Conditions: Pulmonary Arterial Hypertension
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The main purpose of this clinical trial is to examine the feasibility and effects of fulvestrant in post-menopausal women with pulmonary arterial hypertension (PAH). The study will evaluate how well the drug is tolerated. The study will evaluate changes in circulating hematopoietic progenitor cells, plasma hormone levels, NT-proBNP, and other plasma biomarkers after the administration of fulvestrant. Changes in tricuspid annular plane systolic excursion, stroke volume index, right ventricular fractional area change, and other echo parameters after fulvestrant administration will be evaluated as well as changes in distance walked in six minutes.

Detailed description:

Arms:
arm 1: 500 mg administered intramuscularly (as two 5 mL injections) on days 0, 14, 28 and 56

Interventions: intervention 1: Fulvestrant
Intervention descriptions: intervention 1: Fulvestrant 500 mg administered intramuscularly into the buttocks slowly as two 5 mL injections, one in each buttock, on days 0, 14, 28 and 56. Fulvestrant 250 mg (one 5 mL injection) will be used in patients with Child-Pugh Class B liver disease.

Protocol document:
Prot_SAP_000.pdf: 
Estrogen Receptor Antagonist in Patients with 
Pulmonary Arterial Hypertension  
(ERA PAH) 
Protocol 
July 18, 2016 
Version 1.0 
Steven M. Kawut, MD, MS 
Perelman School of Medicine at the 
University of Pennsylvania 
Principal Investigator 
NCT02911844


 1
 
Protocol Summary 
 
OBJECTIVES: 
• To determine changes in circulating hematopoietic 
progenitor cells, plasma hormone levels, NT-
proBNP, and other plasma biomarkers after the 
administration of fulvestrant in subjects with 
pulmonary arterial hypertension. 
 
• To observe changes in tricuspid annular plane 
systolic excursion, stroke volume index, right 
ventricular fractional area change, and other echo 
parameters after fulvestrant administration. 
 
• To determine changes in distance walked in six 
minutes after fulvestrant administration. 
 
• Safety and side effects associated with fulvestrant 
administration in subjects with pulmonary arterial 
hypertension. 
 
 
 
 
 
 
 
 
 


 2
 
STUDY DESIGN: 
 
                                                                
Phase II single-arm, open-label study of 
fulvestrant in five post-menopausal women with 
pulmonary arterial hypertension for twelve 
weeks.  
 
 


 3
STUDY POPULATION:      
 
 
 
                                                                        Inclusion criteria: 
 
• Previous documentation of mean pulmonary 
artery pressure > 25 mm Hg with a 
pulmonary capillary wedge pressure (or left 
ventricular end-diastolic pressure) < 16 mm 
Hg and pulmonary vascular resistance > 3 
WU at any time before study entry.  
• Diagnosis of PAH which is idiopathic, 
heritable, drug- or toxin-induced, or 
associated with connective tissue disease, 
congenital heart disease, portal 
hypertension, or HIV infection. 
• Most recent pulmonary function tests with 
FEV1/FVC >50% AND either a) total lung 
capacity > 70% predicted or b) total lung 
capacity between 60% and 70% predicted 
with no more than mild interstitial lung 
disease on computerized tomography scan 
of the chest. 
• Female, post-menopausal state, defined as:  
• > 50 years old and a) have not 
menstruated during the preceding 
12 months or b) have follicle-
stimulating hormone (FSH) levels > 
40 IU/L or  
• < 50 years and FSH > 40 IU/L or  
• having had a bilateral 
oophorectomy. 
• Informed consent. 
 
Exclusion criteria: 
 
• Age < 18. 
• Treatment with estrogen or anti-hormone 
therapy (tamoxifen, anastrozole, etc.)  
• WHO Class IV functional status. 
• History of breast cancer. 
• Clinically significant untreated sleep apnea. 
• Left-sided valvular disease (more than 
moderate mitral valve stenosis or 
insufficiency or aortic stenosis or 


 4
insufficiency), pulmonary artery or valve 
stenosis, or ejection fraction < 45% on 
echocardiography. 
• Initiation of PAH therapy (prostacyclin 
analogues or receptor agonists, endothelin-
1 receptor antagonists, phosphodiesterase-
5 inhibitors, soluble guanylate cyclase 
stimulators) within three months of 
enrollment; the dose must be stable for at 
least 3 months prior to Baseline Visit. PAH 
therapy which is stopped and then 
restarted or has dose changes which are not 
related to initiation and uptitration will be 
allowed within 3 months prior to the 
Baseline Visit. 
• Hormone therapy. 
• Use of warfarin or other anticoagulant (use 
of aspirin is permitted). 
• Platelet count <100,000. 
• Renal failure (creatinine ≥ 2.0). 
• Child-Pugh Class C cirrhosis. 
• Current or recent (< 6 months) chronic heavy 
alcohol consumption. 
• Current use of another investigational drug 
(non-FDA approved) for PAH. 
                                                              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 5
 
