blood samples from all patients as part of this research study; however,
contribution of biorepository samples is not required for participation in this study. Samples will be
drawn at the same time as required study labs and will not require an additional blood draw. Samples
will be sent to the laboratory of Dr. Keith McCrae, the lead Principal lnvestigator (Pl) for this study,
where they will be stored in a locked -80'freezer. Patient names will be removed from all tubes and
they will be given a unique study lD and barcode. Samples will be used to:
1) determine whether any substances in blood or blood cells predict or correlate with responses
to pomalidomide.
2) better define abnormalities in the blood that may contribute to the symptoms of HHT.
Upon written request and review by the lead Pl, portions of some of these samples may be shared
anonymously with qualified HHT investigators who wish to explore new pathways to HHT therapy.
Providing samples for the biorepository and future research is therefore very valuable to finding out
how pomalidomide works to treat HHT and understanding HHT in general. Therefore, we encourage
all study participants to donate blood for these studies at the specified times, though this is not
required for participation in the study. Please check the appropriate box below if you are willing (or
not willing) to provide blood samples for the biorepository.
tr Yes, I agree to provide samples
! No, I do not agree to provide samples
Can I stop providing samples for the biorepository?
lf you agreed to provide samples and change your mind, you may stop providing samples for the
biorepository at any time. You can stop providing samples by contacting your study team contact
listed in part 2 of this consent.
Can I withdraw my samples?
lf you change your mind and do not want us to store and use your specimens for future research,
you should contact the study team contact listed in Part 2 of this document. We will do our best to
comply with your request but cannot guarantee that we will always be able to destroy your
specimens and data. For example, if some research with your specimens and data has already been
completed, the information from that research may still be used. Also, if the specimens have been
shared already with other researchers, it might not be possible to withdraw them.
ln addition to the planned use and sharing described above, we might remove all identifiers and codes
from your specimens and use or share them with other researchers for future research at the NIH or
other places. When we or the other researchers access your anonymized specimens, there will be no
way to link the specimens back to you. We will not contact you to ask your permission or otherwise
inform you before we do this. lf we do this, we would not be able to remove your specimens to
prevent their use in future research studies, even if you asked, because we will not be able to tell
which are your specimens.
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ALTERNATIVES
What are the alternatives to participation in the research study?
lf you do not wish to participate in this study, the following alternative treatments are available:
r 
Getting treatment or care for your HHT without being in this study
o Getting no treatment for your HHT
o Participating in another HHT clinicaltrial, if available
at arc the risks of nartici ati
in the resea rrh studv?
n
nt
Pomalidomide has been studied in healthy volunteers and in subjects with cancer of the blood and
other organs of the body as wellas in subjects with other diseases. There is always a risk involved in
taking any drugs, but you will be carefully monitored for all problems and you should report any
symptoms you experience even if you do not think it is related to the study drug. As with any other
experimentaltreatment there may be side effects or risks that are unknown or cannot be predicted at
this time. Should you have any questions at any time you should contact the study doctor.
The following is a list of the most serious side effects that have been listed by Celgene (the
pharmaceutical company who makes the drug) to be possibly related to pomalidomide. This is not a
complete list of all side effects that may occur. For more information about risks and side effects,
please ask your study doctor. The study doctor may give you medicines to help lessen the side effects.
Some side effects go away soon after you stop the study drug. ln some cases, side effects can be
serious, can last a long time, and could even be life-threatening. Everyone taking part in the study will
be watched carefully for any side effects and you should report any changes to your health or in the
way you feel to your study doctor.
Almost all of these effects have been seen in patients with multiple myeloma, a type of bone marrow
cancer, for which the use of pomalidomide is approved by the FDA. Patients with multiple myeloma
have usually been treated with chemotherapy before taking pomalidomide, and therefore may have
compromised bone marrow function (ability to produce blood cells) before pomalidomide treatment.
Moreover, these side effects relating to blood cell counts (platelets, red blood cells, and white blood
cells) have been reported in previous myeloma clinical trials, and in many cases may be associated
with multiple myeloma itself rather than pomalidomide treatment. Therefore, it is hard to estimate
the frequency of blood cell related side effects in patients with HHT who have a healthy bone marrow,
but it is likely that they are less common.
Very Common events (>10):
o muscle cramps
o tiredness
o swelling including arms and legs,
. 
a decrease in platelets, the cells that help your blood to clot and could lead to bleeding
o changes in bowel habits, particularly constipation
. 
a decrease in red blood cells (the cells carrying oxygen to your body)that can lead to fatigue
o decreased appetite
o a low number of white blood cells that could result in infection such pneumonia
CCF IRB #; 18-1098
Date:7/26/2023
Date:7/25/2024
Wh
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CCF IRB #: 18-1098
Approval D ate: 7 I 26 I 2023
Expiration Date: 7 125 /2024
. 
rash and itching
Common (l-<1,0o/o):
o infection
o dizziness
o vomiting
. 
sore throat
r 
changes in sensation such as numbness ortingling in your hands orfeet (neuropathy)
o blood clots in legs or lungs
o difficulty in passing urine
Other lmoortant Side Effects
Cancers (including acute myeloid leukemia IAML], cancer of the adrenalgland, cancer of the
urinary bladder, kidney cancer, myelodysplastic syndrome [MDS], skin cancer, and thyroid
cancer) have occurred in patients taking pomalidomide for multiple myeloma, but their
association with the pomalidomide is uncertain.
lnflammation of your lungs.
lf you have any questions or if you do not understand any of the side effects, please ask your study
doctor.
Additional lmportant Precautions
o We do not know if pomalidomide has any effect on you being able to have a child in the
future. Please speak with your doctor about family planning options for the future.
r 
You must agree to abstain from donating blood or sperm while taking study drug (even if you
temporarily stop your medication) and for at least 4 weeks after the last dose.
o No one other than you should handle the study drug capsules. This is especially important for
females who are able to become pregnant and males who are able to father a child.
Pregnancy Risks
Pomalidomide is related to thalidomide. Thalidomide is known to cause human birth defects.
Pomalidomide is therefore considered to have the potential to cause birth defects in humans.
lf you are capable of giving birth to or fathering a child, you and your sexual partner should use
adequate birth control measures while you are in the study. These measures may include abstinence,
lUD, diaphragm, condoms, cervical cap or documentation of medical sterilization. Oral contraceptives
that are estrogen/progestin based, are not an acceptable contraceptive method for this study because
they may have a treatment effect on HHT and confound the research study. Discuss with your study
doctor which birth control measures are acceptable.
Females must not become pregnant while taking pomalidomide. ln order to participate in this study
you must register into and follow the requirements of the POMALYST REMS'" program of Celgene
Corporation. This program provides education and counseling on the risks of fetal exposure, blood
clots and reduced blood counts. You will receive counseling which will be given by both your study
doctor and a REMS certified pharmacist before receiving drug at every treatment cycle. You must also
follow the pregnancy testing and birth control requirements of the program that are appropriate for
a
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you and take surveys regarding your compliance with the POMALYST REMS'" program. Two
pregnancy tests will be required for females with the potentialto become pregnant before initiating
pomalidomide therapy, The first test will be 10-14 days before and the second test will be within 24
hours before study drug order. Pregnancy testing in females of child bearing potential must also occur
weekly during the first four weeks of use. For subsequent treatment cycles, in females of child
bearing potential with regular menses, pregnancy tests will need to be repeated once every four
weeks, in between cycles of pomalidomide therapy. For women with irregular menses, pregnancy
tests will be conducted twice each treatment cycle.
lf you are unwilling to do this, we ask that you not participate in this study. lf you or your partner
become pregnant while taking part in this study you must notify the study doctor immediately.
Risks of Genetic Research
Your medical and genetic information is unique to you. There is a risk that someone outside of the
research study could get access to your study records or trace information in a database back to you.
They could use that information in a way that could harm you. While the chance that someone could
access and misuse your information is believed to currently be very small, it is possible that the risk
may increase in the future as people find new ways to access information.
The Genetic lnformation Nondiscrimination Act (GINA) is a federal law designated to protect you from
health insurance and employment discrimination based on genetic information. lt is illegalfor health
insurance providers and most employers to ask for genetic information to make decisions about a
person's eligibility or coverage or to make employment decisions. The law will not stop health
insurance companies from using genetic information to decide whether to pay claims and also does
not applyto life insurance, disability insurance or long-term care insurance.
The tests performed as part of this study will be specific for genes that are known to be related to
HHT. lf required and if you agree, there will be a total of 6 genes that are going to be tested in this
study: ENG, ACVRLI, SMAD4, EPH84, GDF2, and RASA1. Results from the genetic test will be provided
to you. lrrespective of whether you have a positive or negative result from the genetic testing, in
accordance with GINA, results from the genetic tests will not be shared with your health insurance
providers, employers or any other external agency. Samples collected for genetic testing will not be
shared with anyone else and will not be used for any research purpose otherthan what has been
stated above.
Risks of B
The insertion of the needle to draw blood can be painful; however, the discomfort is brief. For most
people, needle punctures to get blood samples do not cause any serious problem; however they may
cause bleeding, bruising, discomfort, infections, dizziness, or fainting.
ConfidentialiW Risks
There is a potential risk of loss of confidentiality of your data. Every effort will be made to keep your
information confidential, through the use of the following safeguards:
CCF IRB #: l8-1098
Date:7/26/2023
Date:712512024
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CCF IRB #: 18-1098
Approval Date: 7 /26 /2023
Expiration D ate'. 7 / 25 /2024
lnformation collected about you will be stored in a password protected database at the data
coordinating center (Research Triangle lnstitute) that is accessible only by the research team.
The database is 21CFR part 11 compliant, meaning it meets allthe regulatory and safety
standards recommended by the FDA.
lf you decide to be in this study, the study team will obtain information that identifies you and your
personal health information. This may include information that might directly identify you, such as
your name and address. This information will be kept for the length of the study. After that time it will
be destroyed or de-identified, meaning we will replace your identifying information with a code that
does not directly identify you.
Unknown Risks
There may be risks or side effects related to the study drug that are unknown at this time. You will be
notified of any significant new findings that become known that may affect your willingness to
continue in the study.
RESEARCH BENEFITS
What are possible benefits of participating in the research?
You may or may not benefit from participating in this study since we cannot predict whether
pomalidomide will reduce your bleeding. Your participation in this study may aid our understanding
of and lead to new treatments for HHT.
RESEARCH COSTS
Are there any costs to you if you participate in this study?
Study drug will be provided to you at no cost while you are participating on this study. Some of the
services you will receive during this research study are considered to be conventional routine clinical
servicesthatyouwouldhavereceivedevenifyouwerenotparticipatingintheresearchstudy. Youor
your insurance company will be responsible for payment of any standard of care tests or procedures
that would normally be part of the treatment of your hereditary hemorrhagic telangiectasia, such as
blood counts, serum chemistries that measure kidney and liver function and iron studies. The study
will pay for all other non-standard of care treatments and procedures including any research sample
collections, and the exam on research visits.
Genetic Testing
lf you have not been previously genetically tested for HHT, genetic testing of HHT-related genes will
be performed by Ambry Genetics (Aliso Viejo, CA). lf you have non-federal insurance, your primary
insurance will be billed for cost of the genetic tests. For patients who are covered by a government-
funded insurance plan, the HHTNEXT panel will be performed at Ambry Genetics with costs covered
by the study and your insurance will not be billed.
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The costs of genetic testing is usually covered by private insurers. However, if the insurer refuses to
cover these costs, or if you have federal insurance coverage such as Medicare, the study will cover the
costs of genetic testing.
Are there any payments to you if you participate in this study?
You will receive a stipend of 510.00 for each completed study visit to help cover some of your travel
costs. There are a total of 9 visits for this study (Screening, Randomization, 6 Treatment visits and a
final end of study visit). Therefore, you would get a total of 590.00 for the entire study if you complete
all 9 study visits.
Whet 2ro lr.rl rr riohfq ac a research narfirinant?
Taking part in this study is voluntary. You will be told of any new, relevant information from the
research that may affect your health, welfare, or willingness to continue in this study. You may
choose not to take part or may leave the study at any time. Withdrawing from the study will not
result in any penalty or loss of benefits to which you are entitled. Leaving the study at any time will
not affect your regular treatment or medical care. lf you wish to withdraw, you should notify your
study doctor that you no longer want to participate in this study. ln addition, your study doctor may
decide to end your participation in this study at any time after he/she has explained the reasons for
doing so and has helped arrange for your continued care by your own doctor, if needed.
US National lnstitutes of Health (NlH) Clinical Trial Database
A description of this clinicaltrialwill be available on https://www.ClinicalTrials.eov, as required by U.S.
Law. This website will not include information that can identify you. At most, the website will include a
summary of the results. You can search this website at any time.
Please refer to the clinicaltrial registration number NCI03910244 to get more information about this
research study.
Confidentialitv
at will hannen
VO
information that is collected for this research?
to
ur
Cleveland Clinic may share your study information, without anyone knowing that it is related to you
specifically, with others or use it for research projects not listed in this form. Your blood samples or
data may be stored and shared for future research without additional informed consent if identifiable
private information, such as your name and medical record number, are removed. lf your identifying
information is removed from your blood samples or data, we will no longer be able to identify and
destroy them.
Study results may be shared in medicaljournals, at scientific meetings, and in other mediums without
your identifying information. Your records will be confidential and your identity will not be shared in
medicaljournals, at scientific meetings, and in other mediums without your express consent.
CCF IRB #: 18-1098
Date:7/2612023
DaIe:7/25/2024
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CCF IRB #: 18-1098
Approval Date: 7 126 /2023
Expiration Date: 7 125 /2024
POMALYST REMS PTogTam
Pomalidomide has to be dispensed in accordance with the POMALYST REMS program, All recipients of
pomalidomide will have to be registered in Celgene's POMLAYST REMS program and will be counseled
by a REMS-certified pharmacist on the risks of fetal exposure, blood clots and reduced blood counts.
Therefore, to be compliant with the mandatory REMS program, we will need to provide your contact
information to Celgene and their pharmacists.
Certificate of Confidentia I iW
This research is covered by a Certificate of Confidentiality from the National lnstitutes of Health. This
means that the researchers cannot release or use information, documents, or samples that may
identify you in any action or suit unless you say it is okay. They also cannot provide them as evidence
unless you have agreed. This protection includes federal, state, or local civil, criminal, administrative,
legislative, or other proceedings. An example would be a court subpoena'
There are some important things that you need to know. The Certificate DOES NOT stop reporting
that federal, state or local laws require. Some examples are laws that require reporting of child or
elder abuse, some communicable diseases, and threats to harm yourself or others. The Certificate
CANNOT BE USED to stop a sponsoring United States federal or state government agency from
checking records or evaluating programs. The Certificate DOES NOT stop disclosures required by the
federal Food and Drug Administration (FDA). The Certificate also DOES NOT prevent your information
from being used for other research if allowed by federal regulations.
Researchers may release information about you when you say it is okay. For example, you may give
them permission to release information to insurers, medical providers or any other persons not
connected with the research. The Certificate of Confidentiality does not stop you from willingly
releasing information about your involvement in this research. lt also does not prevent you from
having access to your own information.
lf you have any questions about what this notice means and would like to speak to someone, you may
callyour studyteam listed in the contact section in Part 2 of this form orthe Cleveland Clinic
lnstitutionalReview Board (216-2144-29241.|f you would like to read more about Certificate of
Confidentiality, the NIH has a website you can visit online at:
https://era nts. nih.sov/policv/h uma nsu biects/coc. htm '
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Prot_004.pdf: 
POMALIDOMIDE FOR THE TREATMENT OF 
BLEEDING IN HEREDITARY HEMORRHAGIC 
TELANGIECTASIA
NCT03910244
Protocol 133646-2
Version 2.10, September 30, 2022


POMALIDOMIDE FOR THE TREATMENT 
OF BLEEDING IN HEREDITARY 
HEMORRHAGIC TELANGIECTASIA
Protocol Identifying Number:   
133646-2 
IND Number:   
 
 
 
133646
Study Phase:  
 
 
 
2 
Amendment:  
 
 
 
11 
Principal Investigator/IND Sponsor:  Keith R. McCrae, M.D. 
Funded by:  
 
 
 
 
NIH/NHLBI 
Version Number:  
 
 
 
2.10
Version Date:  
 
 
 
September 30, 2022 


 
ii 
 
Table of Contents 
Table of Contents .......................................................................................................................ii 
LIST OF ABBREVIATIONS............................................................................................................. 1 
STATEMENT OF COMPLIANCE ..................................................................................................... 3 
PROTOCOL SIGNATURE PAGE ..................................................................................................... 4 
PROTOCOL SUMMARY ............................................................................................................... 5 
SCHEMATIC OF STUDY DESIGN.................................................................................................... 7 
1 
KEY ROLES .......................................................................................................................... 8 
2  INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE.............................. 9 
2.1 Background Information .................................................................................................. 9 
2.2 Rationale......................................................................................................................12 
2.3 Potential Risks and Benefits ............................................................................................13 
2.3.1 
Known Potential Risks .........................................................................................13 
2.3.2 
Known Potential Benefits ....................................................................................14 
3 
OBJECTIVES AND PURPOSE ..................................................................................................14 
3.1 Primary Objective ..........................................................................................................14 
3.2 Secondary Objectives .....................................................................................................14 
4 
STUDY DESIGN AND ENDPOINTS ..........................................................................................14 
4.1 Description of the Study Design .......................................................................................14 
4.2.1 
Primary Endpoint ...............................................................................................15 
4.2.2 
Secondary Endpoints ..........................................................................................15 
4.2.3 
Exploratory Endpoints.........................................................................................16 
5 
STUDY ENROLLMENT AND WITHDRAWAL..............................................................................17 
5.1 Participant Inclusion Criteria ...........................................................................................17 
5.2 Participant Exclusion Criteria ...........................................................................................17 
5.3 Strategies for Recruitment and Retention .........................................................................18 
5.4 Participant Withdrawal or Termination .............................................................................18 
5.4.1 
Withdrawal or Termination of Subjects from the Study ............................................19 
5.4.2 
Handling of Participant Withdrawals or Termination ...............................................19 
5.5 Premature Termination or Suspension of Study .................................................................19 
6 
STUDY AGENT ....................................................................................................................19 
6.1 Study Agent(s) and Control Description.............................................................................19 
6.1.1 
Acquisition ........................................................................................................19 
6.1.2 
Formulation, Appearance, Packaging and Labeling ..................................................20 
6.1.3 
Product Storage and Stability ...............................................................................20 
6.1.4 
Preparation .......................................................................................................20 
6.1.5 
Dosing and Administration...................................................................................20 
6.1.6 
Route of Administration ......................................................................................21 
6.1.7 
Dosing Schedule.................................................................................................21 
6.1.8 
Dose Adjustments/Modifications/Delays ...............................................................21 
6.1.9 
Duration of Therapy ...........................................................................................25 
6.1.10 Tracking of Dose ................................................................................................25 
6.1.11 Drug/Device Specific Considerations .....................................................................25 


 
iii 
 
6.2 Study Agent Accountability Procedures.............................................................................25 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................................26 
7.1 Study Procedures/Evaluations .........................................................................................26 
7.1.1 
Study Specific Procedures....................................................................................26 
7.1.2 
Standard of Care Study Procedures .......................................................................29 
7.2 Laboratory Procedures/Evaluations..................................................................................29 
7.2.1 
Clinical Laboratory Evaluations .............................................................................29 
7.2.2 
Other Assays or Procedures .................................................................................30 
7.2.3 
Specimen Preparation, Handling, and Storage ........................................................31 
7.2.4 
Specimen Shipment ............................................................................................31 
7.3 Study Schedule..............................................................................................................31 
7.3.1 
Screening ..........................................................................................................31 
7.3.2 
Baseline/Randomization......................................................................................32 
7.3.3 
Treatment Follow-up ..........................................................................................33 
7.3.4 
Final Study Visit..................................................................................................33 
7.3.5 
Discontinuation of Study Medication.....................................................................34 
7.3.6 
Early Termination Visit ........................................................................................34 
7.3.7 
Table 4: Schedule of Events Table .........................................................................35 
7.4 Justification for Sensitive Procedures................................................................................37 
7.5 Concomitant Medications, Treatments, and Procedures......................................................37 
7.5.1 
Precautionary Medications, Treatments, and Procedures .........................................37 
7.6 Prohibited Medications, Treatments, and Procedures .........................................................37 
7.7 Prophylactic Medications, Treatments, and Procedures ......................................................38 
7.8 Rescue Medications, Treatments, and Procedures..............................................................38 
7.9 Participant Access to Study Agent At Study Closure ............................................................38 
8 
ASSESSMENT OF SAFETY......................................................................................................38 
8.1 Specification of Safety Parameters ...................................................................................38 
8.1.1 
Definition of Adverse Events ................................................................................39 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................39 
8.1.3 
Definition of Unanticipated Problems (UP) .............................................................39 
8.2 Classification of an Adverse Event ....................................................................................40 
8.2.1 
Severity of Event ................................................................................................40 
8.2.2 
Relationship to Study Agent .................................................................................40 
8.2.3 
Expectedness.....................................................................................................41 
8.3 Time Period and Frequency for Event Assessment and Follow-Up.........................................41 
8.4 Reporting Procedures.....................................................................................................42 
8.4.1 
Non-serious Adverse Event Reporting ...................................................................42 
8.4.2 
Serious Adverse Event Reporting ..........................................................................42 
8.4.3 
Unanticipated Problem Reporting.........................................................................43 
8.4.4 
Events of Special Interest ....................................................................................43 
8.4.5 
Reporting of Pregnancy .......................................................................................43 
8.5 Study Halting Rules ........................................................................................................45 


 
iv 
 
8.6 Safety Oversight ............................................................................................................45 
9 
CLINICAL MONITORING .......................................................................................................45 
10 STATISTICAL CONSIDERATIONS ............................................................................................46 
10.1 Statistical and Analytical Plans .......................................................................................46 
10.2 Statistical Hypotheses ...................................................................................................46 
10.3 Analysis Datasets .........................................................................................................47 
10.4 Description of Statistical Methods ..................................................................................48 
10.4.1 General Approach ..............................................................................................48 
10.4.2 Analysis of the Primary Efficacy Endpoint(s) ...........................................................48 
10.4.3 Analysis of the Secondary Endpoint(s) ...................................................................49 
10.4.4 Safety Analyses ..................................................................................................49 
10.4.5 Adherence and Retention Analyses .......................................................................50 
10.4.6  Baseline Descriptive Statistics ..............................................................................50 
10.4.7 Planned Interim Analyses ....................................................................................50 
10.4.8  Additional Sub-Group Analyses............................................................................52 
10.4.9  Multiple Comparison/Multiplicity ........................................................................52 
10.4.10 Tabulation of Individual Response Data .................................................................53 
10.4.11 Exploratory Analyses...........................................................................................53 
10.5 Sample Size .................................................................................................................53 
10.6 Measures to Minimize Bias ............................................................................................57 
10.6.1 Enrollment/ Randomization/ Masking Procedures...................................................57 
10.6.2 Evaluation of Success of Blinding ..........................................................................57 
10.6.3 Breaking the Study Blind/Participant Code .............................................................57 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ........................................57 
12 QUALITY ASSURANCE AND QUALITY CONTROL ......................................................................58 
13 ETHICS/PROTECTION OF HUMAN SUBJECTS...........................................................................60 
13.1 Ethical Standard ...........................................................................................................60 
13.2 Institutional Review Board.............................................................................................60 
13.3 Informed Consent Process .............................................................................................60 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants............60 
13.3.2 Consent Procedures and Documentation ...............................................................61 
13.4 Participant and data Confidentiality ................................................................................61 
13.4.1 Research Use of Stored Human Samples,Specimens or Data .....................................61 
13.5 Future Use of Stored Specimens .....................................................................................61 
14 DATA HANDLING AND RECORD KEEPING ...............................................................................61 
14.1 Data Collection and Management Responsibilities ............................................................61 
14.2 Study Records Retention ...............................................................................................62 
14.3 Protocol Deviations ......................................................................................................62 
14.4 Publication and Data Sharing Policy ................................................................................62 
15 STUDY ADMINISTRATION ....................................................................................................65 
15.1 Study Leadership..........................................................................................................65 
16 CONFLICT OF INTEREST POLICY.............................................................................................67 


 
v 
 
17  LITERATURE REFERENCES ....................................................................................................67 
APPENDIX 1 .............................................................................................................................71 
HHT-specific QOL Questionnaire ...........................................................................................71 
 
 
 


 
vi 
 
Version 
Date 
Significant Revisions  
1.0 
February 05, 2018 
 
2.0 
April 05, 2019 
Added epistaxis duration as a key secondary endpoint; 
Clarified study drug dispensation to study sites; Updated 
SAE reporting requirements per guidelines of NHLBI, FDA 
and Cleveland Clinic IRB.  
2.1 
June 23, 2019 
Minor revisions to inclusion criteria language to make it 
concise and avoid repetition; included INR and aPTT tests at 
Screening; Clarified need for CBC with differential at study 
visits; corrected pregnancy testing frequency and 
requirements per REMS mandate; added PAX tube to 
biospecimen collection.  
2.2 
August 19, 2019 
The major change is shifting the genetic testing schedule 
from Screening visit to Randomization/Baseline visit. Other 
minor changes include correcting the monthly pregnancy 
testing schedule as mandated by the Pomalyst REMS 
guidelines and correcting the incorrect number of grade 3 
AEs for halting study drug administration.  
2.3  
May 21, 2020 
The major change to the protocol is to provide flexibility to 
extend the screening period as needed and conduct some 
of the research visits remotely.  
2.4 
August 17, 2020 
The major change to the protocol is to refine the 
inclusion/exclusion criteria and  provide clarifications to a) 
reporting AE severity levels and pregnancy (if it occurs 
during the study); b) handling missed dose and missed 
study visits; and c) use of prohibitive medications.  
2.5 
November 09, 2020 
The major changes made to the protocol were to modify 
the eligibility criteria to allow a) upto 2 sec deviation from 
normal aPTT; b) exclude only those with prior history of 
unprovoked thromboembolism; and c) allow those with 
Gilbert syndrome who typically have greater bilirubin. In 
addition, clarity has been provided for recommended 
follow-up visits after permanent discontinuation of study 
drug. 
2.6 
December 01, 2020 
The major change to the protocol is to allow study 
participants with Grade 3 neutropenia to continue on study 
drug for a week  if their  ANC>800 x 106/L. 
2.7 
February 15, 2021 
The major change to the protocol is to modify the study 
halting rules by only including grade 3 non-neutropenia 
cases. A few inclusion criteria were modified to increase 
pool of potential patients and to eliminate inconsistencies 
within protocol. Remote options have been provided to 
additional study visits: EOS and C3.    


 
vii 
 
Version 
Date 
Significant Revisions  
2.8 
August 02, 2021 
The  major change to the protocol is to reduce the follow-
up period post-treatment completion or post-treatment 
discontinuation from 12 weeks to 4 weeks. Other changes 
include increase in number of sites to 15, update to 
exclusion criterion 14, clarification regarding ET / EOS visits 
and visit assessments, update to biorepository sample 
timepoints 
with RNA tube, clarification regarding 
worsening epistaxis not to be reported as an AE, update to 
contraceptive methods, addition of non-leukopenia to 
halting rules. 
2.9 
April 12, 2022 
Study stopping rule was modified to be as follows: 
randomization of new participants will be halted when 
eight thromboembolic events, defined as any venous 
thromboembolic event requiring medical intervention 
(grade 2 or higher) or any arterial thromboembolic event, 
determined to be related or “probably related” to the study 
drug have been reported.  Other changes include updates, 
clarifications 
to 
exclusion 
criteria and 
prohibited 
medications regarding oral estrogens and progestins, use of 
hemoglobin for anemia determination, aPTT or PTT per 
local laboratory designation, genetic testing and study drug 
dose adjustment / discontinuation for hematologic toxicity 
and peripheral neuropathy. 
2.10 
September 30, 2022 
Satisfaction with Social Roles and Activities was updated 
from the PROMIS to the Neuro-QOL to match the form on 
the eCRF, an additional Other Secondary Outcome was 
added for Change in iron/hemoglobin-related studies 
including iron saturation, ferritin, hemoglobin, hematocrit, 
MCV, and MCHC, the planned statistical methods for 
secondary efficacy outcomes amount of blood transfusions 
and amount of parenteral iron infusions was clarified, 
scoring of the HHT-QOL total score was clarified. 


Protocol 133646-2:  PATH-HHT -  Pomalidomide for the Treatment of Bleeding in HHT 
 
 
Version 2.10; 30 September 2022 
NIH-FDA Clinical Trial Protocol Template v0.1 20160205 
1 
LIST OF ABBREVIATIONS 
 
ACVRL1 
Activin A Receptor Like Type 1 Gene 
ADL 
Activities of Daily Living 
AE 
Adverse Events 
ALT 
Alanine Amino Transferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Amino Transferase 
AVM 
Arteriovenous Malformations 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CCC 
Clinical Coordinating Center 
CMP 
Complete Metabolic Panel 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for 
Adverse Events 
DCC 
Data Coordinating Center 
DSMB 
Data Safety and Monitoring Board 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylene Diamine Tetra Acetic Acid 
EMR 
Electronic Medical Record 
ENG 
Endoglin Gene 
ESS 
Epistaxis Severity Scale 
FCBP 
Female of Child Bearing Potential 
FDA 
US Food and Drug Administration 
FGF 
Fibroblast Growth Factor 
GCP 
Good Clinical Practice 
GDF2 
Growth Differentiation Factor 2 
GI 
Gastrointestinal 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HHT 
Hereditary Hemorrhagic Telangiectasia 
ICH 
International Conference on 
Harmonization 
IMiD 
Immunomodulatory imide Drugs 
IMM 
Independent Medical Monitor 


Protocol 133646-2:  PATH-HHT -  Pomalidomide for the Treatment of Bleeding in HHT 
 
 
Version 2.10; 30 September 2022 
NIH-FDA Clinical Trial Protocol Template v0.1 20160205 
2 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat  
LLN 
Lower Limit of Normal 
NCI 
National Cancer Institute 
Neuro-QOL 
Quality of Life in Neurological Disorders 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH 
National Institute of Health 
PI 
Principal Investigator 
PROMIS 
Patient Reported Outcomes 
Measurement Information System 
PTT 
Partial Thromboplastin Time 
QOL 
Quality of life 
RASA1 
RAS p21 Protein Activator 
REMS 
Risk Evaluation and Mitigation Strategies 
SAE 
Seious Adverse Events 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SMAD4 
SMAD Family Member 4 
TIBC 
Total Iron Binding Capacity 
UP 
Unanticipated Problems 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Count 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the NHLBI Terms of Award, Code of Regulations on the 
Protection of Human Subjects (21 CFR Part 50), Institutional Review Board (21 CFR Part 56),  Standards 
of Good Clinical Practice, as defined by the International Conference on Harmonization (ICH E6) and 
all applicable regulatory requirements.  The CCC and DCC Principal Investigators assure that no 
deviation from, or changes to the protocol will take place without prior agreement and documented 
regulatory approval, except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All key personnel involved in the conduct of this study will complete both Human 
Subjects Protection and Study Related trainings. 
We agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
 
Lead Principal Investigator:  
 
____Keith R McCrae, M.D.___ 
Print/Type Name 
 
 
 
Signed: _____________________________________ Date: ______________________ 
Signature  
 
DCC Principal Investigator:  
 
____Sonia Thomas, DrPH___ 
Print/Type Name 
 
 
 
Signed: _____________________________________ Date: ______________________ 
Signature  
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol 133646-2 
The signature below constitutes the agreement to conduct the study as described in the protocol, and 
provides the necessary assurances that this trial will be conducted in accordance with all stipulations 
of this protocol including, without limitation, all statements regarding confidentiality, the Code of 
Federal Regulations on the Protection of Human Subjects (21 CFR Part 50), Institutional Review Board 
(21 CFR Part 56), and Standards of Good Clinical Practice, as defined by the International Conference 
on Harmonization (ICH E6) and all applicable regulatory requirements.  The Principal Investigator will 
assure that no deviation from, or changes to the protocol will take place without prior agreement 
from the sponsor and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. 
 