 
ENDPOINTS: 
 
• Changes in right ventricular systolic pressure, right 
ventricular fractional area, stroke volume index 
and tricuspid annular plane systolic excursion 
• Changes in six-minute walk distance  
• Changes in plasma NT-proBNP and estradiol levels  
• Assess safety and side effects associated with 
fulvestrant administration in subjects with 
pulmonary arterial hypertension 
 
 
 
 
STUDY OBSERVATIONS:  
 
• Subjects will be evaluated in person at screening, 
baseline, two weeks, four weeks, eight weeks and 
nine weeks.  
• Subjects will have telephone follow-up at week 
twelve. 
• Laboratory tests including a complete blood count, 
hepatic function panel, follicle-stimulating 
hormone, coagulation studies (PT/INR) will be 
performed at the screening visit. 
• Research laboratories such as estradiol (E2) and 
NT-proBNP levels will be evaluated at baseline and 
repeated after nine weeks of fulvestrant 
administration. 
• Subjects will have six minute walk testing at 
baseline and week nine. 
• Subjects will have a transthoracic echocardiogram 
at screening or baseline and week nine. 
 
 
 
 
 
 


 6
 
SAMPLE SIZE AND POWER:  
A total of 5 subjects will be enrolled to receive 
fulvestrant at baseline, two weeks, four weeks, and 
eight weeks. Formal power calculations were not 
performed as this study is intended to show 
feasibility and for hypothesis-generation. 
 
DATA ANALYSIS:  
The study endpoints will be evaluated using 
summary statistics and graphical tools. Univariate 
analysis will be performed for all variables of 
interest. These will be carried out by comparing the 
changes from baseline using signed rank tests for 
continuous variables and McNemar’s test for 
categorical variables. 
 


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Brief Table of Contents   
 
 
ABSTRACT……………………………………………………………………………...11 
 
CHAPTER 1: Background and Significance……………………………………….……12 
 
CHAPTER 2: Objectives and Specific Aims………………………………….…………14 
 
CHAPTER 3: Screening, Subject Selection ………………….... …………………...….15 
 
CHAPTER 4: Treatment……………………………………………………………...….17 
 
CHAPTER 5: Data Collection………………………………………………………...…18 
 
CHAPTER 6: Outcome Measures…………………………………………….………....25 
 
CHAPTER 7: Statistical Considerations………………………………………………...27 
 
CHAPTER 8: Quality Control…………………………………………………………...29 
 
CHAPTER 9: Participant Safety and Confidentiality…………………………………....30 
 
REFERENCES…………………………………………………………………………..40 
 


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Detailed Table of Contents 
 
 
ABSTRACT……………………………………………………………………………...11 
 
CHAPTER 1: Background and Significance……………………………………….……12 
 
1.1 Definition and characterization of PAH……………………….…………..12 
 
1.2 Hormonal effects on the vasculature..........................................................12 
 
1.3 Fulvestrant and estrogen inhibition..……………………..……….……….13 
 
1.4 Summary………………..…………………………………………….……13 
 
CHAPTER 2: Objectives and Specific Aims………………………………….…………14 
 
 
 
2.1 Objectives………………………………………………………………….14 
 
 
 
2.2 Specific aims…………………………………………………………….…14  
 
CHAPTER 3: Screening and Subject Selection …………………….………………..….15 
 
 
3.1 Recruitment………………………………………………………………...15 
 
      3.1.1 Identification and screening process…………….…………………...15 
 
 
3.2 Subject selection criteria……………………………………………….......15 
 
      3.2.1 Inclusion criteria…………………………………….………….……15 
                     3.2.2 Exclusion criteria…………………………………….…………...….15 
  
 
CHAPTER 4: Treatment..…………………………………………………………….….17 
 
 
4.1 Fulvestrant..………………………………………………………...………17 
 
 
4.2 Management of other medical therapies during the trial……………….….17 
 
 
CHAPTER 5: Data Collection………………………………………………………...…18 
 
 
5.1 Study Visit.…..…………………………………………………………….18 
 
      5.1.1 Screening……………………………………………………….…….18 
 
      5.1.2 Study day (Baseline)………………………………………….…...…18 
 
      5.1.3 Visit 2….. ...…………………………………...………………….….20 
 
      5.1.4 Visit 3…...…………………..……………………………….……….20 
 
      5.1.5 Visit 4 …..……...………………………………………………..…...21 


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      5.1.6 Visit 5………………..…………………...……………. ……..…..…22 
 