 
Clinical Site Name: 
 
________________________________________ 
 
 
Site Principal Investigator:  
________________________________________ 
Print/Type Name 
 
 
Signature: 
 
 
________________________________________ 
 
 
Date:   
 
 
________________________________________ 
 
 
 
 


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PROTOCOL SUMMARY 
Title: 
Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic 
Telangiectasia 
Précis: 
This is a Phase II placebo-controlled double-blind 
study of 
pomalidomide in patients with hereditary hemorrhagic telangiectasia 
(HHT) with moderate to severe epistaxis who have anemia and/or 
require parenteral iron infusions or blood transfusions. A total of 159 
patients will be randomized 2:1 to treatment with oral pomalidomide 
or matching placebo for 24 weeks. Mean change from baseline to 24 
weeks in the Epistaxis Severity Score (ESS) will be compared between 
treatment groups to determine pomalidomide efficacy.  
Objectives: 
Primary Objective: To determine efficacy of pomalidomide compared 
to placebo for the reduction in severity of epistaxis after 24 weeks of 
treatment. 
Secondary Objectives: To determine the safety and tolerability of 
pomalidomide for the treatment of HHT; to determine if pomalidomide 
treatment improves quality of life in HHT; to determine whether a 
continued response to pomalidomide is evident 4 weeks after 
treatment discontinuation;  to develop a biorepository for future 
studies to define biomarkers predictive of pomalidomide response and 
allow investigations into the biology of HHT and mechanisms of 
pomalidomide.   
Endpoint: 
Primary endpoint: Change from baseline to 24 weeks in the Epistaxis 
Severity Score. 
Secondary endpoints: Total parenteral iron (mg) infused and packed 
red blood cells (units) transfused during the 24 week treatment period, 
change from baseline to 24 weeks in total weekly duration of epistaxis, 
change in quality of life (QOL) scores assessed using NIH Neuro-QOL 
Satisfaction with Social Roles and Activities, PROMIS Emotional Distress 
- Depression and PROMIS Fatigue instruments, and HHT-specific QOL 
questions,  proportion of patients requiring no blood transfusions or 
iron infusions during the 24 week treatment period, change from 
baseline in the Epistaxis Severity Score averaged across weeks 16-24 
and at each study visit, proportion of patients requiring endoscopic 


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interventions for bleeding, safety assessed by adverse events and side 
effects.   
Population: 
Adults 18 years and older with moderate to severe epistaxis due to 
hereditary hemorrhagic telangiectasia who require parenteral iron 
infusions or blood transfusions. 
Phase: 
Phase II 
Number of Sites 
Enrolling 
Participants: 
up to 15 
Description of Study 
Agent: 
Pomalidomide, a third generation derivative of thalidomide, given orally 
at a starting dose of 4 mg/day for days 1-28 of six 28-day cycles. The 
dose may be reduced to 3 or 2 mg/day based on specific AE criteria.  
Study Duration: 
5 years 
Participant 
Duration: 
32 weeks 
 
 
 


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SCHEMATIC OF STUDY DESIGN 
 
Figure 1: Study Design Schematic. After recruitment, patients will be screened for their iron 
infusion/transfusion history, undergo laboratory testing, and have the ESS with 3-month recall 
calculated for eligibility. After a minimum 28 day  (up to 56 days allowed for scheduling flexibility) 
period following the screening ESS, during which patients will record the duration of each epistaxis 
event, eligible patients will return for genetic and QOL testing and determination of an ESS with 28 
day recall to serve as the baseline for comparison with monthly ESS scores performed throughout the 
study. Patients will then be randomized 2:1 to pomalidomide or an identical-appearing placebo. 
Patients will initiate treatment after receipt of the drug/placebo, and subsequently will be seen every 
4 weeks for 24 weeks, corresponding to six 4-week cycles of therapy. Pomalidomide will be 
discontinued after the 24 week end-of-treatment visit, and patients will be seen once more 4 weeks 
after treatment discontinuation to determine the stability of their response. ESS, iron studies, CBC, 
and CMP will be assessed monthly , and QOL will be determined at baseline, at 12 and 24 weeks after 
treatment initiation, and at the end of study.  Patients will record the duration of each epistaxis event 
during the 4-week periods between weeks 8-12 and weeks 20-24 post initiation, and 4 weeks after 
treatment discontinuation. 
 


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1 
KEY ROLES 
Keith R McCrae, M.D. 
Lead Principal Investigator 
Departments of Hematology and Medical Oncology and Cellular and Molecular Medicine 
Cleveland Clinic 
9500 Euclid Avenue, Cleveland, OH 44195 
Phone: 216-445-7809 
Mobile: 216-618-9296 
Email: mccraek@ccf.org 
 
Sonia Thomas, DrPH 
Data Coordinating Center Principal Investigator 
RTI International 
3040 E. Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709 
Phone: 919-541-6737 
Email: smthomas@rti.org 
 
Diane Catellier, DrPH 
Data Coordinating Center Co-Investigator 
RTI International 
3040 E. Cornwallis Rd, PO Box 12194, Research Triangle Park, NC 27709 
Phone: 919-541-6447 
Email: dcatellier@rti.org  
 
Marianne Clancy 
Patient Recruitment Liason 
Executive Director, Cure HHT Foundation 
P.O. Box 329, Monkton, MD 21111 
Phone: 410-357-9932 
Email: mariannes.clancy@curehht.org 
 
Andrei L. Kindzelski, M.D., Ph.D.  
NHLBI Program Officer 
Division of Blood Diseases and Resources  
National Heart, Lung, and Blood Institute  
6701 Rockledge Dr.Room 9170, MSC 7950, Bethesda, MD 20892-7950  
Phone: (301) 435-0070; Fax: (301) 480-1046  
Email: kindzelskial@nhlbi.nih.gov 
 
 


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2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
BACKGROUND INFORMATION  
This study will address the efficacy of pomalidomide in the treatment of epistaxis in patients with 
Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or 
iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT is an inherited 
disease clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and recurrent 
epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations (AVMs) or 
telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal dominant). 
Patients with three criteria are considered to have definite HHT, and those with 2 criteria probable 
HHT, while one or no criteria make the diagnosis unlikely 1. Patients eligible for this study will have a 
diagnosis of definite or probable HHT.  Estimates suggest that HHT affects between 1 in 1,330 and 1 
in 10,000 individuals 2. Since many physicians are not familiar with the disease, only 10% of patients 
with HHT may actually be diagnosed. Significant manifestations of HHT often do not appear until the 
third or fourth decades, sometimes later.  
Approximately 90% of patients with HHT harbor mutations in one of three genes, which encode 
endoglin (ENG), activin receptor-like kinase (ACVRL1) or SMAD43,4. Additional genes such as RASA1 
and GDF2 have been implicated in several cases, and in some patients no underlying mutations are 
identified5. While the clinical manifestations of patients with mutations in ENG or ACVRL1 are 
generally similar, those with SMAD4 mutations, who account for less than 5% of the HHT population, 
display a unique clinical phenotype characterized by the development of colonic polyps with a high 
incidence of neoplastic transformation, often at a young age6. Due to the complex management of 
these patients and the fact that bleeding is often not their primary clinical concern, patients with 
known SMAD4 mutations will not be included in this study. Genetic testing will be confirmed or  
assessed in all study patients in order to determine whether genotype correlates with clinical 
responses to pomalidomide.  
In addition to epistaxis, AVMs involving the gastrointestinal (GI) tract, particularly the small bowel, 
are responsible for GI bleeding as the primary symptom in 15-20% of patients with HHT7.  HHT may 
also be associated with additional manifestations including brain abscesses and stroke resulting from 
cerebral AVMs and paradoxical right to left shunts through pulmonary AVMs8. Patients may also 
develop liver AVMs which in extreme cases may cause high output congestive heart failure8,9.  
Treatment of HHT 
There are no evidence-based guidelines for managing HHT, and there is no medical therapy universally 
accepted as efficacious; thus, treatment is not standardized. Historically, interventional procedures 
have formed the mainstay of HHT therapy10. However, though often effective initially, such 
procedures are associated with a high incidence of recurrent bleeding from new AVMs or AVMs not 
visualized during endoscopic procedures10. Epistaxis is the most common clinical manifestation of 
HHT, affecting ≥ 80% of patients, and leading to significant impairment in quality of life11,12. 


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Hemostatic agents such as epsilon-aminocaproic acid (Amicar) and tranexamic acid, administered 
locally or systemically, have been  used to treat epistaxis in HHT, though results have been 
inconsistent13-15. A retrospective study of tranexamic acid in 42 patients with HHT demonstrated that 
chronic therapy reduced the epistaxis severity score (ESS) but not the need for blood transfusion or 
hospitalization. Hormonal agents such as estrogens and octreotide benefit occasional patients with 
HHT though their limited efficacy has not led to widespread utilization16,17.  A randomized study of 
high-dose estrogen failed to significantly reduce bleeding18. Moreover, the thrombosis risk and 
acceptance of estrogens, particularly in males, limits their use. For these reasons, epistaxis  is often 
treated with temporizing approaches such as laser photocoagulation12. 
Bevacizumab, an anti-VEGF antibody, has been used as therapy for HHT based on the presumption of 
excessive VEGF-induced angiogenesis causing telangiectasia. Small, uncontrolled studies and, more 
recently, several retrospective case series demonstrate  activity in HHT19-21. However, not all patients 
respond, and in some individuals responses are relatively short-lived, requiring frequent retreatment. 
Moreover, intravenous administration is required, and systemic toxicity may be significant, 
particularly the development of hypertension20, life-threatening thromboembolism22 and other 
complications. Such concerns have led to studies of bevacizumab nasal spray in HHT. However, in the 
ELLIPSE study, a phase I randomized, dose escalation trial of bevacizumab nasal spray in HHT, no 
efficacy was demonstrated at doses up to 100 mg/spray23. In the NOSE study, patients with HHT were 
randomized to twice per day use of nasal sprays containing placebo, bevacizumab, tranexamic acid or 
estriol24. Though small differences in the ESS were seen at 12 weeks in all groups, no significant 
differences in the ESS, or the duration or frequency of epistaxis were observed in any of the treatment 
groups compared to placebo.  
Taken together, these considerations demonstrate the  continuing need to identify efficacious agents 
for managing patients with HHT.  
Quality of life studies in HHT and survey results 
Work performed during the development of this study, funded by a NHLBI U34 Clinical Trial Planning 
Grant, as well as that of others, demonstrates a significant reduction in quality of life in patients with 
HHT25, reflecting a high incidence of anxiety, depression and fear of social situations due to 
uncertainty of when an episode of epistaxis will occur. The ESS generally correlates well with QOL, 
with a minimal important difference as small as 0.7 significantly associated with decreased QOL26. 
There exists very little information concerning the effect of therapy on QOL in patients with HHT. To 
assess the effect of pomalidomide on QOL in HHT patients, we will administer QOL assessments 
before, during and after therapy. We have worked closely with the CureHHT foundation to assess the 
responses of HHT patients to validated NIH PROMIS QOL measures. We emailed a survey of quality of 
life questions to CureHHT members, and the responses to three PROMIS instruments were compared 
with a set of four HHT-specific questions developed during the planning of this study. An additional 
item recorded a self-assessment of HHT severity. Overall, 492 surveys were returned, of which 290 


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(59%) had all four instruments fully completed; 121 (25%) were completed in enough detail that at 
least one instrument could be scored, and 81 were blank or not able to be scored. 
The following three NIH PROMIS instruments were used:  
1. Satisfaction with Participation in Social Roles Short Form V1.0,  
2. Satisfaction with Participation in Discretionary Social Activities Short Form V1.0  
3. Emotional Distress – Depression Short Form V1.0 
The total scores from these instruments were compared with each other, and with four HHT-specific 
questions developed during the design of this study: 
1. How often in the past month has an activity related to your job been interrupted by a nose 
bleed? 
2. How often in the past month has an activity with your family been interrupted by a nose 
bleed? 
3. How often have you avoided social activities because you were worried about having a nose 
bleed? 
4. How often do you miss work or school due to HHT related problems? 
Analysis of the responses revealed the following key points: 
 
29% of respondents reported their HHT as “mild”, 46% as “moderate” and 25% as “severe” 
 
Overall, 49% of respondents indicated that HHT significantly interfered with daily activities on 
at least one of the HHT questions; mostly those rating their HHT as moderate or severe, similar 
to the patients who will be in the current study.  Of those that rated their HHT moderate,  40% 
missed work due to HHT at least “sometimes” and 18% did not work due to HHT.  Of those 
rating their HHT severe, 25% missed work “frequently” and 47% did not work due to HHT. 
 
The 3 PROMIS scores and the HHT-specific questions all correlated with HHT severity 
(correlations ranged from 0.40 – 0.61) 
 
The two PROMIS instruments related to social activities were highly correlated (r=.89). 
PROMIS has subsequently released a new instrument consolidating these measures called the 
PROMIS Satisfaction with Social Roles and Activities Short Form V2.0, which will be used in 
this study. 
 
The 4 HHT Questions were moderately correlated with each other (one pairwise correlation 
of 0.40, all others ranged from 0.52 to 0.64). 
 
The 4 HHT Questions were moderately correlated with the 3 PROMIS measures (pairwise 
correlations ranged from 0.35 to 0.71). 
These responses confirm that HHT is indeed strongly associated with significant interference with 
work and social activities leading to a reduced QOL, and that these variables are captured by the 
selected PROMIS instruments. Additional analysis demonstrated that the subset of items comprising 
the PROMIS short form instruments captured these QOL responses with similar accuracy as the longer 


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item banks, demonstrating the feasibility of the short form NIH PROMIS measures for assessing QOL 
response to pomalidomide in this study.  
The moderately high correlation among the 4 HHT-specific responses and between these responses 
and the PROMIS scores provides evidence of good convergent validity to support the use of this 
abbreviated HHT-specific questionnaire to capture the psychodynamic effects of pomalidomide 
therapy on QOL in treated patients.  To enhance clarity, a revised version of the survey questions will 
be used in this protocol and is described in section 7.1.1.3. 
2.2
RATIONALE 
Rationale for the use of pomalidomide in HHT builds upon prior experience with thalidomide 
Pomalidomide is an analogue of thalidomide (Figure 2), which was initially developed in Germany in 
the 1950s and marketed as a sedative to treat morning sickness in pregnancy. Thalidomide was 
withdrawn from the market in the early 1960s due to  teratogenicity. Despite the clinical ban, research 
on its vascular and immunomodulatory effects continued, and the FDA approved its use in 1998 for 
the treatment of cutaneous manifestations of erythema nodosum leprosum, and in 2006 for the 
treatment of multiple myeloma. 
The antiangiogenic activity of thalidomide is not well understood, but is thought to be due in part to 
the suppression of production of vascular endothelial cell growth factor (VEGF) and basic fibroblast 
growth factor (bFGF)27. This suggested potential benefit in gastrointestinal angiodysplasia, since the 
expression of VEGF may be increased in the bowel wall of patients with this disorder28. Several small 
studies suggested efficacy of thalidomide in patients with GI angiodysplasia, including many with 
associated comorbidities29-40. Some evidence suggests that in patients with GI angiodysplasia and 
refractory bleeding, thalidomide reduces serum levels of VEGF29. However, in none of these studies 
were patients assessed for HHT, which has been increasingly recognized as a cause of angiodysplasia 
in the GI tract over the last decade.  
Several small reports  also describe  the use of thalidomide in patients with HHT41-47.  In a study by 
Lebrin et al, five of six patients with HHT-related epistaxis had significant responses  to thalidomide; 
none of four untreated controls showed any improvement over the same three month period45. 
Figure 2: Structures of pomalidomide and thalidomide 


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Biopsies of nasal mucosa in patients with epistaxis before and after treatment demonstrated that 
thalidomide induced vessel maturation, characterized by enhanced mural cell coverage and 
improvement in vessel wall defects. Similar improvements in vessel architecture were seen in mice 
heterozygous for a null mutation in ENG48. A recent single arm study of thalidomide also 
demonstrated a high, and durable response rate in 31 HHT patients with epistaxis, with some patients 
treated for up to 10 years49. Another  study reported the efficacy of a second generation thalidomide 
analogue, lenalidomide, in a patient with HHT and refractory GI bleeding 50. However, there are no 
reports of patients with HHT treated with pomalidomide.  
These results, taken together with those derived from the Principal Investigator’s phase I pilot study 
demonstrating the activity and safety of pomalidomide in HHT,  provide the rationale and evidence of 
feasibility for an expanded study of pomalidomide. When compared to thalidomide and lenalidomide, 
pomalidomide is potentially superior due to its efficacy and reduced toxicity profile, including a lower 
incidence of peripheral neuropathy and cytopenias.  
2.3 
POTENTIAL RISKS AND BENEFITS  
2.3.1 KNOWN POTENTIAL RISKS  
Risks of this study include the reported toxicities of pomalidomide. These include: 1) teratogenicity, 
2) thromboembolism, 3) cytopenias, 4) hepatotoxicity, 5) allergic reactions (including rash), 6) 
dizziness and confusional state, 7) peripheral neuropathy, 8) fatigue, 9) GI intolerance and 10) new 
cancers.  
The data source from which these toxicies were identified consists of patients with multiple myeloma, 
a plasma cell neoplasm involving the bone marrow and other organs that is associated with 
thrombosis, cytopenias and neuropathy—among the most common toxicities seen with 
pomalidomide. Therefore, the incidence of these toxicities in patients with HHT and normal bone 
marrow function is unknown but likely to be much lower than that in myeloma patients.  
The incidence of these toxicities, specifically thromboembolism, cytopenias, fatigue, and peripheral 
neuropathy appears to be lower with pomalidomide than with thalidomide. The only drug related AEs 
seen in the PI’s current pilot study are Grade 1-2 fatigue, two allergic reactions and one cytopenia 
occurring at a pomalidomide dose (5 mg daily) that exceeds the dose that will be used in this study. 
The risk of teratogenicity remains a concern and precautions to prevent exposure of pregnant women 
to pomalidomide are embedded in this protocol. Pomalidomide and placebo will be provided by 
Celgene and the study will adhere to the FDA-mandated pomalidomide risk evaluation and mitigation 
strategies (REMS) protocol. The study will closely monitor and if necessary manage other toxicities.  
 
 


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2.3.2 KNOWN POTENTIAL BENEFITS  
HHT is associated with substantial morbidity, leading to a reduced quality of life, decreased rate of 
employment and a high incidence of depression. There currently exists no medical therapy recognized 
as consistently efficacious in HHT. Reports of the efficacy of thalidomide in HHT, as well as interim 
results of our pilot trial of pomalidomide in HHT provide evidence of efficacy with minimal toxicity. 
The favorable efficacy:toxicity ratio of pomalidomide suggest that it may benefit patients with HHT. 
3 
OBJECTIVES AND PURPOSE 
3.1 
PRIMARY OBJECTIVE  
To determine efficacy of pomalidomide compared to placebo for the reduction in severity of epistaxis 
after 24 weeks of treatment.  
3.2 
SECONDARY OBJECTIVES  
1. To determine the safety and tolerability of pomalidomide for the treatment of HHT. 
2. To determine if pomalidomide treatment improves quality of life in HHT. 
3. To determine whether a continued response to pomalidomide is evident 4 weeks after 
treatment discontinuation.  
4. To develop a biorepository for future studies to define biomarkers predictive of 
pomalidomide response and allow investigations into the biology of HHT and mechanisms of 
pomalidomide. 
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This is a multi-center, double blind, placebo-controlled study that will investigate the efficacy and 
safety of pomalidomide in patients with HHT and chronic epistaxis leading to iron-deficiency anemia 
or requiring intravenous iron infusions or blood transfusion.  
After recruitment, patients will be screened for study eligibility. The screening evaluation will include 
the ESS with three month recall, which will reflect the patient’s history of epistaxis and bleeding over 
the prior three months, as well as detailed review of iron infusion and red cell transfusion over the 
preceding six months.  Eligible patients will be provided a diary to record the duration of each epistaxis 
event that occurs during the 4 weeks prior to the  baseline visit. Eligible patients will then return for 
the baseline randomization visit between 28 and 56 days later, at which time patients will undergo 
genetic testing, if this has not been previously performed or if results for ENG, ACVRL1 and SMAD4 
genes are not available. A repeat ESS with 4 week recall will be performed and will be considered the 
“baseline” ESS. Patients will also complete QOL surveys at this visit. Patients will then be randomized 
2:1, stratified by study site, to either pomalidomide, 4 mg/day for 28 days during each of six 28 day 
cycles (24 weeks), or placebo, administered on an identical schedule.  


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Patients will be seen every four weeks during the study to measure the ESS (with 4 week recall), 
measure iron stores, and obtain laboratory studies, which will include CBC, metabolic profile and iron 
studies. The iron replete state will be defined as a ferritin ≥ 50 ng/ml and a transferrin saturation ≥ 
30% (since ferritin levels may be elevated due to concurrent inflammation). Investigators will be 
encouraged to replete iron stores in patients in both arms of the study based on these parameters, 
and the amount of iron infused (in mg) recorded. There is no mandate for the use of a particular iron 
preparation. Investigators will be encouraged to use iron infusions prior to blood transfusion, though 
the latter will be mandated for a hemoglobin below 6.5 gm/dl, and recorded as units of packed red 
blood cells administered. Blood transfusion may also be given at the investigator’s discretion based 
on symptoms that may include shortness of breath, severe fatigue, or other cardiovascular 
manifestations. Patients will be assessed for adverse events (AE) throughout the study. Treatment 
dosage may be reduced, or temporarily or permanently discontinued following AE-specific guidelines 
related to fatigue, cytopenias or other toxicities.  
The effect of pomalidomide on QOL will be assessed by measuring QOL at the baseline visit, at the 12 
and 24 week visits, and at the 4 week post-treatment follow-up visit using validated NIH instruments 
of 1) Neuro-QOL satisfaction with social roles and activities, 2) PROMIS emotional distress – 
depression, and 3) PROMIS fatigue. We will also assess responses to an HHT specific questionnaire 
developed specifically for this study and shown to correlate with these PROMIS items. The effect of 
pomalidomide on duration of epistaxis will be assessed via diary between weeks 8-12, 20-24 and the 
4 weeks post-treatment discontinuation.  
4.2.1 PRIMARY ENDPOINT 
The primary endpoint of this study is change of the Epistaxis Severity Score from baseline to week 24 
in the placebo and pomalidomide-treated groups. The ESS at baseline and each follow-up visit will 
reflect the patient’s symptoms and bleeding over the previous 4 weeks.   
4.2.2 SECONDARY ENDPOINTS 
Key Secondary endpoints 
1. Amount of parenteral iron administered (in mg) during the 24 week treatment period in the 
pomalidomide and placebo groups (calculated as average mg/4-week interval to account for 
patients who discontinue early). 
2. Amount of packed red blood cell transfusions (in units) during the 24 week treatment period 
in the pomalidomide and placebo groups (calculated as average units/4-week interval to 
account for patients who discontinue early). 
3. Change in Neuro-QOLTM Satisfaction with Social Roles and Activities Short Form (V1.1) T-score 
from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-
treatment follow-up visit in the pomalidomide and placebo groups. Although developed as 
part of an assessment system for people with neurological conditions, the Satisfaction with 


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Social Roles and Activities is scored relative to a general population sample, supporting its use 
in non-neurologic health conditions.  
4. Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key timepoint), 
and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups.  
5. Change in average weekly epistaxis duration from the four week screening period prior to 
baseline to weeks 8-12 and to weeks 20-24 (key timepoint), and to the 4 weeks post-
treatment in the pomalidomide and placebo groups. 
Other Secondary endpoints 
6. Change in PROMIS® Emotional Distress – Depression Short Form (V1.0) T-score from baseline 
(randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-treatment 
follow-up visit in the pomalidomide and placebo groups. 
7. Change in PROMIS® Fatigue Short Form (V1.0) T-score from baseline (randomization visit) to 
weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the 
pomalidomide and placebo groups. 
8. Proportion of patients requiring no red blood cell transfusion or parenteral iron infusion 
during the 24 week treatment period in the pomalidomide and placebo groups. 
9. Change in the ESS from baseline to that recorded at each individual patient assessment, 
including the 4 week post-treatment follow-up visit.  
10. Change in the ESS from baseline to the average of the week 16, 20 and 24 assessments.   
11. Proportion of patients requiring endoscopic interventions for management of bleeding during 
the 24 week treatment period in the pomalidomide and placebo groups. 
12. Incidence and severity of adverse events in the pomalidomide and placebo groups including 
but not limited to: 
 
Venous thromboembolism 
 
Arterial thromboembolism 
 
Thrombocytopenia 
 
Neutropenia 
 
Peripheral neuropathy 
 
Fatigue 
 
Constipation/diarrhea 
 
Rash 
 
Any other AEs or SAEs of at least moderate severity that are possibly related to 
pomalidomide 
13. Change in iron/hemoglobin-related studies including iron saturation, ferritin, hemoglobin, 
hematocrit, MCV, and MCHC.  
4.2.3 EXPLORATORY ENDPOINTS 


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1. Rate of relapse at the 4 week post-treatment follow-up visit, where relapse is defined as a 
return of the ESS to the baseline value or greater in pomalidomide (or placebo)-treated 
subjects. 
2. Median time after initiation of pomalidomide to obtain a decrease in the ESS of at least 1.0  
in the in pomalidomide-treated subjects compared to placebo.   
3. Effect of genotype on the response to pomalidomide. 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 
1. A clinical diagnosis of HHT as defined by the Curacao criteria  
2. Age > 18 years 
3. Platelet count ≥ 100 x 109/L 
4. WBC ≥ 2.5 x 109/L 
5. INR ≤ 1.4 and normal ± 2 sec activated partial thromboplastin time (aPTT or PTT per local 
laboratory designation) by local laboratory criteria (except for patients on a stable dose of 
warfarin or direct oral anticoagulants)   
6. Epistaxis severity score ≥ 3 measured over the preceding three months, measured at the 
screening visit 
7. A requirement for anemia, as determined by local laboratory hemoglobin assessment and 
normal ranges, and/or parenteral infusion of at least 250 mg of iron or transfusion of 1 unit 
of blood over the  24 weeks preceding the screening visit 
8. All study participants must agree to be registered into the FDA mandated POMALYST REMS 
program, and be willing and able to comply with the requirements of the POMALYST REMS 
program 
9. Females of childbearing potential (FCBP)† must adhere to the pregnancy testing schedule 
mandated by the POMALYST REMS program (see Section 8.4.5)  
10. Ability to understand and sign informed consent 
†A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
1. Women currently breast feeding or pregnant 
2. Renal insufficiency, serum creatinine > 2.0 mg/dl 
3. Hepatic insufficiency, bilirubin > 2.0 (or >4.0 in the setting of a prior clinical or genetic 
diagnosis of Gilbert's syndrome) or transaminases > 3.0x normal 
4. Prior treatment with thalidomide or other Immunomodulatory imide drugs (IMiDs) within 
previous 6 months 
5. Prior treatment with bevacizumab (systemic or nasal) within previous 6 weeks* 


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6. Prior treatment with pazopanib within previous 6 weeks* 
7. The use of octreotide or oral estrogens within the previous month* 
8. History of prior unprovoked thromboembolism confirmed by venous ultrasound or other 
imaging modalities 
9. Known peripheral neuropathy, confirmed by neurologic consultation 
10. Known underlying hypoproliferative anemia (i.e. myelodysplasia, aplastic anemia) 
11. Currently enrolled in other interventional trials 
12. Known hypersensitivity to thalidomide or lenalidomide 
13. The development of erythema nodosum if characterized by a desquamating rash while taking 
thalidomide or similar drugs 
14. Known SMAD-4 mutation, unless there has been a colonoscopy with normal (negative) 
results, or in which the patient has had no more than 5 small (in the opinion of the 
gastroenterologist) colonic polyps completely removed within the preceding 18 months  
15. Anything that in the investigator’s opinion is likely to interfere with completion of the study 
* Use of these treatments is not permitted during study participation.  See protocol section 7.6 
for additional details regarding prohibited treatments. 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
We estimate that we will need to screen 200 patients in order to enroll and randomize 159 
participants (106 treated with pomalidomide, 53 with placebo), assuming 80% of screened patients 
will enroll.  
To meet this recruitment goal, patients will be recruited at each of up to 15 institutions all of which 
are nationally-designated HHT Centers of Excellence; three of these centers contributed patients to 
the NOSE study, with our Utah site being the highest enroller. A national recruitment process will also 
be employed through the outreach of CureHHT, an international patient advocacy group that 
communicates regularly with more than 10,000 HHT patients. Details describing the trial will be 
posted on the CureHHT website and the study website maintained by the DCC after approval from 
the central IRB at the Cleveland Clinic. CureHHT will publicize the trial through regular email blasts to 
its constituency and mailings. The trial will also be listed on www.clinicaltrials.gov.  
Randomization will be performed in a 2:1 manner to enhance patient enthusiasm for participation in 
the trial. To alleviate the risk of exposure to COVID-19, site PIs will be given the flexibility to conduct 
some of the research visits remotely. We anticipate that half of the patients will be recruited from 
existing populations treated at the study sites, and that half of the patients will respond to 
communications issued through CureHHT and other mechanisms. Original study timelines were that 
enrollment would be completed within 2.5 years, with each site screening 9 to 10 patients and 
randomizing 6-8 patients per year.  However, the COVID-19 pandemic has impacted enrollment 
prolonging study timelines.  
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 


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5.4.1 WITHDRAWAL OR TERMINATION OF SUBJECTS FROM THE STUDY 
Subjects will be encouraged to remain in the study until completion, but informed that they have the 
right to stop taking medication or withdraw from the study at any time without compromise to their 
subsequent care. Causes for study withdrawal may include unacceptable side-effects, a decision to 
pursue another treatment modality, or personal issues that preclude continued study participation. If 
a subject elects to stop taking study medication or if study medication is permanently stopped by the 
study PI due to toxicity concerns, they should be encouraged to complete follow-up visits after 
stopping study medication as indicated in Section 7.3.5.   
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
For subjects who withdraw from the study, data collected up to the time of study withdrawal will 
remain in the trial database and will be used in the analysis.  A discussion of how data from subjects 
with early treatment stop or early study withdrawal will be handled in the statistical analysis is 
described in Section 10, Statistical Considerations. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the clinical coordinating center to NHLBI and the FDA. If the study is prematurely 
terminated or suspended, the PI will promptly inform the IRB and will provide the reason(s) for the 
termination or suspension. In the case of unanticipated, unacceptable risks to participants, the 
Principal Investigator will make the determination to terminate or suspend the study based on 
recommendations of the Medical Monitor or Data Safety Monitoring Board (DSMB).  
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping (per DSMB review of interim 
analysis) 
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
• 
Determination of futility (per DSMB review of interim analysis) 
If suspended, the study may resume once concerns about safety, protocol compliance, and/or data 
quality are addressed and satisfy the sponsor, DSMB, IRB and/or FDA.  
6 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 ACQUISITION 


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Pomalidomide (POMALYST®) or placebo will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Pomalidomide will be 
provided in accordance with the Celgene Corporation’s POMALYST REMS™  program.  Per the standard 
POMALYST REMS™ program requirements, all physicians who prescribe pomalidomide for research 
subjects enrolled into this trial, and all research subjects enrolled into this trial, must be registered in 
and must comply with all requirements of the POMALYST REMS™ program.   
Drug will be shipped on a per patient basis by a contract pharmacy to the clinic site or research subject.  
In accordance with the POMALYST REMSTM program, only enough pomalidomide for one cycle of 
therapy (i.e., 28 days) will be supplied to the subject.  
6.1.2 FORMULATION, APPEARANCE, PACKAGING AND LABELING 
Pomalidomide or matching placebo will be supplied as 4.0 mg capsules for oral administration. 
Capsules of 3.0 and 2.0 mg pomalidomide or matching placebo will also be provided for patients who 
experience hematologic toxicity, fatigue or muscle cramping thought to be drug related, per 
guidelines described in Section 6.1.8. The new dose may be initiated after the unused capsules from 
the previous dose are collected.  
Pomalidomide is dispensed to research subjects as individual bottles containing capsules.  Each bottle 
will identify the contents as study medication.  It is suggested as a component of the pomalidomide 
REMS program that patients not open or extensively handle pomalidomide capsules.  All bottles will 
contain the following warning label:  “WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS.” 
Placebo will contain Microcrystalline Cellulose (Type PH-102) (Compendia: NF, Ph Eur, JP) and the 
Swedish Orange (6180) Opague Global Capsule Shell (Coni-Snap). Placebo will be indistinguishable 
from pomalidomide.  
6.1.3 PRODUCT STORAGE AND STABILITY 
The study drug and placebo should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold. 
6.1.4 PREPARATION 
No preparation of pomalidomide is necessary. 
6.1.5 DOSING AND ADMINISTRATION 
Females of child bearing potential must have two negative pregnancy tests to enter this trial, the first 
test being 10-14 days before and the second test within 24 hours prior to prescribing study drug. The 
dose of pomalidomide is 4 mg per day for days 1-28 of a 28 day cycle. For the purposes of this study, 
one cycle will be defined as 28 days. Subsequent cycles may begin within 5 days of completion of the 


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previous cycle, to allow time for patient assessment and provision of new drug to the study 
participant.  
6.1.6 ROUTE OF ADMINISTRATION 
Pomalidomide capsules should be swallowed whole, and should not be broken, chewed or opened.  
Pomalidomide should be taken without food, at least 2 hours before or 2 hours after a meal (water is 
allowed), preferably around the same time each day. 
6.1.7 DOSING SCHEDULE 
This study employs a fixed dose of 4 mg of pomalidomide daily. This is the FDA approved dose for 
multiple myeloma, and has been shown to be active in a pilot trial of pomalidomide for patients with 
HHT. In the event that patient experiences adverse events that cannot be managed, the dose may be 
reduced stepwise to 3 mg or 2 mg/day at the site PI’s discretion.  
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
Study drug dose may be reduced, or temporarily or permanently discontinued following the guidelines  
specified in the sections below. 
6.1.8.1  
MISSED DOSE 
If a dose of pomalidomide is missed, it should be taken as soon as possible on the same day, within 6 
hours.  If it is missed for the entire day, it should not be made up the next day. The regular dose should 
be taken on the next day. Vomitted doses should be considered as dose missed for the entire day. 
6.1.8.2 
OVERDOSE 
Patients who take more than the prescribed dose of pomalidomide should be instructed to contact 
study staff immediately to review the dose taken and symptoms, and determine if urgent medical 
care is necessary.  
6.1.8.3 
DOSE ADJUSTMENT FOR HEMATOLOGIC TOXICITY 
The primary toxicity of pomalidomide is hematologic. Hematologic toxicity will be monitored monthly  
during the study. Dose adjustments will be undertaken any time the hematologic parameters dictate, 
as described in the tables below. Table 1A lists the NCI CTCAE grading of adverse event severity related 
to neutropenia and thrombocytopenia. Table 1B lists the interventions that will be used for 
neutropenia or thrombocytopenia according to NCI CTCAE grade. There is a lower threshold for 
intervention and/or discontinuation of pomalidomide for either neutropenia or thrombocytopenia 
than in multiple myeloma, as HHT is not a malignant disease.  
 


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TABLE 1A: NCI CTCAE FOR NEUTROPENIA AND THROMBOCYTOPENIA‡ 
 
Grade 
Adverse 
Event 
1 
2 
3 
4 
5 
Neutrophils 
(ANC) 
<LLN-1.5 x 109/L 
<1.5-1.0 x 109/L 
<1.0-0.5 x 109/L 
<0.5 x 109/L  
Death 
Platelets 
<LLN-75 x 109/L 
<75-50 x 109/L 
<50-25 x 109/L 
<25 x 109/L 
Death 
‡ Units for blood cells counts are expressed as 109/L, which is equivalent to 103/µl or 103/mcl. ANC = 
absolute neutrophil count.  
 
TABLE 1B: INTERVENTIONS FOR NEUTROPENIA AND THROMBOCYTOPENIA BY NCI CTCAE GRADE 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Neutrophils 
 (ANC) 
None 
None 
Interrupt pomalidomide 
treatment, follow CBC weekly 
Resume pomalidomide when 
ANC is >1.0 x 109/L, at 1 
mg/day less than previous 
dose* 
Interrupt 
pomalidomi
de 
treatment, 
proceed as 
for Grade 3 
Off study  
Platelets 
(thrombocytopenia) 
None 
None 
Interrupt pomalidomide 
treatment, follow CBC weekly 
Resume pomalidomide when 
platelets are >0.5 x 109/L, at 1 
mg/day less than previous 
dose 
Off study 
drug 
permanently 
Off study  
* For Grade 3 neutropenias in which the ANC is > 0.8 x 109/L, patient may remain on the same dose 
of drug for up to 1 week  at which time a repeat CBC should be obtained. If the ANC is persistently 
less than 1.0 x 109/L, study drug should be discontinued until recovery of the ANC to > 1.5 x 109/L 
and the patient then restarted on the next lower dose.  
6.1.8.4 
DOSE DISCONTINUATION BASED ON INVESTIGATOR’S DISCRETION 
Pomalidomide may be held for an indefinite period at the discretion of the investigator for reasons 
including but not limited to safety and/or patient benefit (for example, surgery or other drug or 
disease related or unrelated medical problem). Study drug can be resumed at the discretion of the 
investigator based on the investigator’s opinion that it is safe to do so.  Patients should still attend 
regular study visits while study drug is held. 
If the study drug is held during a cycle, the patient may begin the next dose cycle even if the previous 
cycle was not completed, assuming that the reason for holding the drug was not due to an adverse 
event requiring dose adjustment.  


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6.1.8.5 
SURGERY 
In the specific case of surgery it is recommended that pomalidomide be stopped at least 7 days prior 
to surgery. Pomalidomide may be restarted 14-21 days after surgery, at the investigator’s discretion.  
6.1.8.6 
FATIGUE 
Fatigue may be observed in some patients. This may be difficult to separate from fatigue due to 
underlying 
HHT/anemia. 
For 
fatigue 
of 
CTCAE 
Grade 
3 
or 
higher 
(    
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm, 
version 
4.0), 
pomalidomide may be stopped for 1-2 weeks at the investigator’s discretion and then resumed at a 
dose of 3 mg daily, or simply reduced to a dose of 3 mg/daily. This dose may be continued for the 
remainder of the study or further reduced to 2 mg daily if fatigue is persistent. 
6.1.8.7 
RASH 
The incidence of rash in patients with myeloma treated with pomalidomide  is < 10%, though in one 
study of myeloma patients  only 1 of 70 patients were forced to stop drug because of rash. The rash 
usually develops at the time of drug initiation,  and involves the trunk and extremities and may be 
intensely prurititic. It may sometimes resolve with continued therapy, and is often not of sufficient 
severity to require drug cessation. Recommended therapies include topical hydrocortisone, oral 
corticosteroids, antihistamines, cimetidine, oatmeal baths, and ketoconazole shampoo.   
6.1.8.8 
MUSCLE CRAMPING 
In the case of muscle cramping, which may occur in some patients on higher doses of pomalidomide, 
treatment with over-the-counter quinine water as well as muscle relaxants such as cyclobenzaprine 
is allowed. If these do not diminish the intensity of symptoms to a tolerable level, the dose of 
pomalidomide may be reduced to 3 mg/day for  two weeks, and the effect on cramping assessed. If 
this is unsuccessful in improving symptoms, the dose may be reduced to 2 mg/day. If symptoms 
remain intolerable, the patient will be removed from the study. 
6.1.8.9 
THROMBOEMBOLISM 
Thromboembolic disease has been associated with pomalidomide in patients with multiple myeloma, 
who are often on concomitant high-dose corticosteroids and have a predisposition to thrombosis due 
to their underlying cancer. Thrombosis has not been observed in a pilot study of HHT treated with 
pomalidomide with approximately 60 pt-months of exposure. The development of thrombosis in a 
patient on this study being treated with pomalidomide warrants study drug discontinuation.  
6.1.8.10 
HEPATOTOXICITY 
Pomalidomide hepatotoxicity is rare. Elevations in bilirubin or transaminases > 3 times the baseline 
value should prompt temporary discontinuation of pomalidomide. Laboratory testing should be 


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performed two weeks after discontinuation to assure that abnormalities have resolved. If so, therapy 
may be resumed at a dose of 3 mg/day.  
6.1.8.11 
RENAL TOXICITY 
Renal toxicity of pomalidomide is rare. Renal toxicity is defined by CTCAE version 4.0 criteria. An 
increase of creatinine of > 0.3 mg/dl, or a baseline creatinine > 1.5 with an increase at least 2x  above 
baseline define Grade 1 nephrotoxicity. If these abnormalities are confirmed, the pomalidomide dose 
should be reduced to 3 mg/day. For higher levels of nephrotoxicity, the drug will be discontinued until 
the abnormalities have resolved and pomalidomide will then be reintroduced at a dose of 3.0 mg/day. 
6.1.8.12 
DOSE ADJUSTMENT FOR PERIPHERAL NEUROPATHY 
Dose adjustments will be undertaken for peripheral motor neuropathy and peripheral sensory 
neuropathy as described in the tables below.  Table 1C lists the NCI CTCAE Version 4.0 grading of 
adverse event severity for peripheral motor neuropathy and peripheral sensory neuropathy.  Table 
1D lists the intervention that will be used for each type of neuropathy according to NCI CTCAE grade. 
 
TABLE 1C: NCI CTCAE FOR PERIPHERAL NEUROPATHY 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Peripheral 
Motor 
Neuropathy 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self 
care ADL; 
assistive 
device 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Peripheral 
Sensory 
Neuropathy 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self 
care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 


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6.1.9 DURATION OF THERAPY 
The duration of pomalidomide therapy will be 24 weeks.  
6.1.10 TRACKING OF DOSE 
Only enough pomalidomide capsules for 1 cycle (i.e., 28 days) of therapy will be provided to the 
patient each cycle. Patients will be instructed to return empty bottles or unused capsules at each in-
person visit. 
Returned empty bottles or unused study drug will be disposed by the clinical site (according to site 
procedures) after documentation. If any study drug is lost or damaged, its disposition should be 
documented in the source documents. 
6.1.11 DRUG/DEVICE SPECIFIC CONSIDERATIONS 
Pomalidomide (POMALYST®) or matching placebo will be provided to research subjects for the 
duration of their participation in this trial at no charge to them or their insurance providers.  
Pomalidomide will be provided in accordance with the POMALYST REMS™  program.  Per the standard 
POMALYST REMS™ program requirements, all physicians who prescribe pomalidomide for research 
subjects enrolled into this trial, and all research subjects enrolled into this trial, must be registered in 
and must comply with all requirements of the POMALYST REMS™ program.   
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
Patients will be instructed to return all empty bottles or unused capsules at each of the 6 treatment 
visits. Pill counts will be conducted at every treatment visit to determine compliance.  
TABLE 1D: INTERVENTIONS FOR PERIPHERAL NEUROPATHY BY NCI CTCAE GRADE 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Peripheral 
Motor 
Neuropathy 
None 
Hold Pomalidomide 
treatment for up to 4 
weeks; restart at  next 
lowest dose if 
symptoms resolve or 
improve to Grade 1 
Off study drug 
permanently 
Off study drug 
permanently 
Off study  
Peripheral 
Sensory 
Neuropathy 
None 
Hold Pomalidomide 
treatment for up to 4 
weeks; restart at  next 
lowest dose if 
symptoms resolve or 
improve to Grade 1 
Off study drug 
permanently 
Off study drug 
permanently 
Off study  


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7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  
7.1.1.1 
EPISTAXIS SEVERITY SCORE 
The epistaxis severity score (ESS) was developed by Hoag et al and is a clinically-validated score for 
quantifying epistaxis in HHT which correlates inversely with QOL11,26. The ESS takes only 1-2 minutes 
to perform and will be obtained during screening to assess for eligibility, at the start of therapy, and 
at each study visit. The ESS will be determined by the study nurse, coordinator or investigator. At 
screening, the ESS will assess symptoms and bleeding over the previous 3 months. All other time 
points will assess symptoms and bleeding over the prior 4 weeks. Questions comprising the ESS are 
depicted in Table 2. The ESS captures the frequency, duration and severity of epistaxis. Clinical 
characteristics of the bleeding frequency and severity are collected and assigned a numerical score, 
which is added and multiplied by specific coefficients to determine the final ESS. Historically, sixty 
percent of patients with an ESS of 4-7 have required invasive treatment. The maximum ESS score is 
10, with patients in the 7-10 range being considered to have severe epistaxis.  Calculations for 
determining the ESS are depicted in Table 3, and an automated determination of the ESS may be 
obtained in real time through electronic entry of scores as depicted in Table 2 
(https://curehht.org/resource/epistaxis-severity-score/). Question 4 “have you sought medical 
attention for your nose bleeding” will not include scheduled study visits UNLESS the participant would 
have sought medical attention had the study visit not been scheduled-we suggest that this question 
refer to emergent visits for bleeding, such as those to an emergency department. Question 5 “are you 
anemic (low blood counts) currently” will be based upon the hemoglobin results of laboratory testing 
related to that particular study visit. The presence of anemia will be defined using local laboratory 
cutoffs as used for study eligibility.  
 


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Table 2: Questions comprising the epistaxis severity score.  
 
Table 3: Sample table for calculation of the ESS. 
Question Response
Coefficient
Result
Less than monthly
0
Once per month
1
Once per week
2
Several per week
3
Once per day
4
Several per day
5
< 1 minute
0
1-5 minutes
1
6-15 minutes
2
16-30 minutes
3
>30 minutes
4
No
0
Yes
1
No
0
Yes
1
No
0
Yes
1
I don't know
Drop
0
No
0
Yes
1
Total
Denominator 
(Sum Den)
Raw 
Score
6
X
0.31           
(0.31 Den)
5
X
4
X
0.30           
(0.30 Den)
0.20           
(0.20 Den)
0.25          
(1.00 Den)
3
X
0.25           
(0.25 Den)
Multiplied by
1
X
0.14           
(0.70 Den)
2
X
Raw 
Score
Denominator 
(2.76) 
10
Normalized
HHT-EES


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7.1.1.2 
EPISTAXIS DURATION 
In addition to the ESS, subjects will be asked to determine the total duration of epistaxis at several 
four week intervals  during the study (4 weeks prior to baseline, and between weeks 8-12 (C2-C3), 20-
24 (C5-C6), and 4 weeks  after treatment discontinuation (C6-EOS)) using an electronic diary with 
paper backup. The total weekly epistaxis duration averaged over these four week intervals will be 
assessed as a secondary endpoint as described in sections 4.2.2 and 10.2.   
7.1.1.3 
QUALITY OF LIFE INSTRUMENTS 
QOL instruments will be performed at baseline, after 12 and 24 weeks of treatment, and 4 weeks after 
the end of treatment.  The QOL is assessed using three validated NIH  instruments as well as the HHT-
specific questionnaire developed during the design of this study  (described in Section 2.1): 
The three NIH instruments are:  
1. Neuro-QOL Satisfaction with Social Roles and Activities Short Form  V1.1.  8 questions. Total 
score is calculated as a T score using Neuro-QOL scoring engine.  
2. PROMIS Emotional Distress – Depression Short Form 8b V1.0. 8 questions. Total score is 
calculated as a T score using PROMIS scoring engine.  
3. PROMIS Fatigue Short Form 6a V1.0. 6 questions. Total score is calculated as a T score using 
PROMIS scoring engine.  
The HHT-specific survey 56 (see Appendix 1) includes the following four questions: 
1. How often in the past 4 weeks has an activity related to your work, school, or regularly 
scheduled commitments been interrupted by a nose bleed? 
2. How often in the past 4 weeks has an activity with your partner, family, or friends been 
interrupted by a nose bleed? 
3. How often in the past 4 weeks have you avoided social activities because you were worried 
about having a nose bleed? 
4. How often in the past 4 weeks have you had to miss work, school, or regularly scheduled 
commitments because of HHT related problems other than nosebleeds? 
A total score is calculated by summing the items 1-4 (each ranging from 0-4). The total score ranges 
from 0 (no limitations) to 16 (severe limitations). If any items are not answered, the total score will 
not be calculated.  
7.1.1.4 
COUNSELING 
Patients will be provided with their laboratory results and interpretation at each visit. Their symptoms 
will be reviewed and they will be counseled concerning the relationship of these symptoms, if any, to 
pomalidomide and/or HHT. 


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7.1.2 STANDARD OF CARE STUDY PROCEDURES  
7.1.2.1 
MEDICAL HISTORY 
A full medical history will be taken during the screening visit. An interval history including questions 
to allow calculation of the ESS will be taken at all subsequent visits.  
7.1.2.2 
PHYSICAL EXAMINATION 
A full physical examination including vital signs, examination of the nasal mucosa, examination of the 
heart, lungs, abdomen and extremities, as well as a brief neurologic examination with emphasis on 
peripheral neuropathy will be performed at screening, at month 3 of the treatment period, at the end 
of treatment (cycle 6) and at the end of study. A limited physical examination including vital signs, 
HEENT and cardiopulmonary examinations will be performed during all other visits. At remote visits, 
physical exam will be performed to the extent possible. If the screening visit is performed remotely, 
the baseline visit will include a full physical examination. 
7.1.2.3 
CONCOMITANT MEDICATION 
Patients will be allowed to use any concomitant medications that they require except those listed in 
the exclusion criteria and section 7.6 Prohibited Medications, Treatments and Procedures. They may 
remain on HHT-directed medications other than those listed in the exclusion criteria if they were 
taking these when eligibility was determined. If they remain on such medications, they must remain 
on a stable dose during the study. Concomitant medications will be reviewed at screening, and at each 
study visit.  
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
7.2.1.1 
STANDARD OF CARE LABORATORY STUDIES 
CBC 
A CBC with differential will be performed at the screening visit and at all other study visits. 
Hematologic toxicities of pomalidomide and their grading are discussed in Table 1A. The Hgb, WBC, 
absolute neutrophil count (ANC) and platelet counts at all study visits will be recorded.  
Complete Metabolic Profile 
A complete metabolic profile including renal and liver function studies will be performed at screening, 
at the initiation of therapy, each month during pomalidomide therapy, and at the end of treatment. 
The ALT, AST, alkaline phosphatase, total bilirubin, creatinine and BUN at all study visits will be 
recorded.  


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Iron Studies 
Ferritin, iron and total iron binding capacity (TIBC) (to determine iron saturation) will be obtained at 
screening, at the initiation of therapy, each month during treatment, at the end of treatment and at 
the end of the follow-up period.  
PT/INR (International Normalized Ratio) and Activated Partial Thromboplastin Time  
Hemostasis will be assessed by measuring the PT/INR and activated partial thromboplastin time (aPTT 
or PTT per local laboratory designation) tests. These two tests will only be done at screening and are 
not required at other study visits. For study entry, the INR should be ≤1.4 and aPTT should be within 
the normal range (± 2 sec) per local laboratory guidelines (except for patients on a stable dose of 
warfarin or direct oral anticoagulants).    
7.2.1.2 
NON-STANDARD OF CARE LABORATORY STUDIES 
Genetic Testing 
All patients who provided consent for genetic testing will undergo testing for at least the three 
primary genes associated with HHT (endoglin (ENG), ACVRL1 and SMAD4) if they have not had prior 
testing or if the results for these three genes are not available. Genetic testing will  be performed at 
Ambry Genetics, Aliso Veijo, CA. Samples will be shipped to Ambry, who will determine whether 
genetic testing costs will be covered by the patient’s health care insurer. If not,  Ambry will  perform 
genetic testing at a reduced rate that will be covered by this study.  
Pregnancy Testing 
As mandated by the POMALYST REMS® program, all FCBPs must follow pregnancy testing 
requirements. In FCBP, pregnancy tests will be performed 10-14 days before, and within 24 hours of 
first study drug order. During the first treatment cycle, weekly pregnancy testing is mandated. 
Thereafter, pregnancy testing will be performed once every 4 weeks, during each cycle of treatment, 
preferably during the middle of the treatment cycle, or every 2 weeks for irregular menses. 
Biorepository Samples 
Biorepository blood samples will be obtained at the following times: 1) screening visit, 2) 
randomization (baseline) visit, 3) at 12 and 24 week treatment period visits,  4) at the 4 week post-
treatment (end of study) visit, and 5) early termination visit (if this occurs). These will be shipped to 
the lead PI’s lab for storage. If a study visit is conducted remotely, sample collection for biorepository 
at that visit will be skipped.  
7.2.2 OTHER ASSAYS OR PROCEDURES 
7.2.2.1 
ASSESSMENT OF STUDY AGENT ADHERENCE 


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Adherence to pomalidomide will be conducted by direct questioning and by pill counts at each study 
visit. Deviations from the prescribed dosage regimen should be recorded.  
Patients who are signficantly noncompliant may be discontinued from the study. A patient will be 
considered significantly noncompliant if he or she misses more than 5 consecutive days of study drug 
or more than 10 cumulative days of study drug during the study. Similarly, a patient will be considered 
significantly noncompliant if he or she is judged by the investigator to have intentionally or repeatedly 
taken more than the prescribed amount of study drug. 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Biorepository samples will consist of one serum (SST) vacutainer tube,  one citrate plasma tube and 
one EDTA plasma tube. At the randomization (baseline) visit, end of cycle 3 visit (week 12), end of 
cycle 6 visit (week 24) and early termination visit (if this occurs) we will also obtain one PAXgene blood 
RNA tube. When study visits involving biorepository sample collection are conducted remotely, 
sample collection will be skipped.  Samples will be processed on site to isolate plasma and serum. 
PAXgene tubes do not require processing. Samples including the unprocessed PAXgene tube will be 
stored at -80° C and shipped to the PI’s lab  semi-annually. Samples to be shipped should include all 
samples collected from enrolled subjects up to the shipment date.  Detailed instructions regarding 
processing, storing and shipping of biorespository and genetic testing samples will be described in the 
Manual of Procedures. 
7.2.4 SPECIMEN SHIPMENT 
Shipping information, including shipping labels will be provided to each site. Samples for biorepository 
will be shipped overnight in dry ice and stored at -80°C upon receipt until the time of analysis.  
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
Each patient will require a screening visit to determine study eligibility. During the screening period 
the following information will be obtained.  
• 
Informed consent of potential participant verified by signature on written informed 
consent  
• 
Review enrollment criteria  
• 
Review medical history  
• 
Review of medication history  
• 
Complete ESS with 3-month recall 
• 
Documentation of packed red blood cell transfusions and/or iron infusions over the 
previous six months  
• 
Performance of a detailed physical exam  


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• 
Collect blood for CBC, ferritin, iron and TIBC, renal and liver function, INR and aPTT (or 
PTT per local laboratory designation), and pregnancy testing for women of child 
bearing potential.  
• 
Collect biorepository blood samples (if visit is in-person) 
• 
Determine need for parenteral iron therapy based on results of iron studies.  
• 
Provide participants with instructions for recording epistaxis duration between 
screening and enrollment/baseline visit.  
• 
Schedule study visits for eligible patients.  
• 
Provide participants with instructions for attending the baseline visit.  
At the site PI’s discretion, the screening visit may be conducted remotely. Obtaining signed informed 
consent prior to collecting any information for the study is mandatory for a remote screening visit as 
well.  Physical examination may be limited to the extent possible at a remote visit; vital signs and 
biorepository sample collection will be skipped for remote screening visit. Screening laboratory 
studies may be obtained within 2 weeks before and after the screening visit.   
Participants who do not initially meet eligibility criteria, but may meet criteria at a later time may be 
rescreened.  Screening study procedures should be repeated per protocol and Manual of Procedures 
for rescreening. Baseline visit (if participant meets eligibility criteria) should be scheduled based on 
the rescreen date.  
7.3.2 BASELINE/RANDOMIZATION 
A period of at least 28 days after the screening visit will be required before the 
baseline/randomization visit, which must be conducted in-person. The baseline visit will be 
synonymous with the day of randomization and will include the following: 
• 
Verification of inclusion/exclusion criteria 
• 
Obtain ESS with 28-day recall  
• 
Complete QOL instruments 
• 
Perform pregnancy testing for women of child bearing potential 
• 
Review of concomitant medications and adverse events 
• 
Record vital signs, results of physical exam  
• 
Collect laboratory samples for CBC, iron studies, and genetic testing 
• 
Collect biorepository blood samples 
• 
Collect epistaxis duration information 
• 
Randomization and study drug order 
• 
Study drug dispensation 
Results from the laboratory assessments at baseline should not to be used to re-establish eligibility 
criteria; study eligibility is determined by assessments completed at the screening visit.  


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If the screening visit was done in-person and study eligibility is confirmed, randomization and study 
drug order may be done 3-5 days before the baseline visit to ensure that study drug is available on 
site for dispensation on the day of visit. Patients may be instructed to initiate the drug the same day 
or the following day.  
If the screening visit was done remotely, randomization and study drug order will be done at the 
baseline visit. A detailed physical examination will be performed at the baseline visit and biorepository 
sample collection tube will include PAXgene RNA tube in addition to the SST, sodium citrate and EDTA 
plasma tubes.   
After randomization, study drug will be shipped overnight to the study site (or directly to the patient)  
from the experimental pharmacy. Patients will be instructed to initiate the drug upon receipt or the 
following day.  
7.3.3 TREATMENT FOLLOW-UP  
Follow up studies and procedures during the treatment phase are as noted in the Schedule of Events 
(Section 7.3.7). At the follow-up treatment visits, study drug order may be initiated 3-5 days before 
the scheduled visit day to ensure that study drug is available for dispensation on visit day. Patients 
will be asked to bring empty bottles and remnant capsules (if any) at each in-person treatment visits 
for drug accountability. Laboratory studies may be completed ± 1 week of the study visit; however, it 
is strongly recommended that laboratory assessments be completed and test results be available at 
the study visit to evaluate safety. 
At the site PI’s discretion, visits at the end of treatment cycles 1, 2, 3, 4 and 5 may be conducted 
remotely. At the remote visits, vital signs recording will be skipped and physical exam may be limited 
to the extent possible. Biorepository sample collection at remote visits will also be skipped. At remote 
visits, study drug will be directly shipped to the patient from the experimental pharmacy. Information 
related to drug return and accountability will be collected at the remote visit with a reminder for the 
patient to bring remnant pills and empty bottles at the next in-person visit. If required, patient may 
be requested to ship the previously dispensed bottle (empty or with remnant pills) to site. The visit at 
the end of treatment cycle 6 (C6, key timepoint) will be conducted as an in-person visit.  
Visit schedule will not be paused or altered for any missed follow-up visit; study follow-up should 
resume at the next scheduled study visit. 
7.3.4 FINAL STUDY VISIT  
Data to be gathered at the final study visit (EOS, end of the 4 weeks post-treatment observation 
period) is listed in the Schedule of Events table (Section 7.3.7). This visit may also be conducted 
remotely according to site PI’s discretion. In addition, the following will be addressed.  
• 
Record final adverse events as reported by participant or observed by investigator.  
• 
Provide final instructions and/or follow up information to participant.  


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• 
Obtain final biorepository sample (if visit is in-person) 
7.3.5 DISCONTINUATION OF STUDY MEDICATION 
Study medication may be stopped by the study PI due to toxicity concerns or a subject may elect to 
stop study medication due to personal reasons. For temporary study drug discontinuations, study 
drug should be restarted after toxicity/safety concerns are resolved. In case of permanent study drug 
discontinuation, subjects should complete the visit associated with their current treatment cycle and 
then complete the EOS visit 4 weeks later (e.g. if a subject permanently stops study drug in the middle 
of their second treatment cycle, they will complete the end of treatment cycle visit 2 (C2) followed by 
an EOS visit 4 weeks later) (Figure 3). Subjects who do not agree to complete the 4 week post-
treatment follow-up must be discontinued due to withdrawn consent and the Early Termination visit 
should be completed per Section 7.3.6 in place of the current treatment cycle visit.  
7.3.6 EARLY TERMINATION VISIT 
If a subject wishes to withdraw consent for study participation, study drug is to be stopped and the 
early termination visit should be completed as soon as possible. Parameters dictated by the Schedule 
of Events (Section 7.3.7) for an early termination visit will be obtained. 
 
Figure 3. Follow-up visit schedule after permanent study drug discontinuation. Dark Green: completed visits; 
Red: stop study medication mid-cycle. 


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7.3.7 TABLE 4: SCHEDULE OF EVENTS TABLE 
SC = Screening; BL = Baseline; C = End of cycle; ESS = Epistaxis severity score; CBC = Complete blood count; CMP = 
Complete metabolic panel; EOS = End of study Visit; ET = Early termination; QOL = Quality of life; Gray boxes: 
flexibility to perform visits remotely in which case physical exam may be mofified; vital signs and biorepository 
samples may not be collected.   
* Window to begin study drug dosing cycle (see Section 6.1.5) 
1 Limited physical examination; *A detailed physical exam if screening visit was remote. 
2 Vital signs will include height (only at first in-person visit), body weight, blood pressure, pulse and O2 saturation.   
3 Genetic testing will be performed only if not done previously or if results for ENG, ACVRL1 and SMAD4 genes are 
not available and consent is obtained. 
4 Information on Iron infusion and Blood transfusion over the past 6 months to be collected at screening visit.  
5 ESS will be a 3-month recall for these visits; for all other visits, it will be a 4-week recall. 
 
Screen and Baseline 
Treatment Period 
End of Study 
Visit 
SC 
BL 
C1 
C2 
C3 
C4 
C5 
C6 
EOS 
ET12 
Study Procedures 
Week -4 
to -813 
Week 0 
Week 4 
0-5 Days* 
Week 8 
0-5 Days* 
Week 12 
0-5 Days* 
Week 16 
0-5 Days* 
Week 20 
0-5 Days* 
Week 24 
0-5 Days  
Week 28  
(4 week 
follow up) 
0-7 Days 
Only for 
withdrawn 
consent 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Enrollment Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam  
X 
X1* 
X1 
X1 
X 
X1 
X1 
X 
X 
X 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic Testing3 
 
X 
 
 
 
 
 
 
 
 
Iron Infusion 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Transfusion 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESS 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Epistaxis Duration Diary 
X 
X6 
 
X 
X6 
 
X 
X6 
X6 
X6 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Iron Studies7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR and aPTT (or PTT per 
local lab designation) 
X 
 
 
 
 
 
 
 
 
 
Biorepository Collection 
X 
X8 
 
 
X8 
 
 
X8 
X 
X8 
QOL9 surveys 
 
X 
 
 
X 
 
 
X 
X 
X 
Pregnancy Testing10 
X 
X 
X 
X 
X 
X 
X 
X 
 
X10 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Drug Dispensation 
 
X 
X 
X 
X 
X 
X 
 
 
 
Drug Return 
 
 
X11 
X11 
X11 
X11 
X11 
X 
 
X 


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6   Epistaxis Duration Diary will be collected at these visits and if applicable a new diary will be dispensed for the 
next set of epistaxis recording. For ET visit, diary will be collected if dispensed for the previous visit.  See MOP for 
additional details. 
7 Iron studies include ferritin levels, serum iron and total iron binding capacity. 
8 One PAXgene RNA tube is included at these visits.  
9 QOL questionnaires will include 3 NIH instruments (Neuro-QOL Satisfaction with Social Roles and Activities Short 
Form V1.1, PROMIS Emotional Distress - Depression Short Form V1.0 and PROMIS Fatigue Short Form V1.0) and 
a HHT specific questionnaire.   
10 In FCBP, pregnancy tests will be performed 10-14 days before, and within 24 hours of first study drug order. 
During the first treatment cycle, weekly pregnancy testing is mandated. Thereafter, pregnancy testing will be 
performed once every 4 weeks, during each cycle of treatment, preferably during the middle of the treatment 
cycle, or every 2 weeks for irregular menses.  For subjects completing an ET visit, pregnancy testing is only 
required if study medication was taken after the last pregnancy test.    
11 Information on remaining drug and empty bottles will be collected over phone, email, or other means, if visit is 
remote. 
12 Early Termination visit should be scheduled as soon as possible not to exceed 4 weeks post study drug 
discontinuation. 
13 Strongly recommended that BL be scheduled 4 weeks after SC. Additional days up to 8 weeks to be used only for 
scheduling purposes.  
 