      5.1.7 Follow-up Phone Call………………………………………………. 22 
 
      5.1.8 End of Study Visit for Early Withdrawal Subjects ………………… 22 
 
 
5.2 Study schedule of procedures……..………………………………….……23 
 
 
5.3 Subjects’ retention and drug compliance………………...……………..….24 
 
 
5.4 Subject reimbursement …………………………………………………….24 
 
CHAPTER 6: Outcome Measures……………………………………………….……....25 
 
 
6.1 Assessments of efficacy…………………………………………………....25 
 
      6.1.1 Plasma estradiol (E2) levels …………………..……………………..25 
 
      6.1.2 Hematopoietic progenitor cells  …………………….……………….25 
 
      6.1.3 Echocardiographic measures .………………………………….……25  
                     6.1.4 Six minute walk test ……………....…………………………………25 
 
      6.1.5 Plasma NT-pro BNP..………………………………………………..25 
 
      6.1.6 WHO functional class ………………….…………………………....25  
 
       
 
CHAPTER 7: Statistical Considerations………………………………………………...27 
 
 
7.1 Study design………………………………………………………………..27 
 
 
7.2 Disposition of subjects and baseline comparisons…………………………27 
 
 
7.3 Statistical procedures……………………………………………………....27 
 
      7.3.1 Data analysis………………………………………………………....27 
 
      7.3.2 Univariate analysis…………………………………………………...27 
 
      7.3.3 Missing data and dropouts……………………………….…..…..…..27 
 
 
7.4 Sample size and power calculations……………………………………….28 
 
 
7.5 Interim monitoring guidelines……………………………………………...28 
 
 
7.6 Protocol violations……………………………………………………...….28 
 
 
7.7 Safety……………………...……………………………………………….28 
 
CHAPTER 8: Quality Control…………………………………………………………...29 
 
 
8.1 Personnel training………………………………………………………….29 
 
 
8.2 Data quality……………...………………………………………………....29 
 


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CHAPTER 9: Participant Safety and Confidentiality…………………………………...30 
 
 
9.1 Consent………………………………………………………………….....30 
 
 
9.2 Institutional review board process………………………………………....30 
 
 
9.3 Laboratory values…………………………………………………………..30 
                     9.3.1 Hematology…………………………………………………………..30 
                     9.3.2 Chemistry…………………………………………………………….30 
 
 
9.4 Fulvestrant  -related laboratory abnormalities of drug interactions……......30 
 
 
9.5 Other events………………………………………………………………..30 
 
 
9.6 Safety and Adverse Events…………………..………………………..…...31 
 
      9.6.1 Definitions…….……………………………………………………...31 
 
 9.6.2 Classifying adverse events…………………………………………...32 
 
      9.6.3 Interpretation of definitions………..……………………………...….33 
                     9.6.4 Reporting procedures for adverse events / unanticipated problems….34 
 
      9.6.5 Subject withdrawal…………………………………………………...37 
 
       
 
 
9.7 Confidentiality of study data……………………………………………….37 
 
9.7.1 Global unique identifier ……………………………………………..38  
 
 
9.8 Potential risks…………………………………………………………........38 
 
 
9.9 Potential benefits………………………………………………….....…..…39 
 
 
9.10 Alternatives………………..…………………………………………...…39 
 
 
 
9.11 Ethical Considerations……………………………..…………………......39 
 
REFERENCES…………………………………………………………………………..40 
 
 
 
 
 
 
 
 
 
 


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ABSTRACT 
 
Pulmonary arterial hypertension (PAH) is characterized by obliteration of the pulmonary 
vascular bed. Right-sided heart failure ensues with severe limitation of exercise and 
eventual progression to death.  
 
The role of female sex in PAH has long been recognized.  Certain types of PAH are more 
common in women and some have implicated hormone therapy in causing or worsening 
PAH. A genetic study has shown that variation in estrogen metabolism is a risk factor for 
PAH. These data strongly suggest estrogen as a potential therapeutic target in the 
treatment of PAH.  
 
Fulvestrant is an FDA-approved estrogen receptor (ER) antagonist, used to treat 
postmenopausal women who are diagnosed with hormone receptor-positive metastatic 
breast cancer. Fulvestrant binds to ER in a competitive manner and downregulates the 
ER protein. We aim to determine if fulvestrant will decrease circulating pro-angiogenic 
hematopoietic progenitors in the plasma and plasma estradiol levels as well as lower 
right ventricular systolic pressure in patients diagnosed with PAH. 
 