 
 


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
All concomitant prescription medications, treatments and procedures taken during study 
participation will be recorded on case report forms (CRFs). For this protocol, a prescription medication 
is defined as a medication that can be prescribed only by a properly authorized/licensed clinician. 
Medications to be reported in the CRF are concomitant prescription medications, over-the-counter 
medications and non-prescription medications. 
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Patients who are on chronic anticoagulation with warfarin or a direct acting oral anticoagulant 
at a stable dose are eligible for the study.  
 
Patients on chronic aspirin are eligible for the study. 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Several drugs may interact with pomalidomide, either directly or indirectly, increasing the risk of 
toxicity. The use of other agents may potentially obscure the therapeutic effect of pomalidomide. 
Therefore, the following restrictions on the use of specific medications must be followed during the 
study. 
 
The use of concomitant octreotide, which may be used for management of gastrointestinal 
angiodysplasia, is prohibited.  
 
Initiation or changing the dose of oral epsilon-aminocaproic acid or tranexamic acid is not 
allowed while the patient is on study. However, if the patient is already on a stable dosing (at 
least a month before study start) of an antifibrinolytic agent he/she may be evaluated for 
study eligibility.  
 
The use of propanolol, timolol, epsilon aminocaproic acid or tranexamic acid nasal sprays will 
be allowed if the patient is already on a stable dosing regimen of one of these agents and 
continues to have epistaxis of a severity that qualifies him/her for this trial. The initiation or 
administration of increased doses of any intranasally-administered agent will not be 
permitted while the patient is on study.   
 
Bevacizumab, either administered intranasally/topically, or systemically, will not be allowed 
while the subject is on study.  
 
Erythropoetic agents and oral estrogen and/or progestin therapy are not allowed.  Nasal 
estriol is allowed if the patient was using this agent before study entry and does not change 
the dose during the study.  Nasal estriol cannot be added during the study. 
 
Ciprofloxacin, fluvoxamine, ketoconazole are not allowed (decreased metabolism and 
potential increase in pomalidomide toxicity). 


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 
Carbamazepine is not allowed (decreased pomalidomide effect) 
 
Initiation of pazopanib will not be allowed while the subject is on study 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Since this is an investigational drug for treatment of HHT, study drug will not be available to patients 
once the treatment period ends. 
8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
A secondary objective of this study will be to define the incidence of toxicities potentially attributable 
to pomalidomide. These include 
 
Venous thromboembolism 
 
Arterial thromboembolism 
 
Thrombocytopenia 
 
Neutropenia 
 
Peripheral neuropathy 
 
Fatigue 
 
Constipation/diarrhea 
 
Rash/pruritis 
Venous and arterial thromboembolism will be considered serious adverse events and result in study 
drug discontinuation. Thrombocytopenia and neutropenia will be managed as outlined in Section 
6.1.8. Peripheral neuropathy will be managed as outlined in Section 6.1.8.12. Management of fatigue 
will involve temporary withholding and/or dose reduction of study drug  at the investigator’s 
discretion.  
The incidence of these toxicities has been determined in studies of patients with multiple myeloma, 
who have compromised bone marrow function, a predisposition to thrombosis, and reduced 
immunity. Therefore, estimates of toxicity based on this population are likely not relevant to the 
current study. However, subjects taking pomalidomide will be continuously monitored for these 
toxicities.  


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8.1.1 DEFINITION OF ADVERSE EVENTS  
An adverse event (AE) is defined as any untoward or unfavorable medical occurrence in a human study 
participant, including any abnormal sign (e.g. abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the participants’ involvement in the research, 
whether or not considered related to participation in the research.  
For the purposes of this protocol, worsening of epistaxis, and seeking medical attention for epistaxis 
is not to be reported as an AE, as epistaxis is part of the disease being studied and evaluated for 
primary and secondary endpoints. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator 
or sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
For the purposes of this protocol, worsening of epistaxis and seeking medical attention for epistaxis 
is not to be reported as an SAE unless it results in death.  
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
Unanticipated problems are defined as including any incident, experience, or outcome that meets all 
of the following criteria: 
 
unexpected (in terms of nature, severity, or frequency) study procedure that is outside of the 
given (a) research procedures that are described in the protocol-related documents, such as 
the IRB-approved research protocol and informed consent document; and (b) characteristics 
of the subject population being studied; 
 
related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
Corrective actions or changes that will be considered in response to an UP include:  


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• Modification of inclusion or exclusion criteria to mitigate the newly identified risks  
• Implementation of additional safety monitoring procedures  
• Suspension of enrollment of new participants or halting of study procedures for enrolled 
participants  
• Modification of informed consent documents to include a description of newly recognized 
risks  
• Provision of additional information about newly recognized risks to previously enrolled 
participants. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 SEVERITY OF EVENT 
National Cancer Institute (Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) for 
use in reporting adverse events. The website for the CTCAE is: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.  
The CTCAE includes a grading (severity) scale for each adverse event term. Grades were developed 
using the following guidelines: 
 
Grade 1 –Mild adverse event 
 
Grade 2 –Moderate adverse event 
 
Grade 3 –Severe or disabling adverse event 
 
Grade 4 - Life threatening adverse event 
 
Grade 5 –Fatal adverse event 
8.2.2 RELATIONSHIP TO STUDY AGENT 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory 
rechallenge procedure if necessary.  
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 


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reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfill this definition.  
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, 
other factors may have contributed to the event (e.g., the participant’s clinical condition, 
other concomitant events). Although an AE may rate only as “possibly related” soon after 
discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or“definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration 
of the trial medication) and in which other drugs or chemicals or underlying disease 
provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• 
Not Related – The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
8.2.3 EXPECTEDNESS  
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study agent. Determination of the expectedness 
of an adverse event will be made by the site PI after evaluating the study subject. All AE reports will 
be reviewed by the IMM, who will make the final determination concerning relatedness of the event 
to the drug.   
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All 
AEs including local and systemic reactions will be captured on the appropriate CRF. Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, relationship to 
study product (assessed by the site PI or his/her designee), and time of resolution/stabilization of the 
event and any additional medical treatment employed in its management (assessed by the site PI or 
his/her designee). All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution.  
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates at 
any time during the study, it will be recorded as an AE. UPs will be recorded in the data collection 
system throughout the study.  


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If there are changes to severity of an AE during a single episode, the maximum severity experienced 
for that episode should be recorded. AEs characterized as intermittent require documentation of 
onset and duration of each episode.  
The study site will record all adverse events with start dates occurring any time after informed consent 
is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study drug . At each 
study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 
8.4 
REPORTING PROCEDURES 
Reporting requirements of AEs are calibrated to the seriousness of the event and the perceived 
relationship to the study treatment. This study will be using the descriptive terminology developed by 
the National Cancer Institute (Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) 
for 
use 
in 
reporting 
adverse 
events. 
The 
website 
for 
the 
CTCAE 
is: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. The site needs to be 
aware of the distinction between a severe AE and serious AE: severe refers to the intensity of the AE 
whereas serious refers to the AE that fulfils the criteria as defined in section 8.1.2. During the trial, 
occurrence of all AEs and SAEs will be documented on dedicated eCRFs (and the corresponding paper 
version, if applicable) on an ongoing basis in a manner consistent with ICH Requirements.51 Reporting 
timelines and requirements for AEs that are deemed to be serious or non-serious differ and the site 
must follow the appropriate reporting procedures.  
8.4.1 NON-SERIOUS ADVERSE EVENT REPORTING  
For AEs that are non-serious the site should use the AE eCRF within Medidata RAVE to enter all event 
information within 5 working days of becoming aware of the event. All reported AEs will be followed 
until resolution or study completion, whichever occurs first.  After review by the study monitor, the 
site may be requested to provide additional details. The site should additionally follow local IRB 
guidelines for submission of these AEs to their local IRBs.  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
SAEs will be promptly reported by the site to the DCC using the SAE eCRF within Medidata RAVE, within 
24 hours of becoming aware of the event. The DCC may contact the site for additional information on 
the SAE, if required. All SAEs must also be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable, whichever occurs first. All 
updates to SAEs must also be promptly provided within 48 hours of becoming aware of the updates. 
The DCC will review and categorize all SAEs with the independent medical monitor to facilitate reporting 
by the CCC.  
All sites are expected to adhere to the specified timelines and procedures for SAE reporting in order 
to facilitate SAE reporting by the CCC to meet specific timelines mandated by the FDA, NHLBI 
(https://www.nhlbi.nih.gov/grants-and-training/policies-and-guidelines/nhlbi-adverse-event-and-


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unanticipated-problem-reporting-policy), DSMB, Celgene Drug Safety, and the Cleveland Clinic IRB, as 
applicable.  
8.4.3 UNANTICIPATED PROBLEM REPORTING  
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. It is the site investigator’s responsibility to report UPs to their IRB and to the DCC/study 
sponsor. The UP report will include the following information:  
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
• 
UPs that are SAEs will be reported to the DCC and institution IRB (as applicable) within 24 
hours of the investigator becoming aware of the event. 
• 
Any other UP will be reported to the DCC and institution IRB (as applicable) within 72 
hours of the investigator becoming aware of the problem. 
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and OHRP within 7 days of the IRB’s receipt of the report of the problem from the 
investigator. 
8.4.4 EVENTS OF SPECIAL INTEREST  
AEs of special interest are listed in Section 8.1. 
8.4.5 REPORTING OF PREGNANCY  
1. All FCBP are screened for pregnancy at the screening visit, and subsequently managed as 
mandated by the pomalidomide REMS. The REMS has the following requirements for 
pregnancy screening throughout the study. 
2. Females taking Pomalidomide must avoid pregnancy during active treatment and for at least 
four weeks after taking pomalidomide. 
3. Female patients of reproductive potential must either completely abstain from heterosexual 
sexual contact or must use two effective methods of contraception (at least one highly effective 
method and one effective method) at the same time (see Table 2 below). 
4. The 2 effective contraceptive methods include using at the same time at least 1 highly effective 
method and at least 1 additional method of birth control every time they have sex with a male. 


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5. The 2 effective contraceptive methods must be started at least 4 weeks before POMALYST 
therapy, during therapy (including dose interruptions), and for at least 4 weeks following 
discontinuation of therapy.  
6. The subject will undergo pregnancy testing twice prior to pomalidomide initiation. They must 
obtain a negative pregnancy test 10 to 14 days before first study drug order and again within 24 
hours before study drug order even if continuous abstinence is the chosen method of birth 
control.  
7. Pregnancy testing must occur weekly during the first four weeks of use.  
8. During subsequent cycles, pregnancy testing must occur every 4 weeks if they have regular 
menses or every two weeks if menses are irregular.  
9. The sensitivity of the pregnancy test should be at least 50mIU/ml. 
10. Since oral estrogen may have a potential therapeutic effect in HHT, oral contraceptives are 
not considered an acceptable means of contraception during this study. 
Table 2. REMS Program Contraceptive Methods 
Highly Effective Methods 
Additional Effective Methods 
Unacceptable Methods 
 Intrauterine device (IUD) 
 Hormonal methods: 
- 
Hormonal patches 
- 
Injections 
- 
Vaginal rings 
- 
Implants 
 Tubal ligation 
 Partner's vasectomy 
 Male latex or synthetic 
condoms 
 Diaphragm 
 Cervical cap 
 Progesterone-only “mini-pill” 
 IUD progesterone T 
 Female condoms 
 Natural family planning 
(rhythm method) 
 Breastfeeding 
 Fertility awareness 
 Withdrawal 
 Cervical shield* 
*A cervical shield should not be confused with a cervical cap which is an effective secondary form of contraception. 
Pomalidomide is present in semen of males taking the drug and therefore males must always use a 
latex or synthetic condom during any sexual contact with females of reproductive potential while 
taking pomalidomide and for up to 4 weeks after discontinuing pomalidomide, even if they have 
undergone a successful vasectomy. Male patients taking pomalidomide must not donate sperm.  
Study subjects must not donate blood during treatment with pomalidomide and for 1 month following 
discontinuation.  
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on pomalidomide, or within at least 
28 days of the subject’s last dose of pomalidomide, are considered reportable events.  Pomalidomide 
is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to the DCC and institutional IRB (as applicable) as an SAE. The subject should be 
referred to an obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
further evaluation and counseling. The Investigator will follow the female subject until completion of 
the pregnancy, and must notify the DCC and institutional IRB (as applicable)  about the outcome of 
the pregnancy (either normal or abnormal outcome) within 15 days. 


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All neonatal deaths that occur within 28 days of birth should be reported, without regard to causality, 
as SAEs. In addition, any infant death after 28 days that the Investigator suspects is related to the in 
utero exposure to the pomalidomide should also be reported to the DCC and institutional IRB (as 
applicable) within 24 hours of the Investigator’s knowledge of the event using the SAE Report Form. 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking pomalidomide should notify the Investigator, and the pregnant female partner should 
be advised to call their healthcare provider.  
8.5 
STUDY HALTING RULES  
Randomization of new participants will be halted when eight thromboembolic events, defined as any 
venous thromboembolic event requiring medical intervention (grade 2 or higher) or any arterial 
thromboembolic event, that are determined to be related or “probably related” to the study drug are 
reported to the DCC.  
The DCC will notify the study monitor, study sponsor, PI and investigators immediately when the  
eighth thromboembolic event (as defined above) is reported and randomization functionality will be 
deactivated. The PI will inform the DSMB members within 24 hours of this occurrence and the DCC 
will provide the DSMB with AE listing reports. The DSMB will convene an ad hoc meeting by 
teleconference or in writing as soon as possible. The DSMB will provide recommendations for 
proceeding with the study to the study sponsor/NIH. The clinical coordinating center will inform NHLBI 
and the FDA of the temporary enrollment halt and the disposition of the study. 
8.6 
SAFETY OVERSIGHT 
This study will be reviewed for safety by an independent data safety monitoring board (DSMB) who 
are familiar with HHT, selected by NHLBI (per protocol), work independently of the PI, and thus have 
the appropriate expertise to monitor the safety and risk/benefit ratio of pomalidomide for HHT. 
Serious adverse events that arise in this study will be brought to the attention of the PI, DCC, IRB, FDA, 
NHLBI, and Celgene. The DSMB will meet every 6 months during the study.  Two meetings will include 
a planned interim analysis for efficacy or futility after 50% and 75% of subjects have completed the 
24 week treatment period. See section 10.4.7 for further details. 
9 
CLINICAL MONITORING 
Site monitoring visits will be conducted by the Data Coordinating Center to inspect study data, 
informed consent forms, subjects’ medical records, and Case Report Forms, pursuant to US GCPs and 
other federal and local regulations. Monitoring visits will occur in the first year after site activation and 
every other year thereafter. The study site principal investigator will permit authorized 
representatives of the FDA, NHLBI, and local health authorities to inspect relevant facilities and 
records. 


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10 
STATISTICAL CONSIDERATIONS  
10.1 
STATISTICAL AND ANALYTICAL PLANS 
A detailed statistical analysis plan (SAP) will be prepared by the study statistician and approved by the 
trial Steering Committee and the DSMB prior to database lock and unblinding of the study data. Details 
of all analyses including data reduction steps, calculation of derived variables, primary, secondary, 
subgroup, and confirmatory analyses will be provided in the SAP. The SAP will have table templates 
as appropriate. The SAP will also fully specifiy the criteria to make decisions at the interim and final 
analyses, including: 
 
Definition of the endpoint(s) that will be considered when deciding if the trial should continue 
beyond the pre-planned interim analysis. These endpoints will include the primary efficacy 
and safety endpoints, but may also include other outcome measures. 
 
Decision criteria. The rules that pre-specify the criteria for recommending that the trial stop 
at the interim analysis. The decision criteria will be specified using established methods for 
group sequential trial design that will assure that the pre-trial statistical operating 
characteristics are not altered by the interim analysis. 
 
Methods for implementing the interim analyses: often the pre-trial timing of the interim 
analysis must be altered to accommodate differences from the pre-trial assumptions about 
event rates and timing of DSMB meetings. The SAP will pre-specify the procedures that will 
be used to modify the decision rules to accommodate changes in the timing of the interim 
analysis. 
 
Bias-adjusted inference: the SAP will specify the method for reporting of trial results that will 
adjust for the bias that is introduced by the interim analysis.  
10.2 
STATISTICAL HYPOTHESES 
Primary efficacy endpoint:  
The primary efficacy endpoint is the change from baseline to Week 24 in the ESS total score. 
Null hypothesis: There is no difference in the mean change in ESS score at Week 24 between 
the pomalidomide and placebo treatment groups. 
Alternative hypothesis: There is a difference in mean change in ESS score at Week 24 between 
the pomalidomide and placebo treatment groups. Specifically, pomalidomide will have a 
larger improvement from baseline than placebo.  
Secondary efficacy endpoints:  
The pomalidomide and placebo treatment groups will be compared for the following secondary 
endpoints:  
Key Secondary endpoints 


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1. Amount of parenteral iron administered (in mg) during the 24 week treatment period in the 
pomalidomide and placebo groups (calculated as average mg/4-week interval to account for 
patients who discontinue early). 
2. Amount of packed red blood cell transfusions (in units) during the 24 week treatment period 
in the pomalidomide and placebo groups (calculated as average units/4-week interval to 
account for patients who discontinue early). 
3. Change in Neuro-QOLTM Satisfaction with Social Roles and Activities Short Form (V1.1) T-score 
from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-
treatment follow-up visit in the pomalidomide and placebo groups. 
4. Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key timepoint), 
and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups.  
5. Change in average weekly epistaxis duration from the four week screening period prior to 
randomization to weeks 8-12 and to weeks 20-24 (key timepoint), and to 4 weeks post-
treatment in the pomalidomide and placebo groups. 
Other Secondary enpoints 
6. Change in PROMIS® Emotional Distress – Depression Short Form (V1.0) T-score from baseline 
(randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-treatment 
follow-up visit in the pomalidomide and placebo groups. 
7. Change in PROMIS® Fatigue Short Form (V1.0) T-score from baseline (randomization visit) to 
weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the 
pomalidomide and placebo groups. 
8. Proportion of patients requiring no red blood cell transfusion or parenteral iron infusion 
during the 24 week treatment period in the pomalidomide and placebo groups. 
9. Change in the ESS from baseline to that recorded at each individual patient assessment, 
including the 4 week post-treatment follow-up visit.  
10. Change in the ESS from baseline to the average of the week 16, 20 and 24 assessments.   
11. Proportion of patients requiring endoscopic interventions for management of bleeding during 
the 24 week treatment period in the pomalidomide and placebo groups. 
12. Change in iron/hemoglobin-related studies including iron saturation, ferritin, hemoglobin, 
hematocrit, MCV, and MCHC. 
Null hypothesis: For each secondary endpoint, there is no difference between the pomalidomide and 
placebo treatment groups. 
Alternative hypothesis: There is a difference between between the pomalidomide and placebo 
treatment groups. Specifically, pomalidomide will have a larger improvement  
10.3 
ANALYSIS DATASETS 
Modified Intention-to-Treat Analysis Dataset: Randomized participants who took at least one dose 
of double-blind study medication and have at least one post-baseline efficacy measurement. 


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Per-Protocol (PP) Analysis Dataset: Randomized participants who complete the study with no major 
protocol violations and took at least 80% of the prescribed double-blind medication. 
Patients who withdraw consent for further follow-up will be treated as lost to follow-up at the time 
that consent was withdrawn, and data will be used up to the time of study withdrawal. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
This is a Phase II trial in which the primary goal is to evaluate the safety and efficacy of pomalidomide 
in the treatment of  epistaxis in patients with HHT. 
For descriptive statistics, categorical data will be presented as proportions and 95% confidence 
intervals and continuous data as means with standard deviations, median, and range. Estimates from 
linear models will be presented by mean, standard error, and 95% CI. Estimates from logistic 
regression will be presented by odds ratios and 95% CIs. All statistical tests will be 2-tailed. 
Checks of assumptions (e.g., normality) underlying statistical procedures will be performed and 
corrective procedures such as use of a transformation or application of nonparametric tests will be 
applied. 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The primary analysis will be fully pre-specified in a written SAP.  
Treatment groups will be compared for the change from baseline in the ESS Total Score at Week 24 
using a mixed effects analysis of covariance model for repeated measures (MMRM).  The observed 
change from baseline score at each scheduled post-baseline visit (Weeks 4, 8, 12, 16, 20, 24, and 4 
Weeks post-treatment) is the dependent variable. The model will include the baseline ESS score as a 
covariate, with fixed effect categorical factors for treatment group (Active and Placebo), site, visit, 
and the treatment × visit interaction. The interaction remains in the model regardless of significance, 
and treatment group comparisons at each visit are estimated by differences of least squares (LS) 
means.  A heterogeneous Toeplitz covariance pattern will estimate the variance-covariance of the 
within-subject repeated measures, and the Kenward-Roger method will be used to calculate 
denominator degrees of freedom. Estimates, p-values and 95% confidence intervals will be presented 
for treatment group comparisons at each visit. In an intent-to-treat fashion, all data will be included 
in the primary model, regardless of the treatment actually taken by the patient. 
This model assumes missing data (such as due to a missed visit or due to early study discontinuation) 
is missing at random. Sensitivity analyses to this assumption to be specified in the SAP will be explored, 
including methods that assume that data are missing not at random, such as imputation of missing 
outcomes in the pomalidomide treatment group based on data from the placebo group (control-


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based imputation).  We will also investigate if the season of the year of enrollment is a relevant 
baseline covariate, given that there may be seasonal variation of epistaxis during colder months due 
to drier room air and increased prevalence of upper respiratory infections.  
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
A Hochberg multiple comparison adjustment will be applied to the 5 key secondary endpoints to 
maintain the overall Type 1 error rate, as described in Section 10.4.9. Treatment groups will be 
compared for the secondary endpoints as follows: 
Treatment groups will be compared for the total amount of packed red blood cell transfusions 
(average units/4-week interval) and iron (average mg/4-week interval) infused during the 24 week 
treatment period, using an analysis of covariance or rank analysis of covariance if not normally 
distributed, with adjustment for baseline value, defined as the average amount over the 6 months 
prior to the screening visit and clinical site. Missing data from early discontinuations will be addressed 
assuming MAR by averaging each subject’s available data.  Sensitivity analyses will be specified in the 
SAP.  If packed red blood cell transfusions are rare, then we will switch to either a zero-inflated 
Poisson regression model or logistic regression. 
Groups will be compared for the proportion of patients relapsed, requiring no blood or iron, and 
requiring endoscopic interventions using logistic regression with adjustment for baseline assessment 
(ESS score, whether the patient had required a blood transfusion or required an iron infusion of at 
least 250 mg in the 6 months before the screening visit, and ESS score, respectively), and study site.  
Treatment group comparisons of the ESS score averaged over the week 16, 20, and 24 week visit 
assessments and at each study visit will be assessed in the same model as the primary outcome.  
Change from baseline in weekly epistaxis duration averaged over weeks 8-12, 20-24, and 4 weeks 
after treatment, and Quality of Life scores at weeks 12, 24, and 4 weeks after treatment will be 
analyzed using the same MMRM model as the ESS score.  
10.4.4 SAFETY ANALYSES 
In addition to expedited reporting of unexpected SAEs outlined in Section 8.4.2, the DCC will 
determine the frequency of toxicities potentially attributable to pomalidomide treatment that were 
described in Section 8.1 (e.g., venous/arterial thromboembolism, thrombocytopenia, neutropenia, 
peripheral neuropathy, fatigue, constipation/diarrhea, rash/pruritis). The DCC will determine the 
number of subjects experiencing each type of event and the frequency with which each occurs in the 
affected subjects. Treatment and resolution of all safety endpoints will also be documented. 
Treatment groups will be compared for incidence of events with a chi-squared or Fisher’s exact test, 
and incidence density (events per person-months of exposure) will be calculated for toxicities in the 
pomalidomide group. Adverse event incidence rates will be included in semi-annual safety reports to 
the DSMB and annually to the FDA. 


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10.4.5 ADHERENCE AND RETENTION ANALYSES 
Missing data and missed visits will be monitored in real-time. In the event a scheduled visit is missed, 
site coordinators will contact the patient before the follow-up period closes to encourage them to at 
least obtain measurements relevant to the primary endpoint. For any missing data that do occur, we 
will record and describe the reasons the data are missing when reporting results.  
In the event that one or more ESS or QOL score is missing during the treatment, or post-treatment 
periods, the MMRM analysis approach which assumes data are missing at random (MAR) will be used 
to compare treatments based on the available data and the correlation between observations with a 
person. To guard against bias if the MAR assumption is incorrect, sensitivity analyses will be explored, 
as specified above in section 10.4.2. 
10.4.6 BASELINE DESCRIPTIVE STATISTICS 
Baseline and demographic characteristics will be summarized by standard descriptive summaries (e.g. 
means and standard deviations for continuous variables such as age and percentages for categorical 
variables such as gender). 
10.4.7 PLANNED INTERIM ANALYSES  
The Data Coordinating Center will prepare regular data reports, and the DSMB will review those 
findings to ensure that patients are not exposed unnecessarily to clearly inferior or dangerous 
treatments and to accelerate scientific and clinical progress if clear evidence can be obtained much 
earlier than originally expected. DSMB reports prepared by the DCC will include summaries of AEs and 
SAEs, primary endpoint measures, and metrics of study enrollment, retention, and data quality on 
which the DSMB can base their recommendations. Biostatisticians from the DCC will develop a DSMB 
Charter and an interim statistical analysis plan (ISAP) detailing interim stopping criteria and the DSMB 
will review and amend as needed.  We plan to have DSMB reviews once each 6 months, with a formal 
interim analysis for efficacy after 50% and 75% of patients have completed the 24 week treatment 
period or discontinued from the study.  
10.4.7.1 
SAFETY REVIEW 
Safety reviews will take place every 6 months corresponding to DSMB meetings. In addition to the 
interim safety reviews, all adverse events will be reviewed by the trial independent medical monitor, 
Dr. Jason Valent, who will also refer all major events to the DSMB chair for potential consideration 
and discussion by the DSMB. 
Study halting rules are described in Section 8.5. Briefly, randomization of new study participants will 
be halted when  eight thromboembolic events, defined as any venous thromboembolic event 
requiring medical intervention (grade 2 or higher) or any arterial thromboembolic event, that are 
determined to be related or “probably related” to the study drug are reported to the DCC.  


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Safety monitoring is described in detail in Section 8.  
10.4.7.2 
EFFICACY REVIEW 
We will perform a formal interim analysis to evaluate for early overwhelming efficacy based on the 
change in ESS score from baseline to 24 weeks after 50% and 75% of subjects have completed the 24 
week visit or discontinued the study.  Futility will also be assessed at 75%, and each formal interim 
analysis will include a full DSMB safety review.  
For assessing early efficacy, the significance level for the interim and final analysis will be based on 
Lan-DeMets α-spending functions with O’Brien-Fleming boundaries in order to maintain the study-
wise α level at 0.05. The α level will be 0.0031 at 50%, 0.0183 at 75% and 0.0440 at the final analysis. 
The exact α level at the interim will be determined based on the actual percent of data available at 
the interim. Assuming 90% power at the end of the study, there is a 26% chance of meeting the 
stopping boundary at the 50% interim, and a 69% chance at the second interim. If the study actually 
has 80% power (for example, due to higher than expected discontinuation rate or ESS standard 
deviation), then there is a 54% chance of meeting the stopping boundary at the second interim. 
Conversely, if the study actually has power > 95% (for example if treatment group difference in ESS 
change is 1.2 rather than 1.0 or lower than expected standard deviation), then the chance of stopping 
is 41% at the first interim and 84% at the second interim. 
Futility will be assessed at 75% based on conditional power of the primary efficacy variable.  The DSMB 
may recommend study stop due to futility if the upper limit of the 80% confidence interval for 
conditional power does not exceed 50%.  
With our planned enrollment rate, we expect approximately 6 months of randomization visits to take 
place after the 50% interim analysis (Table 5), and so there is a potential to decrease the overall study 
sample size in the event that the DSMB recommends stopping enrollment based on the interim 
analysis results. If enrollment proceeds as planned, then randomization will be essentially complete 
by the time of the 75% interim analysis. In this case, we will request the DSMB to skip the second 
interim analysis in order to maximize the alpha level at the end of the study. Otherwise, if enrollment 
is slower than expected, then the results of the second interim analysis still provide a chance to 
decrease the study sample size. 
 
 


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Protocol Timeline 
Y1  
Y2  
Y3  
Y4  
Y5  
  
Q
1 
Q
2 
Q
3 
Q
4 
Q
1 
Q
2 
Q
3 
Q
4 
Q
1 
Q
2 
Q
3 
Q
4 
Q
1 
Q
2 
Q
3 
Q
4 
Q
1 
Q
2 
Q
3 
Q
4 
Recruitment* 
     
x x x x x x x x x x   
  
  
  
  
  
  
Randomized after screening (1-2M) 
 
 
 
 
x x x x x x x x x x  
 
 
 
 
 
24W visit (end of treatment) 
 
 
 
 
 
 
x x x x x x x x x x  
 
 
 
28W visit (4W post-trt follow-up) 
 
 
 
 
 
 
 
x x x x x x x x x x  
 
 
Interim - 50% completed 24W 
 
 
 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
 
 
Interim - 75% completed 24W 
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
 
 
 
 
 
Database lock 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x  
 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x x x x 
*assumes 10 patients randomized at the end of the first year, and 7 patients/year at 10 sites in 
subsequent years. (6 patients/site/year would add an extra 3 months to recruitment period). 
Table 5.  Timing of interim analysis relative to planned Study Milestones 
10.4.8  
ADDITIONAL SUB-GROUP ANALYSES 
We will evaluate treatment group comparisons for the primary outcome and key secondary outcomes 
in subgroups of participants defined by genetic confirmation of HHT (yes or no),  gender and race (per 
NIH guidelines).  
10.4.9  
MULTIPLE COMPARISON/MULTIPLICITY 
For inferential tests, the p-value for determination of statistical significance (Type I error) for the single 
primary efficacy outcome (change in ESS from baseline to week 24) will be evaluated relative to 0.044 
to adjust for the interim efficacy analysis.  
Significance of the treatment group comparison for 5 key secondary outcomes will be evaluated as 
follows:  If the primary endpoint is found statistically significant at p < 0.044, then the key secondary 
endpoints will be evaluated for statistical significance with a Hochberg52 modification to the 
Bonferroni adjustment, in which the p-values of the 5 outcomes will be ordered. The largest p-value 
will be compared relative to p <0.05, and if met, all 5 endpoints will be considered significant.  If not, 
then the second largest p-value will be assessed relative to p < 0.05/2 = 0.025, and if met then it and 
the other three endpoints will be considered significant, and so on for the 3rd p-value compared at 
0.05/3 = 0.017, the fourth compared to 0.05/4 = 0.012, and the firth compared to 0.05/5 = 0.010. 
Results from analyses of all other secondary endpoints and subgroup analyses will not be evaluated 
relative to statistical significance.  
 
 


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10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
Subject-level data will be produced internally at the DCC that will allow detection of potential issues 
that could only be detected by examining trends across multiple visits. For example, such reports 
could enable rapid identification of patterns in missed visits or missed entries for patient-reported 
data (ESS, QOL data), medical incongruencies, or data outliers, or trends in the number of adverse 
events.  
10.4.11 
EXPLORATORY ANALYSES 
Exploratory analyses include estimating the rate of relapse at the 4 week post-treatment follow-up 
visit, where relapse is defined as a return of the ESS to the baseline value or greater in pomalidomide-
treated subjects, and  estimating the median time after initiation of pomalidomide to obtain a 
decrease of at least 1.0 in the ESS in pomalidomide-treated compared to placebo subjects.  To try to 
understand which demographic or biomarkers are predictive of greater response to pomalidomide 
we will fit generalized linear models to predict treatment response based on presence of the specific 
mutations in the endoglin (ENG) or activin-like kinase (ACVRL1) genes. In future studies, the 
biorepository specimens obtained in this study may be analyzed for the predictive value of growth 
factors, proteins, microRNAs, or other potential biomarkers measured in participant biospecimens.  
10.5 
SAMPLE SIZE 
We will randomize 159 patients,  106 on pomalidomide, 53 on placebo. 
Design: Since HHT is a rare disorder and our study is unlikely to be repeated, we wish to power the 
study at 90%.  To assist in participant recruitment, we will randomize in a 2:1 ratio of pomalidomide 
to placebo in order to maximize active intervention for study participants and also maximize the 
amount of safety data for pomalidomide. Treatment group comparison for the single primary 
endpoint will be evaluated for statistical significance relative to alpha <0.0444, reduced from 0.05 to 
adjust for two planned interim analyses after 50% and 75% of patients complete the treatment period 
(see section 10.4.7.2). 
Effect Size: The primary endpoint is ESS change from baseline to 24 weeks.  We wish to power the 
study to identify a difference between pomalidomide and placebo of 1.0. Table 6 provides a summary 
of ESS scores from available HHT studies.  In our small pilot study of patients with moderate to severe 
epistaxis treated with pomalidomide, we found an average reduction in ESS score at 24 weeks of 2.7. 
On the other hand, the NOSE study53 of 121 HHT patients identified an improvement in ESS across all 
study participants receiving placebo or non-effective treatments of 1.5 at 12 weeks.  Although we 
anticipate a difference of at least 1.2 between groups in our study, we have planned the sample size 
to detect a difference of 1.0.  This value is above the estimated minimally important difference of 0.7 
as determined by patient’s assessment of QOL54. We conservatively estimate that the standard 
deviation for the ESS change from baseline score will be 1.7, based on standard deviations from the 


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recent large double-blind NOSE trial and with support from other small studies in Table 6, many of 
which range from 1.5 to 1.7.  
Discontinuation Rate: Table 6 also summarizes early study discontinuation rates for HHT study 
participants, either due to drop-out (from placebo or treatments with minimal side effects), or due to 
AEs (from our pilot study of pomalidomide and studies of the more toxic thalidomide).  Based on an 
average of these sources, we anticipate a 10% discontinuation rate during the 24-week treatment 
interval.  Patients with HHT regularly see their doctors and are not expected to be lost to follow-up, 
and so we anticipate being able to obtain post-baseline ESS scores even for participants who stopped 
taking the double-blind study drug before that time. We also expect to minimize study 
discontinuations by allowing patients with some side effects to temporarily halt study drug and then 
re-start with a lower dose.  Nevertheless, it is likely that some participants may discontinue the study 
without providing any post-baseline data, and it is possible that discontinuations due to AE may be 
larger than 10%.  By planning for 90% power with a 10% discontinuation rate, we plan to have 
sufficient sample size so that the study would still be well powered if the study discontinuation rate 
were as high as 30%. 
Author 
Treatment 
N 
ESS 
Baseline 
mean (SD) 
Post-trt 
assessment 
time 
Rate of 
Discontinuation, 
dose-limiting 
AEs or missing 
data 
ESS Post-
BL mean 
(SD) 
ESS Change from 
baseline 
Mean (SD), N 
Source of SD 
for change 
from baseline 
McCrae pilot 
study of 
Epistaxis and 
GI bleeding 
Pomalidomide 
9 (8 with 
epistaxis, 
1 with 
GI 
bleeding) 
5.9 (1.47) 
N=7 
(1 recent 
enrollment 
not yet 
included)   
12W  
22% (2/9) due to 
rash at 2W.  
3.5 (0.99) 
N=5 
-2.5 (2.11), N=5 
 
Calculated 
from data 
24W  
 
3.3 (0.61) 
N=5 
-2.7 (1.92), N=5 
Whitehead  
NOSE study 
(JAMA 2016) 
 
Randomized, 
double-blind 
Bevacizumab, 
estriol, 
tranexamic acid, 
or placebo nasal 
spray 
(There were no 
differences 
between the 4 
TRT groups) 
121  
 
5.4 (1.38) 
N=120 
12W  
12%  
(6% patient 
decision,  
6% missing diary 
data or protocol 
violation) 
3.7 
(1.68) 
N=105 
-1.5 (1.48), N=105 
By trt grp: 
B: -1.6 (1.2) 
E: -1.4 (1.5) 
TA:-1.4 (1.6) 
Placebo: -1.7 (1.6) 
Calculated 
from data 
provided by 
Author 
12W after 
TRT stop  
 
4.1 
(1.65) 
N=83 
-1.0 (1.53), N=83 
SD varied by trt grp: 
(1.3, 1.3, 1.7, 1.8) 
Dupuis-Girod 
ELLIPSE 
study 
(JAMA 2016)  
Randomized 
double-blind  
Bevacizumab or 
placebo nasal 
spray 
80 
N/A 
6 months 
8 %  
(6% patient 
decision, 
2% missing data 
or protocol 
violation) 
N/A 
N/A 
N/A 
Vivek 2018 
Retrospective 
review 
IV Bevacizumab 
34 
6.6 (2.2) 
N=30 
3 months 
N/A – not a 
study 
4.4 (1.8) 
N=14 
-2.4 (3.0), N=14 
SD is higher, 
perhaps due to 
standard of 
care vs study 
ESS scores 
Thompson, 
2014 
Non-rand. 
Bevacizumab low 
dose infusion 
6 
7.2 (2.1) 
N=6 
24W 
0% 
3.3 (1.9) 
N=6 
-3.9 (1.7), N=6 
Calculated 
from data in 
manuscript 
Invernizzi,  
 
Non-rand. 
Thalidomide 
31 
N/A 
4 months 
10% dose-
limiting AEs 
N/A 
N/A 
N/A 
Fang, 2017 
 
Thalidomide 
7 
5.3 (2.05) 
N=7 
Varied 8W-
18W 
30% (2/7) due to 
AEs 
0.9 (0.84) 
-4.4 (1.55), N=7 
Calculated 
from data 


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Author 
Treatment 
N 
ESS 
Baseline 
mean (SD) 
Post-trt 
assessment 
time 
Rate of 
Discontinuation, 
dose-limiting 
AEs or missing 
data 
ESS Post-
BL mean 
(SD) 
ESS Change from 
baseline 
Mean (SD), N 
Source of SD 
for change 
from baseline 
McCrae pilot 
study of 
Epistaxis and 
GI bleeding 
Pomalidomide 
9 (8 with 
epistaxis, 
1 with 
GI 
bleeding) 
5.9 (1.47) 
N=7 
(1 recent 
enrollment 
not yet 
included)   
12W  
22% (2/9) due to 
rash at 2W.  
3.5 (0.99) 
N=5 
-2.5 (2.11), N=5 
 
Calculated 
from data 
24W  
 
3.3 (0.61) 
N=5 
-2.7 (1.92), N=5 
Whitehead  
NOSE study 
(JAMA 2016) 
 
Randomized, 
double-blind 
Bevacizumab, 
estriol, 
tranexamic acid, 
or placebo nasal 
spray 
(There were no 
differences 
between the 4 
TRT groups) 
121  
 
5.4 (1.38) 
N=120 
12W  
12%  
(6% patient 
decision,  
6% missing diary 
data or protocol 
violation) 
3.7 
(1.68) 
N=105 
-1.5 (1.48), N=105 
By trt grp: 
B: -1.6 (1.2) 
E: -1.4 (1.5) 
TA:-1.4 (1.6) 
Placebo: -1.7 (1.6) 
Calculated 
from data 
provided by 
Author 
12W after 
TRT stop  
 
4.1 
(1.65) 
N=83 
-1.0 (1.53), N=83 
SD varied by trt grp: 
(1.3, 1.3, 1.7, 1.8) 
Dupuis-Girod 
ELLIPSE 
study 
(JAMA 2016)  
Randomized 
double-blind  
Bevacizumab or 
placebo nasal 
spray 
80 
N/A 
6 months 
8 %  
(6% patient 
decision, 
2% missing data 
or protocol 
violation) 
N/A 
N/A 
N/A 
Vivek 2018 
Retrospective 
review 
IV Bevacizumab 
34 
6.6 (2.2) 
N=30 
3 months 
N/A – not a 
study 
4.4 (1.8) 
N=14 
-2.4 (3.0), N=14 
SD is higher, 
perhaps due to 
standard of 
care vs study 
ESS scores 
Thompson, 
2014 
Non-rand. 
Bevacizumab low 
dose infusion 
6 
7.2 (2.1) 
N=6 
24W 
0% 
3.3 (1.9) 
N=6 
-3.9 (1.7), N=6 
Calculated 
from data in 
manuscript 
Invernizzi,  
 
Non-rand. 
Thalidomide 
31 
N/A 
4 months 
10% dose-
limiting AEs 
N/A 
N/A 
N/A 
Non-rand. 
3M after 
trt. Stop 
 
2.0 (1.34) 
-3.3 (1.35), N=7 
listed in 
manuscript 
Yin 
N/A 
604 
5.3 (2.03) 
N/A 
N/A 
N/A 
N/A 
N/A 
Table 6. ESS scores and discontinuation rates from HHT studies 
Analysis Method: We conservatively conduct initial sample size calculations based on a T-test with 
equal variances (using the Power procedure within SAS).  Since the primary analysis is an MMRM 
model with adjustment for baseline score, we next perform sensitivity power calculations which 
account for expected improvement in power based on the analysis plan.  Data provided from the 
NOSE study indicated that the correlation between baseline and change from baseline at post-
baseline visits is likely to be -0.4, and correlation between post-baseline visits is likely to be 0.5. 
Adjustment for baseline would reduce the standard deviation of the residual from 1.7 to 1.6. To 
evaluate power of the MMRM model in the face of increasing percent of missing data across study 
visits, we compute power using the formula by Lu, Luo, and Chen55.  
Calculation and Sensitivity Analysis: A total sample size of 159 patients (106 pomalidomide, 53 
placebo) will provide 90% power to identify a treatment group difference in ESS change from baseline 
at 24 weeks of 1.0 with p<0.044, assuming a standard deviation of 1.7 and 10% early discontinuation 
rate. Power will remain above 80% if there is a substantially higher than expected study 
discontinuation rate of 30% (with 10% providing no post-baseline data): 81% based on a conservative 


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T-test, or 90% with the planned MMRM analysis. If the standard deviation is 1.8 instead of 1.7, the 
power for the planned MMRM analysis would be 91% with 10% discontinuation, and 87% with 30% 
discontinuation.  Table 7 provides calculations for sample size selection, and Table 8 provides 
sensitivity of the power for the selected sample size.  
 
Pomalidomide 
vs placebo 
Mean 
difference in 
ESS change 
from BL at W24  
Std Dev 
of ESS 
change 
from BL 
at W24  
Effect size 
= (mean 
difference) 
/SD 
Power 
Planned sample 
size with post-
baseline data  
Planned 
study early 
D/C rate 
Total sample size. 
 
-1.0 
1.9 
0.526 
90% 
180 (120:60) 
10% 
198 (132:66) 
-1.0 
1.8 
0.556 
90% 
162 (108:54) 
10% 
178 (119:59) 
-1.0 
1.7 
0.588 
90% 
144 (96:48) 
10% 
159 (106:53) 
-1.0 
1.6 
0.625 
90% 
129 (86:43) 
10% 
141 (94:47) 
 
 
 
 
 
 
 
-1.2 
1.7 
0.706 
97% 
144 (96:48) 
10% 
159 (106:53) 
-0.7 
1.7 
0.412 
62% 
144 (96:48) 
10% 
159 (106:53) 
Note: In each row, the bolded number was calculated. All other items in the row were fixed. Calculations based on a 2-
sample T-test 
Table 7. Sample size calculations for 2:1 randomization and Alpha = 0.044. 
 
Calculation Method 
Std Dev 
Planned study 
early D/C rate 
Power 
T-test 
1.7 
10% 
90% 
MMRM* 
1.7 
10% 
94% 
 
 
 
 
T-test 
1.7 
20% 
87% 
MMRM* 
1.7 
20% 
92% 
 
 
 
 
T-test 
1.7 
30% 
81% 
MMRM* 
1.7 
30% 
90% 
 
 
 
 
T-test 
1.8 
10% 
87% 
MMRM* 
1.8 
10% 
91% 
 
 
 
 
T-test 
1.8 
20% 
83% 
MMRM* 
1.8 
20% 
89% 
 
 
 
 
T-test 
1.8 
30% 
76% 
MMRM* 
1.8 
30% 
87% 
Note: MMRM includes adjustment for baseline assuming a correlation of -0.4 between baseline 
and change from baseline, and assumes 10% have no post-baseline data, and half of the remaining 
drop-outs occur between the first and second post-baseline visits.  
     Table 8. Power Sensitivity Analysis for N=159, Mean Difference=-1.0 and Alpha = 0.044. 


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With 159 patients, we will also have at least 90% power to identify a treatment group difference of 
30% for a binary secondary endpoint of proportion of participants requiring at least one packed red 
blood cell transfusion or iron infusion at any time during the 24-week treatment period with p < 0.05, 
whether assuming a rate in the placebo and  pomalidomide groups of 90% and 60%, or 50% and 20%, 
as demonstrated in Table 9.   
Total sample size. 
Planned 
discontinuati
on rate 
Planned sample size 
(completers)  
Power for selected proportions  
(Pomalidomide vs placebo) 
60% vs 90% 
20%vs 50% 
159 (106:53) 
10% 
144 (96:48) 
98% 
96% 
159 (106:53) 
20% 
126 (84:42) 
97% 
93% 
159 (106:53) 
30% 
111 (74:37) 
94% 
90% 
Table 9. Power for comparison of treatment groups for proportion of patients with at least one packed 
red blood cell transfusion or iron infusion during the treatment period for 2:1 randomization with 
Alpha = 0.05. 
10.6 
MEASURES TO MINIMIZE BIAS 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
This study is double-blind. The placebo capsule will be identical in appearance to the pomalidomide 
capsule. After eligibility and consent are confirmed, designated staff will randomize the patient by 
accessing the randomization system through the Medidata Rave electronic data collection system. 
The DCC will create randomization tables for each center that include randomization numbers and 
treatment assignments in a randomly permuted block design. Randomization will be in a 2:1 ratio and 
will be stratified by site. All patients and protocol staff will remain masked to study treatment, except 
the DCC statistician responsible for randomization and submission of reports to the DSMB.  
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Any intentional or unintentional unmasking will be reported as a protocol deviation in the data 
management system. 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
In the event of an emergency, the site PI and/or study coordinator will be able to unmask a patient’s 
treatment assignment through a report from the DCC.  Such unmasking should only happen in a true 
emergency where knowing the treatment assignment would alter the course of treatment for the 
participant. 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Source documents for standard of care laboratory measures, medical history, concomitant 
medications, and HHT-specific interventions such as blood transfusions and iron infusions will be the 


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site’s electronic medical record (EMR). Source documents for data collected directly from the patient 
including items from the ESS, quality of life instruments, and reporting of adverse events will be the 
place upon which this data was first recorded by the site (such as a paper version of the CRF).  
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
The quality assurance (QA) and quality control (QC) program will be based on procedures for 
monitoring the quality of data and procedures implemented at the clinical sites. The QC Committee 
will have monthly conference calls to discuss issues that arise and review QA/QC reports. The DCC will 
work with the QC Committee to develop and provide support for its activities.  
QA activities refer to steps that are taken prior to collection of data that ensure unified data collection 
standards across clinical sites. These QA procedures will include the following: 
 
Detailed Manual of Procedures (MOP) Development. The MOP contains detailed instructions 
on study procedures, such as recruitment and screening, training, certification, data 
collection, quality control procedures, and specimen collection and transfer. The MOP serves 
as a reference guide for study staff, including investigators, coordinators, technicians, and 
data managers and clearly describes the functions of the DCC and CCC. To ensure quality and 
compliance with GCP guidelines, all documents created by the DCC (e.g., data collection 
forms, MOP, and analysis plan) will be reviewed and approved following procedures 
consistent with RTI’s SOPs and ITP guidelines developed in collaboration with NHLBI and 
network investigators. Final version controlled study documents will reside in the private 
portion of the ITP website. 
 
Training. The DCC will lead the training of site investigators, clinical coordinators, and data 
capture and reporting system users in collaboration with the CCC and NHLBI. Before study 
initiation and prior to randomizing any patients, each staff member must review the 
randomization instructions and confirm that they understand the procedures via the private 
portion of the ITP website. The DCC will use short quizzes at the end of training sessions to 
ensure participants understand the information covered during the training session and 
targeted training is provided for missed items. If face-to-face training of lead investigators is 
necessary (i.e., a train-the-trainer approach resulting from a need identified through DCC or 
CCC committees), then this will be conducted in conjunction with national meetings (e.g., 
American Society of Hematology). For training in use of the data capture and reporting 
system, each staff member will complete an e-learning module provided by Medidata and 
attend a live online demonstration of the system by RTI staff and practice session afterward. 
We use chat rooms to allow rapid responses to questions throughout the practice period.  
 
Certification. The DCC certifications will focus on ensuring that the site staff are 
knowledgeable about the protocol and procedures and can demonstrate proficiency in use of 
the data capture and reporting system prior to study initiation. 
 
Trial Operations. The Steering Committee will provide a regular forum for discussing and 
resolving issues, activities and processes related to trial operations, whether they are system-


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wide or site-specific. The Steering Committee will play a central role in ensuring procedures 
are followed and communicating new and revised procedures to the clinical sites.  
QC activities refer to steps that are taken during data collection to ensure unified data collection 
standards across clinical sites. The QC Committee will be responsible for overseeing the development 
of QA/QC reports. The QC Committee will have membership from the DCC and CCC and will hold 
monthly conference calls to discuss issues that arise and review QA/QC reports. These QC procedures 
will include the following: 
 
Monitoring of Data Quality and Implementing Corrective Action. The DCC will conduct site 
monitoring throughout the life of the study, at both the level of the individual data item and 
form and at a more global level, to ensure high-quality data. We focus on high-risk areas such 
as safety and efficacy data, and human subjects issues. Other trial-specific monitoring 
includes adherence to study eligibility criteria and protocol violations. Recent research 
suggests that a vast majority of issues can be identified and resolved cost-efficiently through 
central monitoring. Using the reporting capabilities of Medidata Rave, the DCC will produce 
reports that may signal poor data quality and has reduced the need for repeated costly site 
visits. These reports evaluate performance against SC-established metrics and contain 
detailed information on screening, recruitment, retention, staff training/certification, 
protocol violations, study implementation, data receipt, delinquent data, data quality, and 
edit failures. We identify errors, missing forms, or missing items and produce reports so that 
the site staff can investigate the issue. These routine reports enable us to evaluate general 
site performance and to quickly initiate corrective actions when needed. 
 
Site Visits. Onsite monitoring through site visits helps identify data entry errors (e.g., 
discrepancies between source records and electronic case report forms and missing data in 
source records or electronic case report forms; provide assurance that study documentation 
exists; assess the familiarity of center staff with the protocol and required procedures; and 
assess compliance with the protocol). The DCC and CCC will conduct site visits to clinical sites 
as needed or at the request of NHLBI.  CCC focus is to ensure that treatment procedures and 
follow-up assessments are following the specifications in the protocol and MOP. The DCC 
focus is to ensure data quality and to ensure uniform data collection, management, and 
reporting procedures across the sites, using established checklists and report templates. DCC 
will focus on facilities review to ensure that sites have the needed resources and reviewing 
research records and regulatory documents. Data capture and reporting system reports, such 
as those mentioned previously, are used to guide discussions with study staff. Following the 
site visit, the DCC and CCC will provide a unified written report to the site and NHLBI.  
 
Creation of Statistical Products. The DCC will adhere to written Standard Operating 
Procedures (SOPs) that cover such topics as the purpose and content of analysis plans; the 
steps required when producing sample size estimates, analyses, derived data sets, tables and 
graphs, and macros; or the process for developing and implementing an allocation or 
randomization scheme for clinical studies. Each SOP emphasizes a 3-step process for creating 
statistical products: specification (analysis details are specified in an analysis plan), creation 


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(all programs must use good programming standards to ensure well-documented code), and 
validation (e.g., review of data listings and tables of summary statistics, independent code 
review, independent programming). The analysis plans for each statistical product must 
specify validation requirements, and all analysis plans will be reviewed by the DCC PI. 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1 
ETHICAL STANDARD  
This study will adhere to the seven main principles used to guide the conduct of ethical research, as 
outlined by the NIH clinical center. The study has been and will continue to be analyzed and reviewed 
for adherence to each of these principles by the PI, study monitor, DSMB, DCC, and all participating 
physicians.   
 
Social and clinical value 
 
Scientific validity 
 
Fair subject selection 
 
Favorable risk-benefit ratio 
 
Independent review 
 
Informed consent 
 
Respect for potential and enrolled subjects 
13.2 
INSTITUTIONAL REVIEW BOARD  
This study will use a single IRB (Cleveland Clinic) as dictated by Notice Number: NOT-OD-16-094, 
effective May 25, 2017, applying to all NIH-funded multicenter clinical trials.  
13.3 
INFORMED CONSENT PROCESS  
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
All potential study subjects will be approached by a physician (site PI or CoI), research nurse or any 
assigned site personnel who will review the full consent form with the potential study subject. This 
consent form will include a full discussion of the potential benefits as well as risks of pomalidomide 
therapy, a description of all study procedures and implemented methods to protect patient 
confidentiality. Study subject will be given opportunity to ask questions and all questions will be 
answered by the site study personnel. When study subject expresses their desire to participate in the 
study, the informed consent will be signed by both the study subject and site study personnel 
obtaining consent. Assent will not be used since this study will only enroll adult patients. Informed 
consent document may be translated to a non-English speaking language upon request and will have 
to be approved by the IRB. If a translated consent is used, the translated version will be signed by the 


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participant and the English version will be signed by both the person obtaining consent and the 
interpreter.    
Consent is typically obtained on the day of screening visit in a face-to-face setting. In case of a remote 
screening visit, the consenting process may be conducted over telephone or any approved virtual 
platform. The consenting process should be completed (i.e., signed by both research subject and 
person obtaining consent) before the screening visit, with no more than 10 days between consent 
and the screening visit. 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
Consent procedures are described in 13.3.1. The signed consent form will be collected by the research 
coordinator at each site and stored in a locked cabinet.  
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
The confidentiality of all study subjects will be strictly maintained. Electronic data will be entered 
using a highly secure, password protected system (iMedidata). All study personnel will undergo 
training in patient confidentiality procedures at the study initiation meeting. No patient files will be 
shared by email.  
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES,SPECIMENS OR DATA 
Biorepository samples will be sent to the laboratory of the lead study PI, where they will be stored in 
a locked -80° freezer. Samples will be used to answer study-specific questions, specifically the 
identification of biomarkers that predict responses to pomalidomide. Refer to MOP for details. 
13.5 
FUTURE USE OF STORED SPECIMENS  
Requests from investigators who may have participated or not participated in the study will be 
entertained after study-specific testing has been completed on the collected samples. These will be 
considered on a case-by-case basis by the Steering Committee. 
14 
DATA HANDLING AND RECORD KEEPING  
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Medidata Rave is the primary data collection system for the study. Rave is a commercial, web-based 
data collection system that enables streamlined study design and setup with  integrated real-time 
reporting and analysis tools. This enables continuous data monitoring and analysis.  
Because Medidata Rave is web-based and supports direct data entry, the status of data collection can 
be assessed in real time. In addition, Rave supports the integration of data and metadata with systems 


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for randomization and capitation, and can also accommodate sophisticated within- and between-
form edit checks to ensure the accuracy of data. Real-time reports are available through the web 
interface to monitor open data queries. The DCC’s data management staff and the staff at the sites 
can use these reports to identify and resolve data issues in real time. A complete audit trail of data 
entered and any subsequent changes to the data is available on demand. Both data management staff 
and site staff will be able to routinely monitor data for these issues and resolve them directly in the 
system. Study documentation, including data dictionaries, can be automatically generated from the 
data management system and data can be exported at any time in a variety of standard formats (e.g., 
SAS data sets).  
Web Portal. A well-designed, easy-to-use, comprehensive project website is essential to the success 
of the study. The project website is the central hub to allow easy collaboration and communication 
among study investigators, clinical sites, and other study members. Role-based access  (e.g., core 
member, study coordinator, calendar administrator, and access administrator) will be tightly 
controlled by requiring users to log in using credentials supplied by the DCC, with different users 
having access to different portions of the website, depending on their role on the project. The website 
will include project materials (protocols, manuals, forms), a project calendar, the EDC system, and 
graphical dashboards to track study progress and milestones. Site staff will be allowed to access 
reports for their own site, but will not be allowed to see reports or data from another site. The DCC 
will comply with all aspects of Americans with Disabilities Act and Health Insurance Portability and 
Accountability Act of 1996 (HIPAA) requirements when designing our websites, and we test websites 
with established tools to ensure that we meet those requirements.  
Reporting (Study Monitoring). A centralized, integrated data management system provides the 
information needed to assess overall progress of the study and site performance through real-time 
data on enrollment, follow-up, data quality (completion of all data collection, outstanding queries, 
overdue or missing data and visits). Subject-level reports will also be available to allow detection of 
potential issues that could only be detected by examining trends across multiple visits. Because of the 
real-time nature of the data collection system, all communication regarding data issues can occur 
through the integrated data querying system. In this way, data can be corrected quickly and 
efficiently, and, as with initial data entry, a complete audit of changes is maintained. 
14.2 
STUDY RECORDS RETENTION  
See section 14.4, Data Sharing. 
14.3 
PROTOCOL DEVIATIONS  
Protocol deviations will be reported to the single IRB of record and will be recorded in the Medidata 
web-based data management system. 
14.4 
PUBLICATION AND DATA SHARING POLICY 


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The DCC will work with the Steering Committee (SC) and the funding agency to develop acceptable 
plans for resource sharing (including protocols, manuals, training materials, and study data with 
researchers and other members of the public), while maintaining acceptable levels of patient 
confidentiality. Upon approval from the NHLBI and the SC, we have shared study materials (e.g., 
protocols, manuals, training materials, CRFs that are not copyrighted by other organizations) through 
secure means (e.g., FTP server, encrypted and password protected DVD or email). In some cases, these 
materials have been openly available to the public. In other cases, the SC has limited release of some 
of these materials, and RTI staff have developed procedures to implement the limitations set by 
agreement of the SC. We will work with NHLBI, and the SC to develop plans for release of study 
materials.  
The data collected through the DCC are expected to provide a wealth of information regarding 
treatment for HHT with the potential for translating these findings to practice. The DCC will be 
responsible for working with NHLBI, the SC, and the clinical centers to develop a plan and schedule 
for distributing this valuable resource to both internal and external researchers. The plan for sharing 
the data demands a carefully developed strategy that is cognizant of the importance of protecting 
participants’ rights to individual privacy and is compliant with HIPAA regulations and other compliance 
requirements.  
The DCC will prepare de-identified data files for sharing. Shared data may be aggregated at the 
individual study center level. Data may be shared with investigators, their institutions and with 
outside investigators. Each level of aggregating and sharing data carries its own level of disclosure 
risk. Wherever appropriate, we will work with NHLBI, the SC, and the clinical centers to develop a data 
sharing plan that will strike a balance between the protection of participants’ rights and the desire for 
scientific collaboration. The plan will address the following issues: the expected disclosure risk level 
for each type of data sharing, which data types can be shared, the types of people (within the study 
or outside the study) who can access data at various levels, the form of participant informed consent 
required for each level of data sharing, and procedures for review and approval of data access request 
applications. 
The DCC will take great care to ensure that participant confidentiality is maintained in all shared data. 
Several options to protect privacy of the data include releasing only part of the data, altering the data 
in ways that will not compromise analyses, requiring outside researchers to adhere to strict 
confidentiality requirements, or providing access to the data through a controlled data enclave. At a 
minimum, the DCC will create data sets that have undergone de-identification processes that ensure 
the data satisfy all HIPAA and any related international requirements for protecting participant 
identity by producing de-identified data that conform to both HIPAA requirements and NIH policy on 
data sharing. The DCC will follow procedures developed in our other data coordinating projects, to 
release restricted or public-use data sets. Examples of these procedures include: 
 
replacing the unique participant identification variable in the original data sets with a new 
unique participant identifier produced by a random number generator; 


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 
removing any personal information from the data set (much of this type of data is not included 
in the data submitted to the DCC by the clinical sites); 
 
removing or recoding other distinguishing parameters, such as dates, research sites 
identification numbers, and hospitals where surgery was performed (e.g., dates can be 
recoded relative to a participant-specific reference point, and specific locations can be 
replaced by more general geographic codes). Interviewer or technician identifiers will be 
deleted or recoded; 
 
removing verbatim responses and especially sensitive variables, such as information on 
sensitive medical conditions or sexual activity; and 
 
combining subgroups with low frequencies or truncating distributions to ensure that there 
are a minimum number of participants for each category or value within each 
gender/ethnicity cell. 
Data Sharing With Trial Investigators. The first level of data sharing will be with trial investigators 
once data from the trial have been cleaned and closed, and preliminary analyses indicate that the 
data are ready to be shared among trial investigators. Appropriate documentation will be provided 
including labeled versions of CRFs, raw data sets, edited analysis data sets, format files for variables, 
and data dictionaries. The data can be provided in SAS data sets and export files and documentation 
will be in PDF format. These files can be developed on a periodic basis determined by the SC, for 
instance, 6 months after closed data sets for the trial have been prepared for final analysis or 1 month 
after results of the protocol are published in a peer-reviewed journal. The purpose of granting limited 
access is for researchers to develop appropriate analysis approaches and identify preliminary 
indications of findings.  
Data Sharing With the Broader Research Community. In addition, the DCC will be responsible for 
sharing study data with outside researchers, if approved by NHLBI and the SC. De-identified limited-
access data sets will be created for this purpose. Although the data sets will be stripped of identifiers 
and otherwise modified to prevent easy identification of patients in the study, the narrow focus of 
the population to be analyzed and the possible rarity of some outcome measures and risk factors 
might make it possible for an identification to be made. To protect the confidentiality and privacy of 
the participants, investigators granted access to these data must adhere to strict requirements. The 
SC will define these requirements and establish criteria for access to data by outside researchers. This 
information will be incorporated into a standard Data Distribution Agreement to which investigators 
must adhere. The agreement will be subject to review by legal and IRB departments of RTI and the 
clinical sites, and approved by the SC. In accordance with NHLBI policies, outside researchers will be 
required to submit an approval from their IRB. 
If directed by the NIH, instructions for obtaining access to the trial data and eligibility criteria can be 
publicized and provided through the study website. We can develop a request form to collect 
information deemed necessary by the SC and NIH, including applicant name, organization, and 
purpose of research. Investigators will submit the request form, Data Distribution Agreement, and IRB 
approval to designated DCC staff. The SC or its designated Committee will review each application, 


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and if the requestor meets established criteria for access to the data and provides the required 
documents, the requested data sets and associated documentation will be disseminated by a mode 
agreed upon by the SC in accordance with NHLBI policy. The data can be provided in SAS data sets and 
export files and documentation will be in PDF format. At the close of study funding, RTI staff will work 
with NHLBI and the SC to develop plans for providing continued access to the data. De-identified data 
files will be prepared by the DCC in accordance with NHLBI’s Limited Access Data Policy and Health 
Insurance Portability and Accountability Act (HIPAA) privacy standards and made available for use by 
investigators not associated with the trial, within three years after study completion. The DCC will 
emphasize a clear and searchable documentation of the limited access database, including 
transparent vocabularies and metadata, and its linkage to the pertinent study protocols and forms so 
that researchers of diverse backgrounds can make effective use of this resource. Inclusion of 
standardized derived variables will minimize the need for elaborate data manipulation and facilitate 
standardization of definitions and other technical details across manuscripts. 
15 
STUDY ADMINISTRATION 
15.1 
STUDY LEADERSHIP 
In addition to the clinical centers, the trial is implemented through a Clinical Coordinating Center (CCC) 
at Cleveland Clinic; a Data Coordinating Center (DCC) located in Research Triangle Park, NC at RTI 
International; and various collaborators providing specific expertise as described below and depicted 
in Figure 4. 
 
Figure 4. Organizational Structure of the Pomalidomide for the Treatment of Bleeding in Hereditary 
Hemorrhagic Telangiectasia Study 


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The National Heart, Lung, and Blood Institute (NHLBI) will serve as study sponsor. The Steering 
Committee will consist of NHLBI representatives, and a subset of site investigators who provided input 
to the design of the study as part of the NHLBI U34 Planning Grant. This leadership team will be 
responsible for all major scientific and operational decisions. Other trial committees will report to the 
Steering Committee at regular monthly meetings held by teleconference (or in person if necessary).  
Cure HHT, directed by Ms. Marianne Clancy, is a critical component of the overall structure of this 
trial. The HTTFI maintains a database of more than 10,000 HHT patients, many of whom are not 
followed at HHT Centers of Excellence and thus do not overlap with the rosters maintained by sites 
participating in this study. Cure HHT will serve as the primary marketing and information distribution 
tool for this study, and will work closely with the PI to develop materials for dissemination to patients 
with HHT, and to physicians who treat HHT patients.  
The Data Safety Monitoring Board (DSMB) will consist of approximately seven members and be 
directly appointed by NHLBI following recommendations of qualified individuals by the PI. Individuals 
on the DSMB will be familiar with the conduct of clinical trials, and have expertise in the management 
of HHT. The role of the DSMB will be as follows: 
 
To meet biannually by teleconference with the CCC and DCC PIs who will update trial progress. 
 