 
 


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Chapter 1. Background and Significance 
 
1.1 Definition and characterization of PAH 
 
Pulmonary arterial hypertension (PAH) is defined by a mean pulmonary artery pressure 
> 25 mm Hg, a pulmonary vascular resistance > 3 WU, and a normal pulmonary capillary 
wedge pressure. Endothelial thickening, smooth muscle hypertrophy, and in situ 
thrombosis are present in small pulmonary arteries, however the disease mechanism is 
unknown. The three year survival is only 60%. 
 
1.2 Hormonal effects on the vasculature 
In PAH, abnormal endothelial cell proliferation and expression of angiogenesis markers 
characterize the pulmonary vascular lesions. Animal models and patients with PAH have 
increased pro-angiogenic hematopoietic progenitor cells (HPCs) in the bone marrow and 
circulating in blood.1 Estradiol stimulates HPC mobilization via the estrogen receptor α 
(ERα), and ER α blockade reduces HPC colony formation and endothelial growth. 
Estradiol is metabolized by cytochrome P450 (CYP) enzymes to metabolites which have 
both pro-angiogenic (16α-OHE1, signaling via ERα) and anti-angiogenic (2-OHE, 2-
methoxyestradiol [2ME]) effects. The rs1800440 single nucleotide polymorphism (SNP) 
in CYP1B1 (enzyme that metabolizes estrone) produces a higher urinary 16α-OHE1/2-
OHE ratio, and both the SNP and urinary ratio are risk factors for heritable PAH.2  
Androstenedione and testosterone are converted by aromatase to estrone and estradiol 
(E2) which signal via ER α and β. Female sex and estrogen are traditionally thought to 
have beneficial effects on the lung vasculature. Estrogen attenuates pulmonary vascular 
remodeling and right ventricular changes in hypoxic and monocrotaline animal models 
of pulmonary hypertension.3-5 These findings are however inconsistent with human 
PAH. First, female sex increases the risk of idiopathic and heritable PAH and 
portopulmonary hypertension.6 Austin et al. showed that subjects with certain 
genotypes of CYP1B1 had lower 2-hydroxyestrone:16a-hydroxyestrone ratio and had a 
higher risk of PAH.2 We have shown that SNPs in aromatase raised circulating E2 levels 
and increased the risk of PAH.7 
E2 metabolites may also contribute to pathogenesis. CYP1B1 is highly expressed in the 
lung and oxidizes E2 to 2-OHE and then 2-ME which inhibits angiogenesis and 
endothlein-1.8, 9 16α-OHE1 increases DNA synthesis and cellular proliferation via ER α 
stimulation. The dominant hydroxylation pathway (affected in part by variation in the 
rs1800440 SNP (A>G, Asn453Ser) in CYP1B1) determines the ratio of these E2 
metabolites. The rs1800440 CYP1B1 SNP is associated with a higher 16α-OHE1/2-OHE 
urinary ratio (the “readout” of CYP1B1) and with a higher risk for cancer, a finding 
attributed to enhanced angiogenesis. Accordingly, in the monocrotaline model of 
pulmonary hypertension, administration of 2-ME reduced vascular remodeling by > 50% 
and improved survival.10 All of the known vascular and angiogenic effects of estrogen 


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hormones act via ER α, making this the pivotal receptor in these processes. In summary, 
these data show that female sex and genetic variation in E2 production, activity, and 
metabolism are important risk factors for PAH. These findings implicate that the 
mechanistic pathway between estrogen signaling and PAH warrants exploration. 
1.3 Fulvestrant and estrogen inhibition 
Fulvestrant is an FDA-approved ER antagonist, used to treat postmenopausal women 
who are diagnosed with hormone receptor-positive metastatic breast cancer. 
Fulvestrant binds to ER in a competitive manner and downregulates the ER protein.  
1.4 Summary 
 
Data suggest that E2 may contribute to PAH. Treatment with fulvestrant, an ER 
antagonist, may therefore be effective in PAH. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Chapter 2. Objectives and Specific Aims 
 
2.1 Objectives 
 
This is a Phase II, open-label, single center, “proof of concept” study to examine the 
feasibility and effects of fulvestrant in post-menopausal women with PAH.  
 
2.2 Specific Aims 
 
1. To determine changes in circulating hematopoietic progenitor cells, plasma 
hormone levels, NT-proBNP, and other plasma biomarkers after the 
administration of fulvestrant in PAH. 
 
2. To observe changes in tricuspid annular plane systolic excursion, stroke volume 
index, right ventricular fractional area change, and other echo parameters after 
fulvestrant administration. 
 