As a component of this teleconference, the DSMB will hold a closed-door discussion of 
progress, with specific focus on all AEs, as well as any SAEs that may have occurred.  
 
Following review and discussion of this data, the DSMB will determine whether any potential 
safety issues exist that would preclude the trial from continuing, or that need to be addressed.  
 
The DSMB will provide their recommendations (including continuation/discontinuation of the 
trial) to the NHLBI Director.  
 
The DCC will be responsible for documenting the proceedings of the DSMB meetings, and 
obtaining the signature of the designated DSMB chair.  
Dr. Jason Valent will serve as the Independent Medical Monitor (IMM) for this study. His role will be 
as follows:     
 
To review all AEs that occur during the trial. In particular, he will review all SAEs within 24 
hours of their occurrence.  
 
To prepare regular reports concerning SAEs and submit to the CCC PI, and subsequently to 
the DSMB and, as appropriate, to FDA as required by the IND.  
 
Like the DSMB, decisions of the IMM will be made independently of the PI, and he will have 
the authority to recommend that the trial be placed on hold if he observes an SAE that s/he 
considers trial-related that is of sufficient severity to threaten patient safety.  
 
The IMM may participate in DSMB reviews if he wishes, though this will not be compulsory, 
and in some cases he may wish to seek consultation from the DSMB.  
 
In situations in which the trial is put on hold or terminated, the IMM will communicate this 
directly to the PI and DCC, as well as to NHLBI.  


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 
If the IMM is unavailable for an extended period of time (i.e., extended vacation, sabbatical, 
illness) a backup IMM will be nominated by the CCC PI and approved by the NHLBI Program 
Official. 
The Quality Control (QC) Committee will include experts from the DCC and CCC. Involvement of 
clinical center PIs is optional. The roles of the QC committee will be as follows: 
 
Establish and oversee the development, implementation and monitoring of the essential trial 
quality control processes, including both informatics QC and clinical site QC.  
 
Review regular QC reports and work with the Steering Committee and Operations and 
Recruitment Committee to assure trial quality.  
 
Provide reports on overall trial quality to the Steering Committee on a semiannual basis. 
 
Provide reports on overall trial quality to the PIs for inclusion in annual NIH progress reports.  
16 
CONFLICT OF INTEREST POLICY 
All investigators will be expected to comply with institution-specific conflict of interest procedures 
that could potentially impact this trial. When these occur, they may most commonly be addressed by 
full disclosure. If this is felt to be insufficient, then the investigator will be replaced.  
17  
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2009;21(12):1347-1350. 
41. 
Wang XY, Chen Y, Du Q. Successful treatment of thalidomide for recurrent bleeding due to 
gastric angiodysplasia in hereditary hemorrhagic telangiectasia. Eur Rev Med Pharmacol Sci. 
2013;17(8):1114-1116. 


Protocol 133646-2:  PATH-HHT -  Pomalidomide for the Treatment of Bleeding in HHT 
 
 
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NIH-FDA Clinical Trial Protocol Template v0.1 20160205 
70 
42. 
Franchini M, Frattini F, Crestani S, Bonfanti C. Novel treatments for epistaxis in hereditary 
hemorrhagic telangiectasia: a systematic review of the clinical experience with thalidomide. J 
Thromb Thrombolysis. 2013;36(3):355-357. 
43. 
Chen CH, Hsu HH, Hu RH, Lee PH, Ho CM. Long-term therapy with thalidomide in hereditary 
hemorrhagic telangiectasia: case report and literature review. J Clin Pharmacol. 
2012;52(9):1436-1440. 
44. 
Alam MA, Sami S, Babu S. Successful treatment of bleeding gastro-intestinal angiodysplasia in 
hereditary haemorrhagic telangiectasia with thalidomide. BMJ Case Rep. 2011;2011. 
45. 
Lebrin F, Srun S, Raymond K, et al. Thalidomide stimulates vessel maturation and reduces 
epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med. 2010;16(4):420-
428. 
46. 
Devlin HL, Hosman AE, Shovlin CL. Antiplatelet and anticoagulant agents in hereditary 
hemorrhagic telangiectasia. N Engl J Med. 2013;368(9):876-878. 
47. 
Fang J, Chen X, Zhu B, et al. Thalidomide for Epistaxis in Patients with Hereditary Hemorrhagic 
Telangiectasia: A Preliminary Study. Otolaryngology--head and neck surgery : official journal 
of American Academy of Otolaryngology-Head and Neck Surgery. 2017;157(2):217-221. 
48. 
Ardelean DS, Yin M, Jerkic M, et al. Anti-VEGF therapy reduces intestinal inflammation in 
Endoglin heterozygous mice subjected to experimental colitis. Angiogenesis. 2014;17(3):641-
659. 
49. 
Invernizzi R, Quaglia F, Klersy C, et al. Efficacy and safety of thalidomide for the treatment of 
severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-
randomised, single-centre, phase 2 study. Lancet Haematol. 2015;2(11):e465-e473. 
50. 
Bowcock SJ, Patrick HE. Lenalidomide to control gastrointestinal bleeding in hereditary 
haemorrhagic telangiectasia: potential implications for angiodysplasias? Br J Haematol. 
2009;146(2):220-222. 
51. 
Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician's guide to 
terminology, documentation, and reporting. Ann Intern Med. 2004;140(10):795-801. 
52. 
Hochberg. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75:800-803. 
53. 
Whitehead KJ, Sautter NB, McWilliams JP, et al. Effect of Topical Intranasal Therapy on 
Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized 
Clinical Trial. Jama. 2016;316(9):943-951. 
54. 
Yin LX, Reh DD, Hoag JB, et al. The minimal important difference of the epistaxis severity score 
in hereditary hemorrhagic telangiectasia. Laryngoscope. 2015:10. 
55. 
Lu K, Luo X, Chen PY. Sample size estimation for repeated measures analysis in randomized 
clinical trials with missing data. The international journal of biostatistics. 2008;4(1):Article 9. 
56 
Kasthuri RS, Chaturvedi S, Thomas s, Vandergrift N, Bann C, Schaefer N, Clancy MS, Pyeritz R, 
McCrae KR; Development and performance of a hereditary hemorrhagic telangiectasia-
specific quality-of-life instrument. BLOOD ADV 2022; 6 (14): 4301–4309.  
 
 


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71 
 
APPENDIX 1 
HHT-SPECIFIC QOL QUESTIONNAIRE  
1. How often in the past 4 weeks has an activity for your work, school, or regularly scheduled 
commitments been interrupted by a nose bleed? 
0=Never 
1=Rarely 
2=Sometimes 
3=Often 
4=Always 
2. How often in the past 4 weeks has an activity with your partner, family, or friends been interrupted 
by a nose bleed?  
0=Never 
1=Rarely 
2=Sometimes 
3=Often 
4=Always 
3. How often in the past 4 weeks have you avoided social activities because you were worried about 
having a nose bleed?  
0=Never 
1=Rarely 
2=Sometimes 
3=Often 
4=Always 


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72 
4. How often in the past 4 weeks have you had to miss your work, school, or regularly scheduled 
commitments because of HHT-related problems other than nosebleeds? 
0=Never 
1=Rarely 
2=Sometimes 
3=Often 
4=Always  
Scoring: 
A total score is calculated by summing the items (each scored from 0-4). The total score ranges from 
0 (no limitations) to 16 (severe limitations). If any items are not answered, the total score will not be 
calculated. 

ICF_003.pdf: 
 
 
 
POMALIDOMIDE FOR THE TREATMENT OF 
BLEEDING IN HEREDITARY HEMORRHAGIC 
TELANGIECTASIA 
 
NCT03910244 
Protocol 133646-2 
Part 2 Local Site Information Consent Template 
Version 2.3, March 9, 2020 


Consent Version 2.3/Site to provide date 
Page 1 of 4 
PART 2: LOCAL SITE INFORMATION (customized per site-add 
delete as appropriate delete all highlighted instruction) 
 
Site Name: 
 
Site Principal Investigator: 
 
 
CONTACT INFORMATION 
Who do you contact with questions about the study? 
If you have any questions, you can ask the Site Investigator, (insert name and phone number) and/or 
research staff at (insert name(s) and phone number). 
Who do you contact after hours or in case of an emergency? 
If you need to contact study staff outside normal business hours, you may contact (insert phone 
number and process for 24 hour assistance). 
Where can you get more information? 
If the researchers cannot be reached, or if you would like to talk to someone other than the 
researcher(s) about concerns regarding the study, research participant’s rights, research-related 
injury, or other human subjects research issues, you may contact the Cleveland Clinic Institutional 
Review Board at (216) 444-2924. (Add local IRB if applicable) 
LOCAL REQUIREMENTS (delete section if not applicable) 
 
CONFLICT OF INTEREST (delete section if not applicable) 
 
COMPENSATION AND REIMBURSEMENT 
Are there any payments to you if you participate in this study? (edit per local 
context) 
 
 


Consent Version 2.3/Site to provide date 
Page 2 of 4 
 (Add any IRS tracking information if applicable) 
 
 
RESEARCH RELATED INJURY(add local context if applicable) 
What will happen if you are injured as a result of taking part in the research? 
Cleveland Clinic has not set aside any money to pay you or to pay for your treatment if you suffer a 
research related injury as a result of being in the study. There are no plans for Cleveland Clinic to 
provide other forms of compensation (such as lost wages, pain and suffering, or other direct or 
indirect losses) to you for research related injuries. You are not waiving any legal rights by signing this 
form, including the right to seek compensation for an injury.   
PRIVACY and CONFIDENTIALITY (use this or replace with local HIPAA 
authorization) 
HIPAA AUTHORIZATION 
Authorization to Use or Disclose (Release) Health Information that Identifies You for a Research 
Study  
If you volunteer to participate in this research, you are permitting your site, the Principal Investigator, 
and the research staff to create, collect, use, store, and share protected health information (PHI) that 
identifies you for the purposes of this research. 
The PHI that we may use or disclose (release) for this research may include your name, address, phone 
number, date of birth, Social Security number, information from your medical record, lab tests, or 
certain information relating to your health or condition.. 
Some of the tests and procedures done solely for this research study may also be placed in your 
medical record so other doctors know you are in this study.  Upon completion of the study, you may 
have access to the research information that is contained in your medical record.   
In addition to the investigators and research staff listed above, your PHI may be looked at by other 
groups involved with the study such as the Institutional Review Board.  Your PHI may also be used by 
and/or disclosed (released) to: 
• 
With each other and with other researchers involved with the study; 
• 
With law enforcement or other agencies, when required by law; 
• 
With the sponsor/funding agency of the research, National Heart, Lung and Blood Institute, as 
required to conduct the research and/or confirm the results of the research; 
• 
With non-CCF collaborators of the research study:   
- Research Triangle Institute, (Raleigh, North Carolina); they will serve as the data coordinating 
center 
- Celgene Pomalyst REMS Program (Summit, New Jersey); they will provide study drug and 
administer the REMS program 


Consent Version 2.3/Site to provide date 
Page 3 of 4 
- Ambry Genetics (Aliso Viejo, California); they will perform genetic testing for HHT genes  
• 
With representatives of government agencies (e.g., Food and Drug Administration, The 
Department of Health and Human Services, etc.), review boards including the Cleveland Clinic 
Institutional Review Board and its representatives, and other persons who watch over the 
conduct of research (e.g., data safety and monitoring boards); and 
Once your personal health information is released it may be re-disclosed and no longer protected by 
privacy laws. 
Your research information may be used and disclosed indefinitely, but you may stop these uses and 
disclosures at any time by writing to: 
Dr. Name 
Dr. Address 
Dr. Phone number  
Your participation in the research will stop, but any information previously recorded about you cannot 
be removed from the records and will continue to be used as part of this research.  Also, information 
already disclosed outside your site cannot be retrieved.  This will not affect your rights to treatment or 
benefits outside the research study.    
Your site will not use your information collected in this study for another research purpose without 
your written permission; unless an Institutional Review Board assures your privacy and confidentiality 
is protected.  The IRB is a committee whose job it is to protect the safety and welfare of research 
subjects. 
By signing this informed consent form, you are authorizing such access to your research and medical 
record information.  If you choose not to sign this consent form, you will not be able to participate in 
this research study.  This Authorization does not have an expiration date. 
 


Consent Version 2.3/Site to provide date 
Page 4 of 4 
SIGNATURES 
I have read and have had verbally explained to me the above information and have had all my questions 
answered to my satisfaction.  I understand that my participation is voluntary and that I may stop my 
participation in the study at any time.  Signing this form does not waive any of my legal rights.   I understand that 
a copy of this consent will be provided to me.  By signing below, I agree to take part in this research study. 
I understand and agree to receive counseling and to comply with the pregnancy precaution requirements of the 
POMALYST REMS™ program. 
 
 
Signature of Participant  
 
 
 
Date 
 
 
 
 
 
Printed Name of Participant 
 
I have discussed the information contained in this document with the participant and it is my opinion that the 
participant understands the risks, benefits, alternatives and procedures involved with this research study.  
 
 
 
Signature of Person Obtaining Consent 
 
 
Date 
 
 
 
 
 
 
Printed Name of Person Obtaining Consent 
 
 
 
 
 
 
 

SAP_001.pdf: 
PATH-HHT Statistical Analysis Plan 
Version 1.1 FINAL 2023-09-28; Page i  
STATISTICAL ANALYSIS PLAN 
Protocol 133646-2 
Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia 
(NCT03910244) 
SAP VERSION: 
1.1 
SAP DATE: 
June 19, 2023 – Complete initial version 
June 26-28, 2023 – TOC and formatting revisions 
July 20, 2023 – updated information in concomitant medications 
September 28, 2023 – minor updates after blinded data review meeting 
PI/ IND SPONSOR: 
Keith McCrae, MD 
Cleveland Clinic 
IND number: 
133646 
FUNDER: 
NIH/NHLBI 
PREPARED BY: 
RTI International. 
3040 Cornwallis Rd 
Research Triangle Park, NC 27709-2104 
AUTHOR (S): 
Benjamin Carper, MS 
Derek Marsh, MS 
Sonia Thomas, DrPH 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 2  
 
CONTENTS 
1 
BACKGROUND 
5 
2 
PURPOSE OF THE ANALYSIS 
5 
3 
STUDY OBJECTIVES AND OUTCOMES 
5 
3.1 
STUDY OBJECTIVES 
5 
3.1.1 Primary Objectives 
5 
3.1.2 Secondary Objectives 
5 
3.2 
OUTCOMES 
6 
3.2.1 Primary Outcomes 
6 
3.2.2 Key Secondary Outcomes 
6 
3.2.3 Other Secondary Outcomes 
6 
3.2.4 Exploratory Outcomes 
7 
4 
STUDY METHODS 
8 
4.1 
OVERALL STUDY DESIGN AND PLAN 
8 
4.2 
STUDY POPULATION 
9 
4.3 
STUDY ARM ASSIGNMENT AND RANDOMIZATION 
9 
4.4 
MASKING AND DATA LOCK 
10 
4.4.1 General Masking Procedures 
10 
4.4.2 Database Lock 
10 
4.5 
STUDY FLOW CHART OF ASSESSMENTS AND EVALUATIONS 
10 
5 
ANALYSIS POPULATIONS 
11 
6 
SAMPLE SIZE DETERMINATION 
12 
7 
STATISTICAL/ANALYTICAL ISSUES 
12 
7.1 
GENERAL RULES 
13 
7.2 
ADJUSTMENTS FOR COVARIATES 
13 
7.3 
HANDLING OF DROPOUTS AND MISSING DATA 
13 
7.4 
INTERIM ANALYSES AND DATA MONITORING 
13 
7.4.1 Study Halting Rules 
14 
7.5 
MASKED DATA REVIEW 
14 
7.6 
MULTICENTER STUDIES 
14 
7.7 
MULTIPLE COMPARISONS AND MULTIPLICITY 
15 
7.8 
EXAMINATION OF SUBGROUPS 
15 
7.9 
ASSESSMENT WINDOWS 
15 
8 
STUDY PARTICIPANT CHARACTERIZATION 
15 
8.1 
PARTICIPANT DISPOSITION 
15 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 3  
 
8.2 
PROTOCOL DEVIATIONS 
15 
8.3 
STUDY DRUG EXPOSURE AND COMPLIANCE 
16 
8.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
16 
9 
EFFICACY ANALYSES 
16 
9.1 
OVERVIEW OF EFFICACY ANALYSIS METHODS 
16 
9.2 
EFFICACY VARIABLES 
17 
9.3 
PRIMARY ANALYSIS METHODS 
22 
9.3.1 Sensitivity Analyses 
23 
9.4 
SECONDARY ANALYSIS METHODS 
24 
9.5 
EXPLORATORY ANALYSIS METHODS 
25 
9.6 
FORMAL INTERIM EFFICACY ANALYSIS 
26 
10 SAFETY ANALYSES 
27 
10.1 
OVERVIEW OF SAFETY ANALYSIS METHODS 
27 
10.2 
ADVERSE EVENTS 
27 
10.3 
DEATHS AND SERIOUS ADVERSE EVENTS 
27 
10.4 
LABORATORY EVALUATIONS 
27 
10.5 
CONCOMITANT MEDICATIONS 
28 
11 REPORTING CONVENTIONS 
28 
12 CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
29 
13 REFERENCES 
29 
14 LIST OF POTENTIAL DISPLAYS 
29 
15 APPENDIX 1 EPISTAXIS SEVERITY SCORE SCORING 
30 
16 APPENDIX 2 SCREEN SHOT OF EPISTAXIS DIARY 
32 
17 APPENDIX 2 INTERIM ANALYSIS AT 50% 
33 
18 APPENDIX 3 INTERIM ANALYSIS AT 75% 
35 
 
 
 
 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 4  
 
LIST OF ABBREVIATIONS  
Abbreviation: Deciphered: 
AE 
Adverse Event 
AVM 
arteriovenous malformations 
CRF 
Case Report Form 
CI 
Confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety and Monitoring Board 
EOS 
End of study visit, scheduled to be 4-weeks post-treatment 
ESS 
Epistaxis Severity Score 
HCT 
Hematocrit 
HHT 
Hereditary Hemorrhagic Telangiectasia 
MedDRA 
Medical Dictionary for Regulatory Activities 
Neuro-QoL 
Quality of Life in Neurological Disorders 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH 
National Institutes of Health  
PI 
Principal Investigator 
PROMIS 
Patient Reported Outcomes Measurement Information System 
QOL 
Quality of Life 
REMS 
FDA mandated Risk Evaluation and Mitigation Strategy 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
 
 
 
 
 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 5  
 
1 
BACKGROUND 
This study will address the efficacy of pomalidomide in the treatment of epistaxis in patients with 
Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or 
iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT is an inherited 
disease clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and 
recurrent epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations 
(AVMs) or telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal 
dominant). Patients with three criteria are considered to have definite HHT, and those with 2 criteria 
probable HHT, while one or no criteria make the diagnosis unlikely. Patients eligible for this study 
will have a diagnosis of definite or probable HHT. Estimates suggest that HHT affects between 1 in 
1,330 and 1 in 10,000 individuals. Since many physicians are not familiar with the disease, only 10% 
of patients with HHT may actually be diagnosed. Significant manifestations of HHT often do not 
appear until the third or fourth decades, sometimes later. 
 
There are no evidence-based guidelines for managing HHT, and there is no medical therapy 
universally accepted as efficacious; thus, treatment is not standardized. Historically, interventional 
procedures have formed the mainstay of HHT therapy. However, though often effective initially, such 
procedures are associated with a high incidence of recurrent bleeding from new AVMs or AVMs not 
visualized during endoscopic procedures. Epistaxis is the most common clinical manifestation of 
HHT, affecting ≥ 80% of patients, and leading to significant impairment in quality of life. There 
exists very little information concerning the effect of therapy on QOL in patients with HHT. To 
assess the effect of pomalidomide on QOL in HHT patients, we will administer QOL assessments 
before, during and after therapy. 
 
2 
PURPOSE OF THE ANALYSIS 
This statistical analysis plan (SAP) contains detailed information about statistical analysis to be 
performed to assess the efficacy and safety of pomalidomide as a treatment for reducing the severity 
of epistaxis. 
 
3 
STUDY OBJECTIVES AND OUTCOMES 
3.1 Study Objectives 
3.1.1 Primary Objectives 
1. To determine efficacy of pomalidomide compared to placebo for the reduction in severity of 
epistaxis after 24 weeks of treatment. 
3.1.2 Secondary Objectives 
1. To determine the safety and tolerability of pomalidomide for the treatment of HHT. 
2. To determine if pomalidomide treatment improves quality of life in HHT. 
3. To determine whether a continued response to pomalidomide is evident 4 weeks after 
treatment discontinuation.  
4. To develop a biorepository for future studies to define biomarkers predictive of 
pomalidomide response and allow investigations into the biology of HHT and mechanisms of 
pomalidomide. 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 6  
 
3.2 Outcomes 
3.2.1 Primary Outcomes 
The primary endpoint of this study is change of the Epistaxis Severity Score from baseline to week 24 
in the placebo and pomalidomide-treated groups. The ESS at baseline and each follow-up visit will 
reflect the patient’s symptoms and bleeding over the previous 4 weeks.  
3.2.2 Key Secondary Outcomes 
1. Amount of parenteral iron administered (in mg) during the 24-week treatment period in the 
pomalidomide and placebo groups (calculated as average mg/4-week interval to account for 
patients who discontinue early). 
2. Amount of packed red blood cell transfusions (in units) during the 24-week treatment period 
in the pomalidomide and placebo groups (calculated as average units/4-week interval to 
account for patients who discontinue early). 
3. Change in Neuro-QoLTM Satisfaction with Social Roles and Activities Short Form (V1.1) T-
score from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4-week 
post-treatment follow-up visit in the pomalidomide and placebo groups. 
4. Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key 
timepoint), and the 4-week post-treatment follow-up visit in the pomalidomide and placebo 
groups.  
5. Change in average daily epistaxis duration from the four-week screening period prior to 
baseline to weeks 8-12 and to weeks 20-24 (key timepoint), and to weeks 1-4 post-treatment 
in the pomalidomide and placebo groups. 
3.2.3 Other Secondary Outcomes 
1. Change in PROMIS® Emotional Distress-Depression Short Form (V1.0) T-score from 
baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4-week post-
treatment follow-up visit in the pomalidomide and placebo groups. 
2. Change in PROMIS® Fatigue Short Form (V1.0) T-score from baseline (randomization visit) 
to weeks 12 and 24 (key timepoint), and the 4-week post-treatment follow-up visit in the 
pomalidomide and placebo groups. 
3. Proportion of patients requiring no red blood cell transfusion or parenteral iron infusion 
during the 24-week treatment period in the pomalidomide and placebo groups. 
4. Change in the ESS from baseline to that recorded at each individual patient assessment, 
including the 4-week post-treatment follow-up visit. 
5. Change in the ESS from baseline to the average of the week 16, 20 and 24 assessments. 
6. Proportion of patients requiring endoscopic interventions for management of bleeding during 
the 24-week treatment period in the pomalidomide and placebo groups. 
7. Incidence and severity of adverse events in the pomalidomide and placebo groups including 
but not limited to: 
• 
Venous thromboembolism 
• 
Arterial thromboembolism 
• 
Thrombocytopenia 
• 
Neutropenia 
• 
Peripheral neuropathy 
• 
Fatigue 
• 
Constipation/diarrhea 
• 
Rash 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 7  
 
• 
Any other AEs or SAEs of at least moderate severity that are possibly related to 
pomalidomide and deemed medically relevant at masked data review. 
8. Change in iron/hemoglobin-related studies including iron saturation, ferritin, 
hemoglobin, hematocrit, MCV, and MCHC.  
3.2.4 Exploratory Outcomes 
1. Rate of relapse at the 4-week post-treatment follow-up visit, where relapse is defined as a 
return of the ESS to the baseline value or greater in pomalidomide (or placebo)-treated 
subjects. 
2. Median time after initiation of pomalidomide to obtain a decrease in the ESS of at least 1.0 in 
the in pomalidomide-treated subjects compared to placebo.  
3. Effect of genotype on the response to pomalidomide. 
 
Outcome Modification History:  
The protocol originally specified that the PROMIS® Satisfaction with Social Roles and Activities 
Short Form 8a (V2.0) was to be the 3rd key secondary outcome. Part-way through the study (summer 
2022) it was determined that due to an inadvertent error, the CRF meant to collect the PROMIS 
instrument instead corresponded to the Neuro-QoLTM Short form V 1.1 instrument with the same 
name, number of items, and response categories, but different items. As the study was over 50% 
enrolled when this issue was identified, the decision was made to update the protocol to specify the 
Neuro-QoL instrument instead of the PROMIS instrument. This update was made in Protocol version 
2.10.  
 
Although developed as part of an assessment system for people with neurological conditions, the 
NeuroQoL Satisfaction with Social Roles and Activities is scored relative to a general population 
sample (Gershon et al 2012), supporting its use in non-neurologic health conditions. For both the 
PROMIS and Neuro-QoL instruments, a T-score of 50 represents the average for the United States 
general population with a standard deviation of 10, and calibration testing was performed on a large 
sample of the general population. PROMIS was developed in 2016. Neuro-QoL was developed in 
2014, and the T-score calculations are based on a normative population of over 5,000 individuals. 
The protocol was initially designed with a 12-week follow-up period, which was modified to a 4-
week period in Protocol version 2.8 (August 2, 2021). Prior to the change, 20 participants had 
completed the 12-week rather than 4-week follow-up.  
 
Additionally, protocol update version 2.8 (8/2/2021) clarified that the early termination visit available 
in the EDC system was to be used only for participants who withdrew consent and did not agree to 
complete the 4-week post-treatment follow-up. Prior to the amendment, there were a number of 
subjects with an early termination (ET) visit which should have been recorded as a regular study visit 
or a 4 week (or 12 weeks) post-treatment visit. These cases were manually reviewed, and the ET 
visits will be re-classified in all reporting and statistical analysis to be either a C1-C6 treatment visit, 
or an end-of-study (EOS) visit. If the number of days since the prior visit and prior study drug 
dispensing was within 28 days, it was recoded to the next cycle visit. If the number of days since the 
prior visit or the prior study drug dispensing was > 28 days, then it was recoded as an EOS visit. 
Details are documented in the analysis file specification document. 
 
 
 
 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 8  
 
4 
STUDY METHODS 
4.1 Overall Study Design and Plan 
This is a multi-center, double blind, placebo-controlled study that will investigate the efficacy and 
safety of pomalidomide in patients with HHT and chronic epistaxis with iron-deficiency anemia 
and/or requiring intravenous iron infusions or blood transfusion.  
 
After recruitment, patients will be screened for study eligibility. The screening evaluation will include 
the ESS with three-month recall, which will reflect the patient’s history of epistaxis and bleeding over 
the prior three months, as well as detailed review of iron infusion and red cell transfusion over the 
preceding six months. Eligible patients will be provided a diary to record the duration of each 
epistaxis event that occurs during the 4-week period between screening and baseline visits. Eligible 
patients will then return for the randomization visit between 28 and 56 days later, at which time 
patients will undergo genetic testing if this has not been previously performed or if results for ENG, 
ACVRL1 and SMAD4 genes are not available. A repeat ESS with 4-week recall will be performed 
and will be considered the “baseline” ESS. Patients will also take QOL surveys at this visit. Patients 
will then be randomized 2:1, stratified by study site, to either pomalidomide, 4 mg/day for 28 days 
during each of six 28-day cycles (24 weeks), or placebo, administered on an identical schedule.  
 
Patients will be seen every four weeks during the study (visits C1-C6 at weeks 4, 8, 12, 16, 20, 24 and 
4-weeks post treatment follow-up) to measure the ESS (with 4-week recall, see Appendix 1), 
measure iron stores, and obtain laboratory studies, which will include CBC, metabolic profile, and 
iron studies. The iron replete state will be defined as a ferritin ≥ 50 ng/ml and a transferrin saturation 
≥ 30% (since ferritin levels may be elevated due to concurrent inflammation). Investigators will be 
encouraged to replete iron stores in patients in both arms of the study based on these parameters, and 
the amount of iron infused (in mg) recorded. There is no mandate for the use of a particular iron 
preparation. Investigators will be encouraged to use iron infusions prior to blood transfusion, though 
the latter will be mandated for a hemoglobin below 6.5 gm/dl and recorded as units of packed red 
blood cells administered. Blood transfusion may also be given at the investigator’s discretion based 
on symptoms that may include shortness of breath, severe fatigue, or other cardiovascular 
manifestations. Patients will be assessed for adverse events (AE) throughout the study. Treatment 
dosage may be reduced, or temporarily or permanently discontinued following AE-specific guidelines 
related to fatigue, cytopenia, or other toxicities.  
 
The 4-week diary of epistaxis events (see Appendix 2) will be recorded at selected intervals between 
visits throughout the study (weeks 8-12 and 20-24 as well as 0-4 weeks post treatment follow-up). 
The diary was collected from participants via a phone app developed by RTI available for all smart 
phones, or as a paper diary for participants without access to a smartphone.  
 
The effect of pomalidomide on QOL will be assessed at the baseline visit, at the 12- and 24-week 
visits, and at the 4-week post-treatment follow-up visit using validated NIH instruments of 1) 
NeuroQoL satisfaction with social roles and activities, 2) PROMIS emotional distress – depression, 
and 3) PROMIS fatigue. We will also assess responses to an HHT specific questionnaire developed 
specifically for this study and shown to correlate with these PROMIS items. The effect of 
pomalidomide on duration of epistaxis will be assessed at the 12 and 24-week treatment visits and at 
the 4-week post-treatment follow up visit.  
 


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4.2 Study Population 
The study population is defined by the following eligibility criteria. 
 
Inclusion Criteria: 
1. A clinical diagnosis of HHT as defined by the Curacao criteria  
2. Age > 18 years 
3. Platelet count ≥ 100 x 109/L 
4. WBC ≥ 2.5 x 109/L 
5. INR ≤ 1.4 and normal ± 2 sec activated partial thromboplastin time (aPTT or PTT per local 
laboratory designation) by local laboratory criteria (except for patients on a stable dose of 
warfarin or direct oral anticoagulants)  
6. Epistaxis severity score ≥ 3 measured over the preceding three months, measured at the 
screening visit 
7. A requirement for anemia, as determined by local laboratory hemoglobin assessment and 
normal ranges, and/or parenteral infusion of at least 250 mg of iron or transfusion of 1 unit of 
blood over the 24 weeks preceding the screening visit 
8. All study participants must agree to be registered into the FDA mandated POMALYST 
REMS® program, and be willing and able to comply with the requirements of the 
POMALYST REMS® program 
9. Females of childbearing potential (FCBP) must adhere to the pregnancy testing schedule 
mandated by the POMALYST REMS® program.  
10. Ability to understand and sign informed consent 
 
Exclusion Criteria: 
1. Women currently breast feeding or pregnant 
2. Renal insufficiency, serum creatinine > 2.0 mg/dl 
3. Hepatic insufficiency, bilirubin > 2.0 (or >4.0 in the setting of a prior clinical or genetic 
diagnosis of Gilbert's syndrome) or transaminases > 3.0x normal 
4. Prior treatment with thalidomide or other Immunomodulatory imide drugs (IMiDs) within 
previous 6 months 
5. Prior treatment with bevacizumab (systemic or nasal) within previous 6 weeks 
6. Prior treatment with pazopanib within previous 6 weeks  
7. The use of octreotide or oral estrogens within the previous month 
8. History of prior unprovoked thromboembolism confirmed by venous ultrasound or other 
imaging modalities 
9. Known peripheral neuropathy, confirmed by neurologic consultation 
10. Known underlying hypoproliferative anemia (i.e., myelodysplasia, aplastic anemia) 
11. Currently enrolled in other interventional trials 
12. Known hypersensitivity to thalidomide or lenalidomide. 
13. The development of erythema nodosum if characterized by a desquamating rash while taking 
thalidomide or similar drugs. 
14. Known SMAD-4 mutation 
15. Anything that in the investigator’s opinion is likely to interfere with completion of the study 
 
4.3 Study Arm Assignment and Randomization 
159 randomized individuals are required for this study. Randomization will be performed at a 2:1 
(pomalidomide:placebo) manner to enhance patient enthusiasm for participation in the trial. 