3. To determine changes in distance walked in six minutes after fulvestrant 
administration. 
 
4. Safety, feasibility and side effects associated with fulvestrant administration in 
subjects with PAH. 
 
 
  


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Chapter 3. Screening, Subject Selection 
 
3.1 Recruitment 
 
3.1.1 Identification and screening process 
 
Subjects will be identified by the PH clinicians who care for patients with PAH at Penn 
Medicine. We expect to screen approximately 200 subjects over 12 months. Potentially 
eligible subjects will be approached about the study at a regularly scheduled PH clinic 
visit. After the initial screening, the subject will be provided a consent form before any 
study procedures are performed.  
 
3.2 Subject selection criteria 
 
3.2.1 Inclusion criteria 
 
• Previous documentation of mean pulmonary artery pressure > 25 mm Hg with a 
pulmonary capillary wedge pressure (or left ventricular end-diastolic pressure) < 
16 mm Hg and pulmonary vascular resistance > 3 WU at any time before study 
entry.  
• Diagnosis of PAH which is idiopathic, heritable, drug- or toxin-induced or 
associated with connective tissue disease, congenital heart disease, portal 
hypertension, or HIV.  
• Most recent pulmonary function tests with FEV1/FVC >50% AND either a) total 
lung capacity > 70% predicted or b) total lung capacity between 60% and 70% 
predicted with no more than mild interstitial lung disease on computerized 
tomography scan of the chest 
• Women who are post-menopausal, defined as: 1) > 50 years old and a) have not 
menstruated during the preceding 12 months or b) have follicle-stimulating 
hormone levels > 40 IU/L or 2) < 50 years and follicle-stimulating hormone levels 
> 40 IU/L, or 3) having had a bilateral oophorectomy.  
• Informed consent.  
 
 
3.2.2 Exclusion criteria 
 
• Age < 18 years 
• Treatment with estrogen or anti-hormone therapy (tamoxifen, anastrozole, etc.) 
•  WHO Class IV functional status.  
• History of breast cancer.  
• Clinically significant untreated sleep apnea diagnosed by polysomnography.  


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• Left-sided valvular disease (more than moderate mitral valve stenosis or 
insufficiency or aortic stenosis or insufficiency), pulmonary artery or valve 
stenosis, or ejection fraction < 45% on echocardiography.  
• Initiation of PAH therapy (prostacyclin analogues or receptor agonists, 
endothelin-1 receptor antagonists, phosphodiesterase-5 inhibitors, soluble 
guanylate cyclase stimulators) within three months of enrollment; the dose must 
be stable for at least 3 months prior to Baseline Visit. PAH therapy which is 
stopped and then restarted or has dose changes which are not related to 
initiation and up-titration will be allowed within 3 months prior to the Baseline 
Visit.  
• Hospitalized or acutely ill.  
• Use of warfarin or other anticoagulant (use of aspirin is permitted). 
• Platelet count <100,000. 
• History of bleeding disorder. 
• Renal failure (creatinine ≥ 2.0).  
• Child-Pugh Class C cirrhosis.  
• Current or recent (< 6 months) chronic heavy alcohol consumption.  
• Current use of another investigational drug (non-FDA approved) for PAH.  
 
 
 
 
 
 
 
 


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Chapter 4. Treatment 
 
4.1 Fulvestrant 
 
Fulvestrant is given intramuscularly (IM). Steady state concentrations are reached within 
the first month and plasma levels are maintained for at least one month. It is 
metabolized by the liver as well as multiple biotransformation pathways. Metabolites 
are less active or have similar activity to parent compound.  
 
The majority of clinical studies have been conducted in patients with estrogen-positive 
breast cancer such as the Comparison of Faslodex in Recurrent or Metastatic Breast 
Cancer (CONFIRM) trial, a randomized, double-blind, phase III trial that enrolled 746 
women. Patients were randomly assigned to fulvestrant at two doses: 500 mg or 250 mg 
at days 0, 14, 28 and every 28 days. 
 
The CONFIRM trial suggested that fulvestrant 500 mg is superior to fulvestrant 250 mg. 
The researchers found that there was a 19% reduction in risk of death and a 4.1 month 
difference in overall survival in subjects who were randomized to 500 mg fulvestrant 
dosage compared with fulvestrant 250 mg. The higher dose was well tolerated with no 
new safety concerns. Patients with Child-Pugh Class B liver disease could be safely given 
doses of fulvestrant 250 mg. 
 
This study will utilize fulvestrant 500 mg administered intramuscularly into the buttocks 
slowly (1-2 minutes per injection) as two 5 mL injections, one in each buttock, on days 0, 
14, 28 and 56. Fulvestrant 250 mg (one 5 mL injection) will be used in patients with 
Child-Pugh Class B liver disease.  
 