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Randomization is completed within the Medidata EDC system. Randomization is stratified by site 
using a permuted block design with randomly varying block sizes of 3 and 6. For further details on 
randomization see the PATH-HHT Randomization Specification.  
 
4.4 Masking and Data Lock 
4.4.1 General Masking Procedures 
This is a double-blind, placebo-controlled clinical trial. As such, neither the participant receiving 
study drug nor the site staff that administers study procedures and assessments will be aware of the 
treatment assignment. Additionally, all members of the clinical coordinating center at Cleveland 
Clinic including PI Keith McCrae and the data coordinating center at RTI including DCC PI Sonia 
Thomas are masked except for statisticians responsible for developing the randomization schedule, 
coordinating study drug supplies with Celgene, and producing DSMB reports. Any intentional or 
unintentional unmasking will be reported as a protocol deviation in the data management system. For 
further details on masking and procedures for unmasking see the PATH-HHT Blinding Plan. 
4.4.2 Database Lock 
The database will be locked at the completion of study follow-up. Randomization assignment will not 
be unmasked beyond the details in the blinding plan until after database lock is finalized. 
 
4.5 Study Flow Chart of Assessments and Evaluations 
 
Screen and Baseline 
Treatment Period 
End of Study 
Visit 
SC 
BL 
C1 
C2 
C3 
C4 
C5 
C6 
EOS 
ET 
Study Procedures 
Week -4 
to -8 
Week 0 
Week 4 
0-5 Days 
Week 8 
0-5 Days 
Week 12 
0-5 Days 
Week 16 
0-5 Days 
Week 20 
0-5 Days 
Week 24 
0-5 Days 
Week 28  
(4 week 
follow up) 
0-7 Days 
Only for 
withdrawn 
consent 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Enrollment Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam  
X 
X1* 
X1 
X1 
X 
X1 
X1 
X 
X 
X 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic Testing3 
 
X 
 
 
 
 
 
 
 
 
Iron Infusion 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Transfusion 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESS 
X5 
X 
X 
X 
X 
X 
X 
X 
X5 
X 
Epistaxis Duration Diary 
X 
X6 
 
X 
X6 
 
X 
X6 
X6 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Iron Studies7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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SC = Screening; BL = Baseline; C = End of cycle; ESS = Epistaxis severity score; CBC = Complete blood count; CMP = Complete metabolic panel; EOS 
= End of study Visit; ET = Early termination; QOL = Quality of life; Gray shaded boxes denote flexibility to perform visits remotely in which case 
physical exam may be modified; vital signs and biorepository samples may not be collected. 
1 Limited physical examination; *A detailed physical exam if screening visit was remote. 
2 Vital signs will include body weight, blood pressure, pulse and O2 saturation.  
3 Genetic testing will be performed only if not done previously and consent is obtained. 
4 Information on Iron infusion and Blood transfusion over the past 6 months to be collected at screening visit.  
5 ESS will be a 3-month recall for these visits; for all other visits, it will be a 4-week recall. 
6 Epistaxis Duration Diary will be collected at these visits and if applicable a new diary will be dispensed for the next recording.  
7 Iron studies include ferritin levels, serum iron and total iron binding capacity. 
8 One PAXgene RNA tube is included at these visits; 8* One PAXgene RNA tube will be included if screening was remote.  
9 QOL questionnaires will include 3 NIH instruments (NeuroQoL Satisfaction with Social Roles and Activities Short Form V1.1, PROMIS 
Depression Short Form V1.0 and PROMIS Fatigue Short Form V1.0) and an HHT specific questionnaire.  
10 In FCBP, pregnancy tests will be performed 10-14 days before, and within 24 hours of study drug order. During the first treatment cycle, 
weekly pregnancy testing is mandated. Thereafter, pregnancy testing will be performed once every 4 weeks, during each cycle of 
treatment, preferably during the middle of the treatment cycle. 
11 Information on remnant drug and empty bottles will be collected over phone, email, or other means, if visit is remote. 
 
 
5 
ANALYSIS POPULATIONS 
Randomization can occur either shortly before or at the baseline visit. 
• 
If the screening visit was completed in-person, randomization can be completed before the 
baseline visit and study drug is ordered by the site from McKesson (manager of the study 
drug for Celgene and implementer of the Pomalidomide REMS system) to be shipped to the 
site so it is available at the site on the day of the baseline visit.  
• 
If the screening visit was completed remotely, then eligibility is confirmed at the baseline 
visit and randomization occurs at baseline, and the drug is ordered to ship directly to the 
participant or to the site for dispensing to the participants within a few days of the baseline 
visit.  
Under these scenarios, occasionally a randomized participant might withdraw consent before 
receiving the study medication from McKesson. Participants might also withdraw consent after 
receiving study medication but before the first follow-up visit and they may refuse to provide any 
follow-up assessments. Because these patients have no efficacy data to contribute to the analysis, they 
are excluded from the efficacy analysis populations, as follows:    
 
Modified Intention-to-Treat Population (mITT) 
The modified intention-to-treat population will comprise of all randomized participants who took at 
least one dose of the double-blind study medication AND have at least one post-baseline efficacy 
measurement.  
 
Screen and Baseline 
Treatment Period 
End of Study 
Visit 
SC 
BL 
C1 
C2 
C3 
C4 
C5 
C6 
EOS 
ET 
Study Procedures 
Week -4 
to -8 
Week 0 
Week 4 
0-5 Days 
Week 8 
0-5 Days 
Week 12 
0-5 Days 
Week 16 
0-5 Days 
Week 20 
0-5 Days 
Week 24 
0-5 Days 
Week 28  
(4 week 
follow up) 
0-7 Days 
Only for 
withdrawn 
consent 
INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
Biorepository Collection 
X8 
X8* 
 
 
X8 
 
 
X 
X8 
X 
QOL9 surveys 
 
X 
 
 
X 
 
 
X 
X 
X 
Pregnancy Testing10 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Drug Dispensation 
 
X 
X 
X 
X 
X 
X 
 
 
 
Drug Return 
 
 
X11 
X11 
X 
X11 
X11 
X 
 
X 


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Note that if a participant receives study drug sent by McKesson and does not return a full drug bottle 
to the site, it is assumed that they took at least some study drug. 
 
Participants who receive study drug but do not complete the study will be used in all analyses for 
which data are available. Participants who withdraw consent for further follow-up will be treated as 
lost to follow-up at the time that consent was withdrawn, and data will be used up to the time of study 
withdrawal. 
 
Per-Protocol Population (PP) 
The per-protocol population will comprise of all randomized participants who complete the study 
with no major protocol violations and took at least 80% of the prescribed double-blind medication. 
Participants who were lost to-follow-up will be considered non-compliant for the purposes of the per-
protocol population. 
The blinded data review meeting identified the per-protocol exclusions as the following: 
• 
Participants who did not take at least 34 pills of study drug (20%) for reasons other than 
AEs/side effects,  
• 
Participants discontinued due to lost to follow-up or withdrawal of consent, 
• 
One case of discontinuation due to joint decision of PI and participant, and one case due 
to PI decision, 
• 
Two participants who discontinued study drug due to AEs but continued in the study with 
efficacy assessments for multiple months after study drug discontinuation. 
 
Safety Population (SAF)  
The safety population will comprise all participants that receive any study drug, irrespective of 
amount or duration of treatment.  
 
 
6 
SAMPLE SIZE DETERMINATION 
We anticipate consenting up to 200 participants to reach 159 randomized participants.  
 
A total sample size of 159 patients (106 pomalidomide, 53 placebo) will provide 94% power to 
identify a treatment group difference in ESS change from baseline at 24 weeks of 1.0 with p<0.044 
(per interim analysis alpha spending rules), assuming a standard deviation of 1.7 and 10% early 
discontinuation rate with the planed MMRM analysis. Power will remain above 80% if there is a 
substantially higher than expected study discontinuation rate of 30% (with 10% providing no post-
baseline data): 81% based on a conservative T-test, or 90% with the planned MMRM analysis. If the 
standard deviation is 1.8 instead of 1.7, the power for the planned MMRM analysis would be 91% 
with 10% discontinuation, and 87% with 30% discontinuation. 
 
With 159 patients, we will also have at least 90% power to identify a treatment group difference of 
30% for a binary secondary endpoint of proportion of participants requiring at least one packed red 
blood cell transfusion or iron infusion at any time during the 24-week treatment period with p < 0.05, 
whether assuming a rate in the placebo and pomalidomide groups of 90% vs. 60%, or 50% vs. 20%. 
 
7 
STATISTICAL/ANALYTICAL ISSUES 


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7.1 General Rules 
All statistical computations will be performed, and data summaries created using SAS 9.4 or higher. 
For summaries of study data, categorical measures will be summarized in tables listing the frequency 
and the percentage of subjects in each study arm; continuous data will be summarized by presenting 
mean, standard deviation, median and range; and ordinal data will be summarized by presenting 
median and range.  
Estimates from linear models will be presented by mean, standard error, and 95% CI. Estimates from 
logistic regression will be presented by odds ratios and 95% CIs. All statistical tests will be 2-tailed. 
Checks of assumptions (e.g., normality) underlying statistical procedures will be performed and 
corrective procedures such as use of a transformation or application of nonparametric tests will be 
applied. 
 
7.2 Adjustments for Covariates  
Indicator variables for the study stratification of pooled clinical site (Section 7.6) will be included as a 
covariate in most efficacy analyses performed for this study (details in Section 9). Also, for all scores 
analyzed as a change from baseline, the baseline value will also be a model covariate.  
 
Additionally, demographic and baseline characteristics for subjects will be compared between study 
arms using analysis of covariance techniques for continuous measures, Mantel-Haenszel mean score 
test using standardized mid-rank scores for ordinal measures, and chi-squared tests for general 
association for categorical measures. If sample sizes allow, these analyses will control for the study 
stratification factor of pooled site. If these analyses identify any substantial differences among arms, 
the use as covariates of these parameters on which the arms differ will be explored in sensitivity 
analyses of the primary efficacy outcome (see Section 9.3.1). 
 
7.3 Handling of Dropouts and Missing Data 
Missing data and missed visits will be monitored in real-time. In the event a scheduled visit is missed, 
site coordinators will contact the patient before the follow-up window closes to encourage them to at 
least obtain measurements relevant to the primary endpoint. For any missing data that do occur, we 
will record and describe the reasons the data are missing when reporting results  
 
In the event that one or more ESS or QOL visit assessments is missing during the treatment or post-
treatment periods, the MMRM analysis approach which assumes data are missing at random (MAR) 
will be used to compare treatments based on the available data and the correlation between 
observations within a person. To guard against bias if the MAR assumption is incorrect, missing data 
mechanisms will be explored, and sensitivity analyses will be conducted on the primary outcome to 
assess the robustness of the primary analysis (see Section 9.3.1). Sensitivity analyses are not planned 
for secondary analyses. 
 
7.4 Interim Analyses and Data Monitoring 
Safety outcomes will be assessed at each DSMB meeting. Rates of safety outcomes will be compared 
between treatment groups using Fisher’s exact tests and provided to the DSMB. At each meeting, the 
DSMB will be presented with information about enrollment and outcome data attainment (for 


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example, the percent of expected visits that have been completed) to allow them to determine that the 
study is making reasonable progress. These review meeting will occur once each 6 months. 
 
A formal interim analysis for efficacy after 50% and 75% of patients have completed the 24-week 
treatment period or discontinued from the study. See Section 9.6 for details. 
7.4.1 Study Halting Rules 
Randomization of new participants will be halted when eight thromboembolic events, defined as any 
venous thromboembolic event requiring medical intervention (grade 2 or higher) or any arterial 
thromboembolic event, that are determined to be related or “probably related” to the study drug are 
reported to the DCC.  
 
The DCC will notify the study monitor, study sponsor, PI and investigators immediately when the 
eighth thromboembolic event (as defined above) is reported, and randomization functionality will be 
deactivated. The PI will inform the DSMB members within 24 hours of this occurrence and the DCC 
will provide the DSMB with AE listing reports. The DSMB will convene an ad-hoc meeting by 
teleconference or in writing as soon as possible. The DSMB will provide recommendations for 
proceeding with the study to the study sponsor/NIH. The clinical coordinating center will inform 
NHLBI and the FDA of the temporary enrollment halt and the disposition of the study. 
 
7.5 Masked Data Review 
A masked data review of the primary outcome and secondary outcomes for this study will be 
performed by the protocol team. This review will occur prior to completion of the primary analyses 
prior to any official unblinding. This will include a presentation of descriptive statistics (e.g., means, 
standard deviations, percentiles for continuous variables and counts and percentages of categorical 
variables) of the selected outcomes and model predictor variables. 
 
7.6 Multicenter Studies 
For this multicenter study, randomization of study participants was stratified within center. 
Consequently, for all model-based primary and secondary analyses, center will be included as a fixed 
effect in the models, with small centers pooled.  
Sites will be pooled based on total number of randomized patients and geographical location prior to 
unblinding, such that sites with fewer than 10 participants will be pooled, and no pooled site is larger 
than the largest un-pooled site. If there are several sites with very low enrollment, one pooled site 
may consist of these sites rather than pooling based on geographical location. 
 
Masked data review prior to database lock identified the following site pooling: 
• 
1 pooled group of small sites (n=24): Cleveland Clinic (n=7), Johns Hopkins (n=7), UCSF 
(n=2), Utah (n=6), Florida (n=1) and UCSD (n=1) 
• 
5 non-pooled sites: MGH (n=51), UNC (n=21), Penn (n=16), Wisconsin (n=12), Mayo 
(n=21)  
 
As an ancillary analysis associated with the primary outcome, we will examine descriptively whether 
the treatment effect varies across sites; however, no other analyses will assess site differences in 
treatment effect because sample sizes are inadequate to support evaluation of site-level effects. 


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7.7 Multiple Comparisons and Multiplicity 
For inferential tests, the p-value for determination of statistical significance (Type I error) for the 
single primary efficacy outcome (change in ESS from baseline to week 24) will be evaluated relative 
to 0.044 to adjust for the interim efficacy analysis (see Section 9.6). However, the 75% interim 
analysis was conducted at 80% due to timing of DSMB meetings. This changed the significance level 
for the primary outcome from 0.044 to 0.0425 (see Appendix 3).   
Significance of the treatment group comparison for 5 key secondary outcomes will be evaluated as 
follows: If the primary endpoint is found statistically significant at p < 0.0425, then the key secondary 
endpoints will be evaluated for statistical significance with a Hochberg modification to the Bonferroni 
adjustment (Hochberg, 1988), in which the p-values of the 5 outcomes will be ordered. The largest p-
value will be compared relative to p <0.05, and if met, all 5 endpoints will be considered significant. 
If not, then the second largest p-value will be assessed relative to p < 0.05/2 = 0.025, and if met then 
it and the other three endpoints will be considered significant, and so on for the third p-value 
compared at 0.05/3=0.017, the fourth compared to 0.05/4 = 0.012, and the fifth compared to 0.05/5 = 
0.010. Results from analyses of all other secondary endpoints and subgroup analyses will not be 
evaluated relative to statistical significance. 
 
7.8 Examination of Subgroups 
We will evaluate treatment group comparisons for the primary outcome and key secondary outcomes 
(each in the primary specified analysis population using the primary model and primary timepoint) in 
subgroups of participants defined by: 
• 
genetic confirmation of HHT (yes or no), defined as having one or more mutations of three 
primary genes associated with HHT: endoglin (ENG), ACVRL1 and SMAD4 
• 
gender, and  
• 
race (per NIH guidelines), defined as white versus non-white. 
 
7.9 Assessment Windows 
For the primary analysis, decisions about how to treat out-of-window visits will be made prior to 
unmasking data. We intend for all data to be used but will evaluate if any visits fall substantially 
within another visit window. For secondary analyses, all available data will be used.  
 
 
8 
STUDY PARTICIPANT CHARACTERIZATION 
8.1 Participant Disposition 
Participant eligibility status will be summarized, and overall disposition of study participants will be 
described using a standard CONSORT diagram. The number of participants randomized and those 
completing or discontinuing from study therapy will be summarized. Reasons for study withdrawal 
will be listed. 
 
8.2 Protocol Deviations 
Protocol deviations will be listed with information such as type of deviation, time of occurrence, and 
reason. The number of protocol deviations will also be summarized overall and for each protocol 
deviation category.  


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8.3 Study Drug Exposure and Compliance 
All randomized participants will receive the double-blind study drug either at the baseline visit and at 
subsequent scheduled study visits. The first dose of study drug will be given in the amount of 4 mg 
pomalidomide or placebo, depending on randomization assignment. Dose can be modified by the 
investigator (blinded to active versus placebo) in response to side effects to 3 or 2 mg. All bottles 
contain 28 pills, for a 4-week supply. 
 
The number and percentage of participants receiving each dose level will be presented by visit and 
treatment group. 
 
Participants are instructed to return their medication bottles after each visit and remaining pills are 
counted by study staff. Overall study drug compliance will be calculated as the number of pills 
dispensed minus the number returned divided by the total number that should have been taken from 
the first dose up until study drug completion or early drug discontinuation. The number and 
percentage of participants that are at least 80% compliant will be presented. When a participant does 
not return a bottle, a note is recorded on the CRF as to why it was not returned. The notes will be used 
to assign an assumed number taken based on that note (for example, all pills taken, or no pills taken) 
 
8.4 Demographic and Baseline Characteristics 
Demographic and baseline clinical characteristics and HHT medical history for the study participants 
will be summarized by study arm using the general analysis rules describe above. Demographic 
variables of interest include gender, age (years), race and ethnicity), education, employment and 
marital status, BMI, and baseline levels of all vital signs and QOL measures. Extensive HHT medical 
history is recorded on a CRF, plus genetic testing. 
 
 
9 
EFFICACY ANALYSES 
9.1 Overview of Efficacy Analysis Methods 
• 
All efficacy analyses will be performed on the mITT population, the primary population. 
• 
All efficacy variables will be summarized by treatment group at baseline and at subsequent study 
time points at which assessments were administered and collected. Count (N), mean, standard 
deviation, minimum, and maximum will summarize continuous efficacy variables, whereas 
number and percent will summarize categorical efficacy variables.  
• 
Unless otherwise noted, all analyses of dichotomous outcomes, measured at respective time 
points, will be performed using models as specified in Section 9.3. Efficacy models will be 
adjusted for stratification by clinical site. Baseline value will be an additional covariate for all 
analyses of change from baseline scores. Consistent with the description of the primary analysis 
in the protocol, analyses of primary and secondary outcomes will also include an independent 
variable for study visit. For analysis of measures assessed at multiple time points (for example, 
C1 and C6), longitudinal modeling will be used and the interaction between time and treatment 
groups will be included. Unless otherwise noted, all analyses of continuous efficacy variables 
(e.g., ESS and QOL scales) will be performed using general linear mixed models. Variables with 
distributions substantially different from normal will be transformed prior to analysis.  
 
Models will be adjusted for pooled clinical site. If there are not enough patients per clinical site, 
similar sites will be combined (see Section 7.6)  
 


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9.2 Efficacy Variables 
Primary and secondary efficacy variables as well as exploratory and safety outcomes are described in 
the table below. 
 
Variable 
Type 
Definition 
Primary Outcome 
Change from baseline 
in Epistaxis Severity 
Score at each post-
baseline visit through 
24 weeks and 4 weeks 
post-treatment 
Continuous 
The Epistaxis Severity Score will be computed at 
baseline and at each study visit during which 
assessments are administered and collected using the 
standard scoring algorithm (see Appendix 1). The 
outcome will then be computed as the difference in 
score at each visit and the score at baseline. If data at a 
time point for the assessment are missing, the outcome 
variable will be coded as missing. The total score be 
calculated inside the EDC CRF page. 
Key Secondary Outcomes 
Amount of iron 
administered through 
24 weeks and 4 weeks 
post-treatment 
Continuous 
The 4-week average amount of iron transfusion (in mg/4 
weeks) through 24 weeks will be calculated. For 
subjects who discontinue early, this value will be pro-
rated to 24 weeks. Participants who receive no infusions 
during the 24 weeks will have a value of zero,  
 
In the screening period, the amount of iron received in 
the 6 months prior to screening is calculated as the 
number of infusions received multiplied by the amount 
infused at the last infusion (because the CRF only 
collected the amount infused at the most recent infusion 
prior to screening) 
Amount of red blood 
cell administered 
through 24 weeks and 
4 weeks post-treatment 
 
This was changed to: 
proportion of patients 
receiving at least 1 
blood transfusion in 
the 24-week period.  
Continuous 
 
 
 
Categorical 
(yes/no) 
The 4-week average amount of red blood cell 
transfusion (in units/4-weeks) through 24 weeks will be 
calculated. For subjects who discontinue early, this vale 
will be pro-rated to 24 weeks. 
Note: at masked data review, it was determined the 
overall number of RBC transfusions was small, and this 
outcome will instead be modified to the percentage of 
participants that received any RBC transfusion during 
the 24-week treatment period (and separately, the 4-
week post-treatment period)   
Change from baseline 
in Neuro-QoLTM 
Satisfaction with 
Social Roles and 
Continuous 
The Neuro-QoLTM Satisfaction with Social Roles and 
Activities Short Form (V1.1) T-score will be computed 
at baseline and at each study visit during which 
assessments are administered and collected. Total score 


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Variable 
Type 
Definition 
Activities Short Form 
(V1.1) T-score at 12 
and 24 weeks and 4 
weeks post-treatment 
is calculated as a T score using Neuro-QoL online 
scoring tools 
(https://www.assessmentcenter.net/ac_scoringservice), 
where a score of 50 represents the average of the Neuro-
QoL calibration sample, which is a general US 
population, with a standard deviation of 10. The 
outcome will then be computed as the difference in 
score at each post-baseline visit and the score at 
baseline. Missing items within an assessment are 
handled by the official online scoring tools. 
Change from baseline 
in HHT QoL Total 
Score at 12 and 24 
weeks and 4 weeks 
post treatment 
Continuous 
The HHT QoL Total Score will be computed at baseline 
and at each study visit during which assessments are 
administered and collected by summing all of the items 
(Kasthuri et al 2022). The outcome will then be 
computed as the difference in score at each post-baseline 
visit and the score at baseline. If any data items at a time 
point for the assessment are missing, the outcome 
variable will be coded as missing.  
Change from baseline 
in average daily 
epistaxis duration 8-12 
and 20-24 weeks and 
4-weeks post-
treatment 
Continuous 
The average daily epistaxis duration will be computed at 
baseline and at each study visit during which the 
epistaxis diary is collected (See Appendix 2). The 
outcome will then be computed as the difference in 
average at each post-baseline visit and the average at 
baseline. If data at a time point for the assessment are 
missing, the outcome variable will be coded as missing.  
The daily average is calculated by averaging all non-
missing data across all available days in a dairy. At least 
7 total days for each diary must be present in order to 
calculate the average for that time period.  
If the actual number of minutes for a nosebleed is not 
provided but the duration category is checked, then the 
midpoint of the duration category will be used as the 
duration for that nosebleed as follows: <1: 0.5, 1-5: 3, 6-
15: 10.5, 16-30: 23, 31-60: 45, > 60: 60 
Note: at masked data review, the unit of this outcome 
was modified from weekly to daily. 
Other Secondary Outcomes 
Change from baseline 
in PROMIS® 
Emotional Distress-
Depression Short 
Form (V1.0) T-score 
at 12 and 24 weeks 
Continuous 
The PROMIS® Emotional Distress-Depression Short 
Form (V1.0) T-score will be computed at baseline and at 
each study visit during which assessments are 
administered and collected using the PROMIS online 
scoring algorithm 
(https://www.assessmentcenter.net/ac_scoringservice). 


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Variable 
Type 
Definition 
and 4 weeks post-
treatment 
A score of 50 represents the average of the PROMIS 
calibration sample, which is a general US population, 
with a standard deviation of 10. The outcome will then 
be computed as the difference in score at each post-
baseline visit and the score at baseline. Missing items 
within an assessment are handled by the official online 
scoring tools. 
Change from baseline 
in PROMIS® Fatigue 
Short Form (V1.0) T-
score at 12 and 24 
weeks 
Continuous 
The PROMIS® Fatigue Short Form (V1.0) T-score will 
be computed at baseline and at each study visit during 
which assessments are administered and collected using 
the PROMIS online scoring algorithm 
(https://www.assessmentcenter.net/ac_scoringservice). 
A score of 50 represents the average of the PROMIS 
calibration sample, which is a general US population, 
with a standard deviation of 10. The outcome will then 
be computed as the difference in score at each post-
baseline visit and the score at baseline. Missing items 
within an assessment are handled by the official online 
scoring tools.  
Proportion of patients 
with RBC transfusions 
or iron infusions 
through 24 weeks. The 
treatment goal is 
receiving none (a 
value of No).  
Dichotomous 
(Yes/No) 
The number of iron infusions and RBC transfusions will 
be counted throughout the 24-week treatment 
administration. The outcome is calculated as “No” if no 
transfusions/infusions, and “Yes” if ≥ 1 
transfusion/infusion. 
Proportion of patients 
requiring endoscopic 
intervention through 
24 weeks 
Dichotomous 
(Yes/No) 
The number of endoscopic interventions for 
management of bleeding will be counted throughout the 
24-week treatment administration. The outcome is 
calculated as “Yes” if ≥ 1 endoscopic intervention and 
“No” if no endoscopic interventions. 
 
Endoscopic interventions are recorded by the site on the 
concomitant medications form, can be either nasal or 
gastroenterological interventions. Identification of 
endoscopic interventions (such as nasal cautery) will be 
confirmed by medical review. These were identified 
prior to database lock and include endoscopy, cautery, 
and embolization.  
Incidence and Severity 
of Specific adverse 
events 
Discrete 
The incidence rate and maximum severity of the 
following adverse events will be calculated: 
MedDRA terms identified in blinded data review noted 
for each. 


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Variable 
Type 
Definition 
• 
Venous thromboembolism 
o Portal vein thrombosis, Deep vein 
thrombosis 
• 
Arterial thromboembolism 
o None found 
• 
Thrombocytopenia 
o Thrombocytopenia 
• 
Neutropenia 
o Neutropenia 
o also Leukopenia, and also a category of 
(Neutropenia or Leukopenia) 
• 
Peripheral neuropathy 
o Neuropathy peripheral, Peripheral 
sensory neuropathy 
• 
Fatigue 
o Fatigue 
• 
Constipation/diarrhea 
o Constipation, Diarrhoea, Nausea, 
Abdominal pain 
• 
Rash 
o Rash popular, Rash pruritic, Rash maculo-
papular, Rash, Rash erythematous, 
Urticaria, Pruritus, Palmar erythema 
• 
Any other AEs or SAEs of at least moderate severity 
that are possibly related to pomalidomide and 
deemed medically relevant at masked data review: 
o Pulmonary embolism 
o Mouth ulceration  
o Alanine aminotransferase increased 
o Tremor 
o Dyspnoea and exertional dyspnoea (only the 
cases that meet criteria of at least possibly 
and at least moderate) 
o Tachycardia (only the cases that meet 
criteria of at least possibly and at least 
moderate) 
o Muscle spasms (only the cases that meet 
criteria of at least possibly and at least 
moderate) 
Change from baseline 
in iron (transferrin) 
saturation, ferritin, 
hemoglobin, 
hematocrit, MCV, and 
MCHC.  
Continuous 
Lab parameters are analyzed at each site (including at 
local labs) and entered onto CRFS in the EDC system. 
Transferrin Saturation is calculated within medidata 
from Iron and Iron Binding Capacity.  


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Variable 
Type 
Definition 
The outcome will then be computed as the difference in 
value at each post-baseline visit and the value at 
baseline. 
Thrombocytopenia 
platelet categories 
Categorical 
Normal 
< 150 K/uL 
 < 100 K/uL 
 < 50 K/uL 
Added as additional planned safety presentation at 
blinded data review meeting. 
Categorical assessment of thrombocytopenia will be 
calculated based on all platelets collected post-baseline. 
A person will be classified into one of the 4 categories 
based on the lowest recorded post-baseline platelet 
value. The value of 150 represents the lower normal 
bound.    
Neutropenia 
neutrophils categories 
Categorical 
Normal 
< 1.45 K/uL 
 < 1.00 K/uL 
 < 0.50 K/uL 
Added as additional planned safety presentation at 
blinded data review meeting. 
Categorical assessment of neutropenia will be calculated 
based on all neutrophils collected post-baseline. A 
person will be classified into one of the 4 categories 
based on the lowest recorded post-baseline neutrophil 
value. The value of 1.45 represents the lower normal 
bound.    
Exploratory Outcomes 
Relapse at 4-weeks 
post treatment 
Dichotomous 
(Yes/No) 
The rate of relapse will be calculated at 4 weeks post-
treatment. Relapse is defined as a return of the ESS to 
the baseline value or greater. 
Treatment weeks to 
1.0 decrease in ESS 
Ordinal 
Categorical (4, 
8, 12, 16, 20, 
24, Not 
obtained)  
The time to the first 1.0-unit decrease in ESS will be 
calculated for each participant by computing the 
difference between the baseline ESS and the ESS at each 
study visit and determining the first study visit at which 
the difference is <= -1.0, or “not obtained” if no visit 
had an improvement of at least 1.0  
Oral iron taken during 
the treatment period  
Categorical 
(Always 
taken, Never 
taken, Added 
after baseline, 
Stopped after 
baseline 
All oral iron supplements will be identified from the 
concomitant medications form (using search for Iron, 
Fe, ferrous, Ferrous Sulfate) and confirmed by medical 
review. Oral iron usage will be categorized for each 
participant as always taken if it was taken during the 
screening period before baseline, and also taken post-
baseline, added after baseline if it was started after the 
date of the baseline visit, stopped after baseline if it was 
stopped after the baseline visit, and never taken if a 
patient had no oral iron recorded.  
Other outcomes 


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Variable 
Type 
Definition 
 
Other outcomes include individual questions on the ESS and the diary and iron studies not 
otherwise covered in a secondary or exploratory outcome 
Nosebleed frequency, 
duration, and intensity 
(ESS items 1-3) at 
each visit  
Categorical 
Reported as recorded on CRF, categories may be 
combined based on observed data and to assist in trend 
interpretation.  
Sought medical 
attention for nose 
bleeding (ESS item 4) 
during the 24-week 
treatment period 
Dichotomous 
(Yes/No) 
“Yes” if reported at any visit C1-C6 and "No” if not 
reported at any visit C1-C6 
Anemia (yes/no) (ESS 
item 5) at each visit  
Dichotomous 
(Yes/No) 
Reported as recorded on CRF 
Iron replete status by 
visit, defined as a 
ferritin ≥ 50 ng/ml and 
a transferrin saturation 
≥ 30% 
Dichotomous 
(Replete/Not 
replete) 
Iron replete status is defined as replete if ferritin ≥ 50 
ng/ml and a transferrin saturation ≥ 30% and is defined 
as “not replete” if either ferritin < 50 ng/ml or transferrin 
saturation < 30%.  
Hemoglobin below 6.5 
gm/dl at any time 
during the 24-week 
treatment period 
Dichotomous 
(Yes/No) 
A blood transfusion was mandated for a hemoglobin 
below 6.5 gm/dl. 
Diary frequency, 
duration and intensity 
questions 
To be 
determined 
Presentation of data on frequency, duration and intensity 
questions collected for each nosebleed on the diary will 
be considered as a secondary item after analyses 
specified in the SAP are completed. 
 
9.3 Primary Analysis Methods 
For the primary analysis, the change from baseline in epistaxis severity score after 24 weeks of study 
drug administration will be compared between the pomalidomide and placebo groups using a 
longitudinal general linear model, often referred to as a mixed model for repeated measures (MMRM) 
(Davis SM 2014), using the MITT population.  
 