4.2 Management of other medical therapies during the trial 
 
The subjects’ pre-study medical regimen will be continued after enrollment in the study. 
There will be no constraints on the management of the subjects’ PAH medication during 
the study period. 
 
 
 


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Chapter 5. Data Collection 
 
5.1 Study visit 
 
5.1.1 Screening 
Potential subjects will be identified by the research staff and medical staff who care for 
patients with PAH at Penn Medicine. After reviewing the potential subject’s chart to see 
if she meets most of the inclusion/exclusion criteria, the subject will be approached by a 
research team member during a scheduled PH clinic visit. The study will be explained to 
the subject. After all questions are answered and if the subject agrees to participate, she 
will be scheduled for a screening visit. 
 
The following procedures will be performed during the screening process:  
 
• 
Review of inclusion/exclusion criteria  
• 
Sign and date the informed consent and HIPAA release (must be done before any  
study procedures)  
• 
Review medical history  
• 
Review current medications  
• 
Labs/Phlebotomy: complete blood count, hepatic function panel, platelet count,  
 
coagulation studies, and FSH (if needed) 
• 
Provide instructions on recording of new concomitant medications and dose  
changes  
• 
Instruct subjects to bring a list of routine medications to baseline visit, do not eat  
or drink (except water) 12 hours before baseline visit, and to avoid heavy 
exercise for 12 hours before the baseline visit  
 
If the subject meets the inclusion/exclusion criteria for the study, the subject will be 
scheduled for a baseline study visit within 28 days at the study center. The research 
coordinator will call the subject and the PAH clinician 24 hours after the study visit if 
laboratories were obtained.  
 
The screening visit can be combined with the baseline visit for participants who are 
known to be post-menopausal (i.e., (1) > 50 years old and have not menstruated during 
the preceding 12 months or (2) have undergone bilateral oophorectomy). Review of 
medical history, medications, and informed consent must be obtained prior to the 
combined visit.   
 
5.1.2 Study Day – Visit 1 (Baseline), Day 0 (− 2 days) 
The research coordinator will call the subject 1-2 days before the visit as a reminder to 
not eat or drink (except water) and to avoid heavy exercise for 12 hours before the 
study day assessment. Subjects will be instructed to bring a list of the current 
medications and to take all medications before the visit other than any oral PAH 
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after the blood draw. The subject will be reminded to wear appropriate clothing and 
shoes to complete a 6MWT. 
 
Baseline information will be used to characterize the participants. Safety laboratories 
obtained at the screening visit will be used as baseline measurements. All baseline data 
will be collected prior to study drug administration. If a combined Screening Visit and 
Baseline Visit is performed, all labs (other than FSH for female subjects who are known 
to be post-menopausal per inclusion criteria) must be confirmed and all 
inclusion/exclusion criteria must be met prior to study drug administration.  
 
The subject will arrive at the study site outpatient clinic. The following procedures will 
be performed:  
• Vital signs  
• Labs/Phlebotomy: estradiol level, NT-proBNP, hematopoietic progenitor cells  
(EPCs), and other research labs*  
• Echocardiography   
• Interim medical history  
• Review current medications  
• WHO functional class assessment (must be done by a study physician or  
 
 
 
research nurse) 
• Physical exam   
• Six minute walk testing (6MWT) with Borg scores 
• Assess any adverse events (AEs) or serious adverse events (SAEs)  that have 
occurred since last visit 
• Review of inclusion/exclusion criteria 
• Administration of study drug, fulvestrant, by the study physician or research  
nurse 
• Reinforce instructions on recording of new medications and dose changes   
 
*Screening labs should be drawn if performing a combination baseline/screening visit. 
All screening laboratory tests must be received and all inclusion/exclusion criteria 
confirmed by the PI before the subject can receive study drug.  
 
There is no particular order in which these procedures must be done EXCEPT for the 
administration of the study drug, which should be performed last and only if the subject 
is eligible per inclusion/exclusion criteria.  
 
Blood samples for research study assays will be kept a room temperature and shipped 
to be processed as well as processed on site and banked in a freezer at -70⁰ C. 
 
Echocardiography will be performed. The PI or research nurse will take a history and 
perform a physical examination and the subject will complete the 6MWT.  
 


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The study medication will be administered last by the research nurse or physician. It will 
be administered according to the manufacturer’s instructions. 500 mg will be given as 
two intramuscular injections to eligible subjects who do not have Child-Pugh Class B 
liver disease and 250 mg for eligible subjects who have Child-Pugh Class B liver disease. 
Each syringe holds 250 mg of fulvestrant. 
 
After the completion of the baseline visit, the research coordinator will thank the 
subject for their attendance and reinforce compliance with the visit schedule. The 
subject’s primary PAH physician and medical doctor will be alerted to the subject’s 
participation in the clinical trial. The next clinic visit (Visit 2) will be scheduled for Week 
2 ± 3 days. 
 
5.1.3 Visit 2, Week 2 (Two weeks ± 3 days) 
The research coordinator will call the subject 1-2 days before the visit as a reminder. 
Subjects will be instructed to bring a list of the current medications and to take all 
medications before the visit. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will 
be performed:  
• Interim medical history  
• Assess any AEs/SAEs 
• Vital signs  
• Review current medications  
• Study drug administration by study physician or research nurse 
• Reinforce instructions on recording of new medications  
 
The study medication will be administered last by the research nurse or a study 
physician. It will be administered according to the manufacturer’s instructions. 500 mg 
will be given as two intramuscular injections to eligible subjects who do not have Child-
Pugh Class B liver disease and 250 mg for eligible subjects who have Child-Pugh Class B 
liver disease. Each syringe holds 250 mg of fulvestrant. 
 
The research coordinator will thank the subject for their attendance, schedule the next 
visit and reinforce compliance with the study visit timeline. 
 
5.1.4 Visit 3, Week 4 (Four weeks ± 3 days) 
The research coordinator will call the subject 1-2 days before the visit as a reminder. 
Subjects will be instructed to bring a list of the current medications and to take all 
medications before the visit. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will 
be performed:  
• Interim medical history  
• Assess any AEs/SAEs 


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• Vital signs  
• Review current medications  
• WHO functional class assessment (must be done by study physician or research 
nurse) 
• Physical exam  
• Study drug administration by the study physician or research nurse 
• Reinforce instructions on recording of new medications  
The study medication will be administered last by the research nurse or physician. It will 
be administered according to the manufacturer’s instructions. 500 mg will be given as 
two intramuscular injections to eligible subjects who do not have Child-Pugh Class B 
liver disease and 250 mg for eligible subjects who have Child-Pugh Class B liver disease. 
Each syringe holds 250 mg of fulvestrant. 
The research coordinator will thank the subject for their attendance, schedule the next 
study visit and reinforce compliance with the study visit timeline.  
 
5.1.5 Visit 4, Week 8 (Eight weeks  ± 3 days)  
The research coordinator will call the subject 1-2 days before the visit as a reminder. 
Subjects will be instructed to bring a list of the current medications and to take all 
medications before the visit. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will 
be performed:  
• Interim medical history  
• Assess any adverse events/serious adverse events 
• Vital signs  
• Review current medications  
• Study drug administration by study physician or research nurse 
• Reinforce instructions on recording of new medications  
 
The study medication will be administered last by the research nurse or physician. It will 
be administered according to the manufacturer’s instructions. 500 mg will be given as 
two intramuscular injections to eligible subjects who do not have Child-Pugh Class B 
liver disease and 250 mg for eligible subjects who have Child-Pugh Class B liver disease. 
Each syringe holds 250 mg of fulvestrant. 
 
The research coordinator will thank the subject for their attendance, schedule the final 
study visit and reinforce compliance with the study visit timeline.  
 
5.1.6 Visit 5 (Nine weeks -3 or + 7 days) 
The research coordinator will call the subject 1-2 days before the visit as a reminder. 
The coordinator will instruct the subject to not eat or drink (except water) and to avoid 
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to bring a list of the current medications and to take all medications before the visit 
other than any oral PAH medication(s). The subject should bring their oral PAH 
medication(s) with them to be taken after the blood draw. The subject will be reminded 
to wear appropriate clothing and shoes to complete a 6MWT. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will 
be performed:  
• Labs/Phlebotomy: research labs  
• Echocardiogram 
• Interim medical history  
• Assess any adverse events/serious adverse events 
• Vital signs  
• Review current medications  
• WHO functional class assessment  
• Physical exam  
• 6MWT with Borg scores  
 
There is no particular order in which these procedures must be done, but it is 
recommended that the fasting blood draw be performed first.  
 
Blood samples for study assays will be processed and banked. After obtaining the blood 
samples, the subject will be instructed to take their regular medications. 
Echocardiography will be performed. The investigator or research nurse will take a 
history and perform a physical examination. The subject will complete the 6MWT.  
 
The research coordinator will thank the subject for their participation in the clinic visits 
of the clinical trial. A follow-up phone call will be scheduled. 
 
5.1.7 Follow-up Phone Call (Twelve weeks ± 3 days) 
The research coordinator will call the subject. The following will be reviewed: 
• Any changes in concomitant medication 
• Review all adverse events/serious adverse events  
• Interim medical history 
 
 
If there is a significant increase in symptoms or worsened clinical status the subject will 
be asked to come to the study center for evaluation.  
 