The observed change from baseline score at each scheduled post-baseline visit (Weeks 4, 8, 12, 16, 
20, and 24 and 4-weeks post-treatment) is the dependent variable. For the purposes of this analysis, 
study visit will be treated as a categorical repeated measure. The model will include fixed effects for 
treatment group, study visit, and interactions between those variables and will include the baseline 
ESS score as a covariate. The model will also be adjusted for the design effect of stratification by 
pooled site. A heterogeneous Toeplitz covariance pattern will estimate the variance-covariance of the 


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within-subject repeated measures (study visit), and the Kenward-Roger method will be used to 
calculate denominator degrees of freedom. Estimates, p-values and 95% confidence intervals will be 
presented for treatment group comparisons at each visit. In an intent-to-treat fashion, all data will be 
included in the primary model, regardless of the treatment actually taken by the patient.  
 
The 20 patients with 12-week post-treatment assessments will be included with all 4-week post-
treatment assessments. 
 
Treatment group comparisons of the change in ESS score averaged over the week 16, 20, and 24-
week visit assessments (a secondary outcome) will be assessed via estimate and contrast statements 
within this model. 
 
Sample SAS code for the primary model is as follows: 
 
proc mixed covtest; 
 
where VISIT in ("C1","C2","C3","C4","C5","C6","EOS"); 
 
class subject sitenum trtgp VISIT; 
 
model DELTA_ESS = ESS_BL sitenum trtgp VISIT trtgp*VISIT / ddfm=kenwardroger; 
 
repeated VISIT / subject=subject type=toeph R rcorr; 
 
title "Mixed model for change from baseline ESS"; 
 
lsmeans trtgp*VISIT / cl pdiff=all; 
run; 
 
9.3.1 Sensitivity Analyses 
Per-protocol population 
The primary analysis will be repeated on the per-protocol population.  
 
Imbalanced covariates 
If there are important baseline characteristics that substantially differ between randomized treatment 
groups by chance, additional sensitivity analyses may be conducted to evaluate the impact of 
adjusting for those imbalances. 
 
Clinical Site Effects 
We will examine descriptively whether the treatment effect varies across sites.  
 
Removing 12-week post-treatment data 
A supportive analysis of the 4-week post-treatment assessment time will be completed for the MITT 
population with removal of the 20 patient visits that were conducted at 12 weeks post-treatment. 
 
Missing data 
The MMRM analysis approach assumes missing data due to missed visits or early study 
discontinuations are missing at random (MAR). If a statistically significant difference between 
treatment groups is observed in the primary analysis, then a sensitivity analysis will be conducted on 
the primary outcome to assess the robustness of the primary analysis to the MAR assumption using 
methods that assume that data are missing not at random (MNAR). Specifically, we will use multiple 
imputation of missing data to generate multiple imputed complete datasets (no missing data through 
24 weeks), conduct analysis of covariance for change from baseline at 24 weeks on each dataset 
(model change from baseline at 24 weeks = baseline value + site + treatment group), and use Rubin’s 
rule to combine results across the imputed datasets to obtain a comparison of treatment groups 
(Ratitich, 2014). We will explore 2 sensitivity analyses: (a) impute missing outcomes in the 


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pomalidomide treatment group (and the placebo group) based on data from the placebo group 
(control-based imputation), and (b) impute missing outcomes in the pomalidomide group at varying 
percentages of the observed values (while imputing missing placebo data based on observed placebo 
values) until a statistically significant treatment group difference is no longer identified (tipping point 
analysis) (O’Kelly and Ratitch, 2014). These sensitivity analyses will only be conducted if the 
primary analysis identifies a statistically significant treatment group difference at 24 weeks in the 
MITT population.  
 
Intercurrent concomitant therapy 
It is possible that participants in either treatment group may receive concomitant therapy that might 
impact the ESS score. For example, receiving an RBC transfusion would likely improve the anemia 
status; however, in this case the ESS score would have extra points for seeking medical care and 
receiving an RBC transfusion. Therefore, based on the ESS scoring weights, receiving an RBC 
transfusion would appropriately make the ESS score worse (higher score) in the month it is received. 
Iron infusions may also impact the anemia score, in which case there might be an extra ESS point for 
seeking the medical attention to obtain the iron infusion, thereby a slightly negative impact on the 
ESS score. On the other hand, nasal cautery or other endoscopic intervention may impact bleeding 
and therefore might impact the ESS score to indicate improved ESS due to the endoscopic treatment.  
 
If applicable, we will descriptively evaluate the amount and timing of iron infusions and endoscopic 
interventions such as nasal cautery. If there are a substantial number of these events, we may 
descriptively evaluate if these events seem to have an impact on improving the ESS score, and if so, 
consider a sensitivity analysis of the impact of the intercurrent treatments on the primary treatment 
group comparisons. We will do this evaluation only if warranted by evaluation of the number of 
intercurrent events within the treatment groups.  
 
Pre-specified Covariates/Subgroup analyses 
We will investigate the primary outcome analysis for the MITT population on the pre-planned 
subgroups specified in the protocol: genetic confirmation of HHT (yes or no), gender and race (per 
NIH guidelines). 
 
We will also investigate interactions for type of genetic mutation, and if the season of the year of 
enrollment is a relevant baseline covariate, given that there may be seasonal variation of epistaxis 
during colder months due to drier room air and increased prevalence of upper respiratory infections.  
 
Interactions will be assessed within the primary mixed linear model by adding an interaction term 
between treatment group and subgroup and evaluating this multiple degree of freedom test at the 0.10 
significance level, and if trends are identified then graphing the trajectories over time by subgroup, 
using a model with the treatment group x time x subgroup 3-way interaction.  
 
9.4 Secondary Analysis Methods 
Unless otherwise specified, changes from baseline in continuous secondary outcomes will be 
compared between treatment groups using an MMRM model as specified for the primary outcome 
and analogous generalized linear models will be used for any repeated dichotomous outcomes.  
 
A Hochberg multiple comparison adjustment will be applied to the 5 key secondary endpoints to 
maintain the overall Type 1 error rate. Treatment groups will be compared for the secondary 
endpoints as described in Section 7.7. 
 


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Treatment groups will be compared for the total amount of packed red blood cell transfusions (units) 
and iron (mg) infused during the 24-week treatment period (calculated as average over a 4-week 
period), using an analysis of covariance or rank analysis of covariance if not normally distributed, 
with adjustment for the measure in the 6 months prior to the screening period and pooled clinical site. 
If packed red blood cell transfusions are rare, then we will switch to a zero-inflated Poisson 
regression model or logistic regression, depending on the distribution.  
 
Blinded data review prior to database lock determined the number of RBC transfusions is rare and so 
RBC transfusions during the 24-week treatment period will be analyzed as yes/no using logistic 
regression with adjustment for transfusion in the 6 months prior to screening (yes/no) and pooled site.   
 
The blinded data review also indicated the amount of iron infused during the 24-week treatment 
period is not normally distributed and will be analyzed with rank analysis of covariance (Stokes, 
Davis and Koch 2000).  The rank ANCOVA is completed in 3 steps, (A) ranking the outcome 
variable and the baseline value separately within each pooled site, (B) obtaining the residuals from a 
regression of the ranked outcome variable on the ranked baseline variable, separately for each pooled 
site, and then (C) comparing the treatment groups for the residuals using a Mantel-Haenszel mean 
score test stratified by pooled site. 
 
Sample SAS code for the rank ANCOVA is as follows: 
proc rank nplus1 ties=mean out-ranks; 
 
by sitenum; 
 
var [outcome variable] [baseline variable] 
run; 
 
proc reg data=ranks; 
 
by sitenum; 
 
model [outcome ranked variable] = [baseline ranked variable; 
 
output out=redidual r=resid;] 
run; 
 
proc freq data=residual noprint; 
 
tables sitenum*trtgp*resid / cmh ; 
run; 
 
Groups will be compared for the proportion of patients relapsed, requiring no blood or iron, and 
requiring endoscopic interventions and other yes/no categorical outcomes using logistic regression 
with adjustment for baseline assessment (ESS score, whether the patient had required a blood 
transfusion or required an total iron infusion amount of at least 250 mg in the 6 months before the 
baseline visit, and ESS score, respectively), and study site. If events are rare, exact logistic regression 
will be used. 
 
9.5 Exploratory Analysis Methods 
Exploratory analyses include estimating the rate of relapse at the 4-week post-treatment follow-up 
visit, where relapse is defined as a return of the ESS to the baseline value or greater in pomalidomide-
treated subjects and estimating the median time after initiation of pomalidomide to obtain a decrease 
of at least 1.0 in the ESS in pomalidomide-treated compared to placebo subjects. These outcomes will 
have no statistical testing. 
 
To learn which demographic or biomarkers are predictive of greater response to pomalidomide we 
will fit generalized linear models to the primary outcome in the pomalidomide treatment group to 
predict treatment response based on presence of the specific mutations in the endoglin (ENG) or 


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activin-like kinase (ACVRL1) genes, as well as a set of pre-defined baseline covariates., to include 
age, gender, and baseline disease severity.  
 
An exploratory analysis will evaluate the correlation of the ESS score and the average daily duration 
of bleeding from the diary. 
 
An exploratory analysis will also compare groups for total iron taken during the treatment period, 
combining both oral iron and iron infusions. 
 
9.6 Formal Interim Efficacy Analysis 
We will perform a formal interim analysis to evaluate for early overwhelming efficacy based on the 
change in ESS score from baseline to 24 weeks after 50% and 75% of subjects have completed the 
24-week visit or discontinued the study. Futility will also be assessed at 75%, and each formal interim 
analysis will include a full DSMB safety review.  
 
For assessing early efficacy, the significance level for the interim and final analysis will be based on 
Lan-DeMets α-spending functions with O’Brien-Fleming boundaries in order to maintain the study-
wise α level at 0.05. The α level will be 0.0031 at 50%, 0.0183 at 75% and 0.0440 at the final 
analysis. The exact α level at the interim will be determined using Lan-DeMets α-spending functions 
based on the actual percent of data available at the interim.  
 
Assuming 90% power at the end of the study, there is a 26% chance of meeting the stopping 
boundary at the 50% interim, and a 69% chance at the second interim. If the study actually has 80% 
power (for example, due to higher-than-expected discontinuation rate or ESS standard deviation), 
then there is a 54% chance of meeting the stopping boundary at the second interim. Conversely, if the 
study actually has power > 95% (for example if treatment group difference in ESS change is 1.2 
rather than 1.0 or lower than expected standard deviation), then the chance of stopping is 41% at the 
first interim and 84% at the second interim. 
 
Futility will be assessed at 75% based on conditional power of the primary efficacy variable. The 
DSMB may recommend study stop due to futility if the upper limit of the 80% confidence interval for 
conditional power does not exceed 50%.  
 
With our planned enrollment rate, we expect approximately 6 months of randomization visits to take 
place after the 50% interim analysis, and so there is a potential to decrease the overall study sample 
size in the event that the DSMB recommends stopping enrollment based on the interim analysis 
results. If enrollment proceeds as planned, then randomization will be essentially complete by the 
time of the 75% interim analysis. In this case, we will request the DSMB to skip the second interim 
analysis in order to maximize the alpha level at the end of the study. Otherwise, if enrollment is 
slower than expected, then the results of the second interim analysis still provide a chance to decrease 
the study sample size. 
 
Both interim analyses were carried out. Details are provided in Appendix 2 and Appendix 3. 
 
 
 
 
 


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10 SAFETY ANALYSES 
10.1 Overview of Safety Analysis Methods 
All safety analyses will be performed using all participants in the safety population, regardless of 
eligibility. The frequency of toxicities potentially attributable to pomalidomide treatment will be 
determined (e.g., venous/arterial thromboembolism, thrombocytopenia, fatigue, constipation/diarrhea, 
rash). Treatment and resolution of all safety endpoints will also be documented. Treatment groups 
will be compared for incidence of events with a chi-squared or Fisher’s exact test, and incidence 
density (events per person-months of exposure) will be calculated for toxicities in the pomalidomide 
group. Adverse event incidence rates will be included in semi-annual safety reports to the DSMB and 
annually to the FDA. 
10.2 Adverse Events 
Per the protocol, participants were asked to report any adverse events from initiation of treatment 
through 24 weeks follow-up. All adverse events will be collected on an adverse event log and coded 
using MedDRA.  
 
Adverse events will be listed and summarized by MedDRA system organ class and preferred term. 
Summaries will be of the number of events and number of individuals experiencing events by 
treatment group and will be created for all adverse events, by severity, and by relationship to 
treatment. Any events starting outside of the reportable time frame will be included in separate 
listings and will be excluded from summary tables. If a complete onset date is unknown and it cannot 
be confirmed that the event occurred during this time period, then the event will be considered a 
treatment-emergent adverse event. 
10.3 Deaths and Serious Adverse Events 
A serious adverse event (SAE) is any event that is life threatening, results in death, causes or prolongs 
hospitalization, leads to a disability or birth defect, or requires an intervention to prevent a disability. 
SAEs will be listed, and SAEs and treatment-related SAEs will be summarized in the manner 
mentioned in Section 10.2 if there are enough events to summarize. Deaths will be listed. 
10.4 Laboratory Evaluations 
Laboratory exams (include blood chemistry and hematology) will be collected from each patient and 
will be summarized by study visit. Box and whisker plots will be generated to show the changes 
across study visits for key safety labs. These have been produced for the DSMB reports. 
 
If applicable, linear mixed effect models will be constructed modeling change from baseline for key 
safety lab values over time with study time treated categorically and will be used to compare any 
post-baseline measures to baseline. Change from baseline will be assessed for substantial violations 
of normality and if so, a transformation will be considered. 
 
Incidence of treatment-emergent abnormal safety labs at any post-baseline timepoint for all collected 
lab parameters will be tabulated (similar to that produced for the DSMB reports but DSMB was not 
focused on treatment-emergent labs), and treatment groups will be compared with chi-squared or 
Fisher’s exact test, if applicable. Treatment-emergent abnormal is defined as a lab value post-baseline 
that is outside the normal range during the treatment period but is within the normal range at baseline 
(or at screening, if the baseline value is missing). 
 


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10.5 Concomitant Medications 
Patients will be allowed to use any concomitant medications that they require except those listed in 
the exclusion criteria or protocol section 7.6. They may remain on HHT-directed medications other 
than those listed in the exclusion criteria if they were taking these when eligibility was determined. If 
they remain on such medications, they must remain on a stable dose during the study. Concomitant 
medications will be reviewed at screening, and at each study visit.  
Incidence of taking HHT-directed medications and any exclusionary medications will be presented by 
treatment group, and include the following:  
 
Excluded medications:  
• 
octreotide,  
• 
erythropoetic agents, 
• 
oral estrogen or progestin 
• 
bevacizumab (Avastin) (systemic or nasal) 
• 
pazopanib 
• 
ciprofloxacin 
• 
fluvoxamine 
• 
ketoconazole 
• 
carbamazepine 
Medications allowed to continue if on stable dose at screening but not allowed to initiate or 
increase dose:  
• 
oral epsilon-aminocaproic acid (Amicar) 
• 
oral tranexamic acid 
• 
propranolol  
• 
timolol  
• 
epsilon aminocaproic acid 
• 
tranexamic acid nasal sprays 
• 
nasal estriol 
 
11 REPORTING CONVENTIONS 
Unless required otherwise by journal standards, the following rules are standard: 
• 
Moment statistics including mean and standard deviation will be reported at 1 more significant 
digit than the precision of the data.  
• 
Order statistics including median, min and max will be reported to the same level of precision as 
the original observations. If any values are calculated out to have more significant digits, then the 
value should be rounded so that it is the same level of precision as the original data. 
• 
Following SAS rules, the median will be reported as the average of the two middle numbers if the 
dataset contains even numbers. 
• 
Test statistics including t and z test statistics will be reported to two decimal places.  
• 
P-value will be reported to 3 decimal places if > 0.001. If it is less than 0.001 then report 
‘<0.001’. Report p-values as 0.05 rather than .05. 
• 
No preliminary rounding should be performed, rounding should only occur after analysis. To 
round, consider digit to right of last significant digit: if < 5 round down, if >=5 round up. 
 
 
 


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12 CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
The SAP expands the analysis of the primary and second endpoints described in the protocol. No 
changes from that specified in the protocol were made. 
 
 
13 REFERENCES 
Davis SM. Chapter 5: Mixed models for repeated measures with categorical time effects (MMRM). 
In Clinical Trials with Missing Data: a Guide for Practitioners. O’Kelly, M and Ratitch B. Wiley. 
2014. 
 
Gershon, R.C., Lai, J.S., Bode, R. et al. Neuro-QOL: quality of life item banks for adults with 
neurological disorders: item development and calibrations based upon clinical and general population 
testing. Qual Life Res 21, 475–486 (2012). https://doi.org/10.1007/s11136-011-9958-8 
 
Hochberg. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75:800-803. 
 
Intro to Neuro-QoL (healthmeasures.net) https://www.healthmeasures.net/explore-measurement-
systems/neuro-qol/intro-to-neuro-qol. Accessed August 30, 2022. 
 
Kasthuri R, Chaturvedi S, Thomas S, Vandergrift N, Bann c, Schaefer s, Pyeritz R, Clancy M, 
McCrae K, Development and Performance of a Hereditary Hemorrhagic Telangiectasia Specific 
Quality of Life Instrument. Blood Advances. 2022; 6 (14): 4301–4309. Epub 22 July 2021. DOI 
10.1182/bloodadvances.2022007748 
 
O’Kelly M, Ratitch, B. Chapter 8: Analyses under missing-not-at-random assumptions. In Clinical 
Trials with Missing Data: a Guide for Practitioners. O’Kelly, M and Ratitch B. Wiley. 2014. 
 
Ratitch, B. Chapter 6: Multiple Imputation. In Clinical Trials with Missing Data: a Guide for 
Practitioners. O’Kelly, M and Ratitch B. Wiley. 2014. 
 
Stokes M, Davis C, Koch G Categorical Data Analysis using the SAS system. SAS Institute, 2000. 
 
 
14 LIST OF POTENTIAL DISPLAYS  
List of displays and table shells are in a separate document. Data displays (tables, figures, and 
listings) may be added, deleted, rearranged or the structure may be modified after finalization of the 
SAP. Such changes require no amendment to the SAP as long as the change does not contradict the 
text of the SAP.  
 


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15 APPENDIX 1 EPISTAXIS SEVERITY SCORE SCORING 
 
The epistaxis severity score (ESS) was developed by Hoag et al and is a clinically-validated 
score for quantifying epistaxis in HHT which correlates inversely with QOL. Questions 
comprising the ESS are depicted in below.  
 
Epistaxis Severity Score 
 
 
 
Clinical characteristics of the bleeding frequency and severity are collected and assigned a 
numerical score, which is added and multiplied by specific coefficients to determine the final 
ESS. The maximum ESS score is 10, with patients in the 7-10 range being considered to have 
severe epistaxis.  
 
Calculations for determining the ESS are depicted below, and an automated determination of 
the ESS is programmed to be automatically calculated in the EDC system. The presence of 
missing data will result in no score being calculated. 
 
 
 
 


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Calculation of the Epistaxis Severity Score 
 
 
 
 
 
Question Response
Coefficient
Result
Less than monthly
0
Once per month
1
Once per week
2
Several per week
3
Once per day
4
Several per day
5
< 1 minute
0
1-5 minutes
1
6-15 minutes
2
16-30 minutes
3
>30 minutes
4
No
0
Yes
1
No
0
Yes
1
No
0
Yes
1
I don't know
Drop
0
No
0
Yes
1
Total
Denominator 
(Sum Den)
Raw 
Score
6
X
0.31           
(0.31 Den)
5
X
4
X
0.30           
(0.30 Den)
0.20           
(0.20 Den)
0.25          
(1.00 Den)
3
X
0.25           
(0.25 Den)
Multiplied by
1
X
0.14           
(0.70 Den)
2
X
Raw 
Score
Denominator 
(2.76) 
10
Normalized
HHT-EES


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 32  
 
16 APPENDIX 2 SCREEN SHOT OF EPISTAXIS DIARY 
 
 
 
 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 33  
 
17 APPENDIX 2 INTERIM ANALYSIS AT 50% 
 
The purpose of the 50% interim analysis is to assess for early efficacy of the primary efficacy 
outcome, the change from baseline in the ESS totals score at 24 weeks. Futility is not assessed at the 
50% interim. 
As stated in the protocol, the significance level of the primary outcome at the interim and final 
analysis will be based on Lan-DeMets α-spending functions with O’Brien-Fleming boundaries in 
order to maintain the study-wise α level at 0.05. The α level will be 0.0031 at 50%, 0.0183 at 75% 
and 0.0440 at the final analysis. The exact α level at the interim will be determined using Lan-DeMets 
α-spending functions based on the actual percent of data available at the interim.  
The interim analysis will be reviewed by the DSMB at the meeting on October 19, 2022, based on 
data from a database snapshot date of September 6, 2022.  
If the significance level of the primary outcome is less than the pre-specified alpha level, then the 
DSMB may recommend that study enrollment be halted, with currently active patients completing 
their treatment and follow-up, and the database be cleaned and locked for the final statistical analysis.  
Study Population, Sample size and Alpha level 
The interim efficacy analysis will be conducted on all randomized and treated participants (the 
modified Intent to Treat (MITT) population that will be used for the final statistical analysis as 
specified in the SAP) that have either completed the 24-week (C6) visit or have discontinued from the 
study. Participants that have completed C6 but have not yet completed the 4-week post-treatment 
follow-up are included. 
Randomized participants that are ongoing in the trial and have not yet reached the C6 visit will not be 
included in the interim analysis. While their data collected as of the data snapshot is fully applicable, 
the repeated measures model used for the ESS 24-week analysis assumes that the data not yet 
collected for ongoing participants is missing at random and would be assumed to have a similar 
correlation with prior visits as participants that have complete data. While this assumption is to be 
evaluated for missing data in the final analysis (as specified in the SAP), we do not want to include 
cases with missing data that is yet to be collected in the interim analysis where a decision might be 
made about stopping the trial.  
As of the database snapshot, there were 86 participants that met the criteria for inclusion in the 
interim efficacy analysis, which is 54% of the total 159 planned sample size. Using Lan-DeMets α-
spending functions with O’Brien-Fleming boundaries in order to maintain the study-wise α level at 
0.05 based on the 2 planned interim analyses, the revised alpha level for the 54% initial interim is 
0.0046. The alpha level at the other 2 timepoints is now 0.0179 at 75% and 0.0439 at the final 
analysis.  
Pooled Site  
The statistical efficacy analysis adjusts for pooled site. For the interim analysis, sites with fewer than 
10 participants will be pooled together with another site such that the new pooled site is not larger 
than the largest non-pooled single site. Sites with the smallest enrollment numbers will all be pooled 
together, and sites with moderately small numbers will be pooled with sites that are geographically 
similar. 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 34  
 
The pooled sites for the interim analysis are as follows: 
• 
Pooled small sites (n=14): Cleveland Clinic (n=4), Johns Hopkins (n=4), UCSF (n=2), Utah 
(n=4) 
• 
Pooled moderately small sites (Midwest) (n=19): Wisconsin (n=7) pooled with Mayo (n=12) 
• 
Non-pooled sites: MGH (n=28), UNC (n=15), Penn (n=10).  
 
Tables and Figures  
The efficacy interim analysis will be submitted to the DSMB with a full regular safety DSMB report. 
The safety DSMB report tables and figures include all available data for all randomized participants. 
Because this analysis population is different, a few DSMB displays will be repeated for the interim 
analysis using the interim analysis MITT population.  
The following displays will be included in the interim efficacy analysis based on the interim analysis 
MITT population: 
• 
CONSORT diagram 
• 
Demographics table 
• 
ESS table, showing change from baseline at each visit C1-C6, the average of C4, C5, and C6 
and at the post-treatment follow-up visit. Model estimates, confidence intervals and p-values 
of the differences between treatment groups for the change from baseline at each timepoint 
will be provided. The model will be fitted based on the model provided in SAP Section 9.3. 
The primary p-value to be assessed for early study stopping (relative to the significance level 
of 0.0046) is the comparison between treatment groups at the c6 (week 24) visit. P-values for 
all other timepoints are purely descriptive.  
• 
Table of the key secondary outcomes, showing descriptive statistics by treatment group but 
no statistical testing for the following: 
o Amount of parenteral iron administered (in mg) during the 24-week treatment period 
(pro-rated to 24 weeks in patients who discontinue early). 
o Amount of packed red blood cell transfusions (in units) during the 24-week treatment 
period (pro-rated to 24 weeks in patients who discontinue early). 
o Change in Neuro-QoL Satisfaction with Social Roles and Activities Short Form 
(V1.1) T-score from baseline to weeks 12 and 24 (key timepoint), and the post-
treatment follow-up visit. 
o Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key 
timepoint), and the post-treatment follow-up visit.  
O Change in average weekly epistaxis duration from the four-week screening period 
prior to baseline to weeks 8-12 and to weeks 20-24 (key timepoint), and to weeks 1-4 
post-treatment.  
 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 35  
 
18 APPENDIX 3 INTERIM ANALYSIS AT 75% 
 
The purpose of the 75% interim analysis is to assess for both futility and early efficacy of the primary 
efficacy outcome, the change from baseline in the ESS totals score at 24 weeks. 
As stated in the protocol, the significance level of the primary outcome at the interim and final 
analysis will be based on Lan-DeMets α-spending functions with O’Brien-Fleming boundaries in 
order to maintain the study-wise α level at 0.05. The α level will be 0.0031 at 50%, 0.0183 at 75% 
and 0.0440 at the final analysis. The exact α level at the interim will be determined using Lan-DeMets 
α-spending functions based on the actual percent of data available at the interim.  
The interim analysis will be reviewed by the DSMB in June 2023, based on data from a database 
snapshot date of May 30, 2023.  
If the significance level of the primary outcome is less than the pre-specified alpha level, then the 
DSMB may recommend that study enrollment be halted, with currently active patients completing 
their treatment and follow-up, and the database being cleaned and locked for the final statistical 
analysis.  
Study Population, Sample size and Alpha level 
The interim efficacy analysis will be conducted on all randomized and treated participants (the 
modified Intent to Treat (MITT) population that will be used for the final statistical analysis as 
specified in the SAP) that have either completed the 24-week (C6) visit or have discontinued from the 
study. Participants that have completed C6 but have not yet completed the 4-week post-treatment 
follow-up are included. 
Randomized participants that are ongoing in the trial and have not yet reached the C6 visit will not be 
included in the interim analysis. While their data collected as of the data snapshot is fully applicable, 
the repeated measures model used for the ESS 24-week analysis assumes that the data not yet 
collected for ongoing participants is missing at random and would be assumed to have a similar 
correlation with prior visits as participants that have complete data. While this assumption about 
missing data is to be evaluated in the final analysis (as specified in the SAP), we do not want to 
include cases with missing data that are yet to be collected in the interim analysis where a decision 
might be made about stopping the trial.  
As of the database snapshot, there were 127 participants that met the criteria for inclusion in the 
interim efficacy analysis, which is 80% of the total 159 planned sample size. Using Lan-DeMets α-
spending functions with O’Brien-Fleming boundaries in order to maintain the study-wise α level at 
0.05 based on the 2 planned interim analyses, the revised alpha level for the 54% initial interim was 
0.0046, and the revised alpha level is now 0.0230 at 80% and 0.0425 at the final analysis.  
Futility 
Futility for the primary efficacy outcome will be assessed by conditional power assuming the 
remaining outcome data to be collected will be similar to the data that has been collected thus 
far and not necessarily match the originally hypothesized difference. As stated in the protocol, 
the DSMB may recommend study stop due to futility if the upper limit of the 80% confidence interval 
for conditional power does not exceed 50%. 
 


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 36  
 
Conditional power will be calculated as follows: 
 


(
)
(1
)
(1
)
1
ˆ
where 
/
Z
P
P
P
P
P
Z
T
SE
                   ProbNorm
Z

−
−
−
=


+
−


 
 
• 
probnorm = the lower 1-sided alpha value corresponding to the Z value of the formula in the 
curly brackets based on a normal distribution with mean of zero and standard deviation of 1, 
denoted N(0,1). We are using the lower tail because if the difference is calculated as placebo – 
pomalidomide, the Z will be negative if there is a treatment effect, corresponding to a greater 
decrease in the ESS score for pomalidomide than placebo 
• 
p= the percentage of data available at the interim analysis (=0.80) 
• 
Zα = critical value for the one-sided alpha at the end of the study (= -2.0286, corresponding to Z 
for alpha = 0.0425/2). If the difference is placebo – pomalidomide, the Z will be negative, 
corresponding to a greater decrease in the ESS score for pomalidomide than placebo 
• 
𝑇̂ is the estimate of the treatment group difference (placebo-pomalidomide) from the MMRM 
model at C6 
• 
SE is the standard error of the estimate of the treatment group difference from the MMRM model 
at C6 
 
The 80% confidence interval for the conditional power is calculated as:  
(
)


(1
)
(1
)
(1
)
Z
P
P
P
P
P
                   ProbNorm
Z
Z
Z


−
−
−


+

−
 
Where Zγ is the Z value corresponding to the lower 1-sided tail of the N(0,1) distribution at the alpha 
level = (1-0.8)/2 = 0.10 = -1.28155 
 
Pooled Site  
The statistical efficacy analysis adjusts for pooled site. For the interim analysis, sites with fewer than 
10 participants will be pooled together with another site such that the new pooled site is not larger 
than the largest non-pooled single site. Sites with the smallest enrollment numbers will all be pooled 
together, and sites with moderately small numbers will be pooled with sites that are geographically 
similar. 
The pooled sites for the interim analysis are as follows: 
• 
Pooled small sites (n=21): Cleveland Clinic (n=6), Johns Hopkins (n=6), UCSF (n=2), Utah 
(n=6), and UCSD (n=1) 
• 
Non-pooled sites: MGH (n=43), UNC (n=20), Penn (n=15), Wisconsin (n=11), Mayo (n=17)  
 
Tables and Figures  
The efficacy interim analysis will be submitted to the DSMB with a full regular safety DSMB report. 
The safety DSMB report tables and figures include all available data for all randomized participants. 
Because this analysis population is different, a few DSMB displays will be repeated for the interim 
analysis using the interim analysis MITT population.  


PATH-HHT Statistical Analysis Plan  
 
 
 
  
Version 1.1 FINAL 2023-09-28; Page 37  
 
The following displays will be included in the interim efficacy analysis based on the interim analysis 
MITT population: 
• 
CONSORT diagram 
• 
Demographics table 
• 
ESS table, showing change from baseline at each visit C1-C6, the average of C4, C5, and C6 and 
at the post-treatment follow-up visit. Model estimates, confidence intervals and p-values of the 
differences between treatment groups for the change from baseline at each timepoint will be 
provided. In addition, the conditional power and corresponding 80% confidence interval will be 
provided for the C6 timepoint. The model will be fitted based on the model provided in SAP 
Section 9.3.  
o The primary p-value to be assessed for early study stopping for efficacy (relative to the 
significance level of 0.0230) is the comparison between treatment groups at the C6 (week 
24) visit. P-values for all other timepoints are purely descriptive.  
o Stopping early for futility will be assessed using the upper bound of the 80% confidence 
interval for conditional power at the C6 (week 24) visit (relative to the outpoint level of 
50%).  
• 
Table of the key secondary outcomes, showing descriptive statistics by treatment group but no 
statistical testing for the following: 
o Amount of parenteral iron administered (in mg) during the 24-week treatment period 
(pro-rated to 24 weeks in patients who discontinue early). 
o Amount of packed red blood cell transfusions (in units) during the 24-week treatment 
period (pro-rated to 24 weeks in patients who discontinue early). 
o Change in Neuro-QoL Satisfaction with Social Roles and Activities Short Form (V1.1) 
T-score from baseline to weeks 12 and 24 (key timepoint), and the post-treatment follow-
up visit. 
o Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key 
timepoint), and the post-treatment follow-up visit.  
o Change in average weekly epistaxis duration from the four-week screening period prior 
to baseline to weeks 8-12 and to weeks 20-24 (key timepoint), and to weeks 1-4 post-
treatment.