 
5.1.8 End of Study Visit for Early Withdrawal Subjects 
If a subject withdraws or is withdrawn from the study, they will come to clinic for an End 
of Study Visit. The procedures done at Visit 5, Week 9 will be performed (see Section 
5.1.6.) A follow-up phone call will be done at week 12 if the subject agrees. 
 


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5.2 Study schedule of procedures 
 
The table below summarizes the study procedures. 
 
Table 1. Study Procedures 
Xa: Only to be performed if not done at screening visit. These assessments should be 
reviewed by the PI prior to first administration of study drug to ensure that the subject 
meets inclusions/exclusion criteria. 
 
*Screening Visit procedures may be done at the Baseline Visit for female participants 
who are known to be post-menopausal: (1) > 50 years old and have not menstruated 
during the preceding 12 months or (2) have undergone bilateral oophorectomy. Review 
of medical history, medications, and informed consent must be obtained prior to the 
combined visit.
 
Screening* 
 
Baseline 
 
 
Week 2 
 
 
Week 4 
 
Week 8 
 
Week 9 
 
Week 12  
Follow-up 
Phone Call 
 Visit # 
 
1 
2 
3 
4 
5 
 
 Day# 
-28 - 0 
-2 - 0 
14  ±  3 
28  ±  3 
56  ±  3 
- 3- (63) + 7 
84  ±  3 
 Informed consent 
X 
 
 
 
 
 
 
General Testing 
 
 
 
 
 
 
 
 Physical Exam 
 
X 
 
X 
 
X 
 
 Medical history 
X 
Xa 
 
 
 
 
 
 Vital signs 
X 
X 
X 
X 
X 
X 
 
WHO FC Assessment 
 
X 
 
X 
 
X 
 
Laboratory Test 
 
 
 
 
 
 
 
 Complete blood  
count 
X 
Xa 
 
 
 
 
 
Hepatic function 
panel 
X 
Xa 
 
 
 
 
 
 Coagulation studies    
 (PT/INR) 
X 
Xa 
 
 
 
 
 
 FSH  
X 
Xa 
 
 
 
 
 
 Research labs 
 
X 
 
 
 
X 
 
Study procedures 
 
 
 
 
 
 
 
Study drug 
administration 
 
X 
X 
X 
X 
 
 
Echocardiogram 
X 
Xa 
 
 
 
X 
 
 Six minute walk test 
 
X 
 
 
 
X 
 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
Assess Adverse 
Events/Serious 
Adverse Events 
 
X 
X 
X 
X 
X 
X 


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 5.3 Subjects’ retention and drug compliance 
 
We will enforce subject retention in several ways. We will record extensive contact 
information for each subject at their enrollment in the trial. This will include home, 
work, and cellular telephone numbers. The research coordinator will call before each 
study visit to remind the subject to attend. The research coordinator and physician will 
explain the importance of compliance with the study protocol at each subject contact. If 
a subject fails to comply with a study visit, the coordinator will contact her by 
telephone. If this fails, the coordinator will send two letters by UPS, one week apart, to 
request follow-up. 
 
If a subject wishes to drop-out from the treatment phase of the study or has a serious 
adverse event (whether related to study drugs or not), we will continue to follow-up 
with the subject for study assessments to assist with safety monitoring and to avoid the 
problems introduced by missing data.  
 
5.4 Subject reimbursement 
 
Subjects will be reimbursed for reasonable travel expenses and the inconvenience of the 
study procedures necessary for participation. We acknowledge that participation in this 
study is very burdensome due to many factors such as the route of administration of the 
study drug, the time needed to complete procedures associated with the study, and the 
frequent trips to the clinic to perform study procedures. The subject will be reimbursed 
$100 for completing the screening visit. Each subsequent visit completed (visits 1-5) will 
be reimbursed $250 for a total reimbursement of $1350.  
 
The study drug will be provided free of charge.


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Chapter 6. Outcome Measures 
 
6.1 Assessments of efficacy 
 
• E2 levels and HPCs 
• RV systolic pressure, tricuspid annular plane systolic excursion (TAPSE), 
and RV stroke volume index 
• Six-minute walk distance 
• Plasma NT-proBNP level  
• Safety and side effects associated with short-term fulvestrant 
administration in subjects with PAH 
 
6.1.1 Plasma Estradiol (E2) Levels 
Plasma E2 levels will be measured using a double antibody radioimmunoassay. 
 
6.1.2. Hematopoietic Progenitor Cells (HPCs) 
Plasma HPC levels will be measured using flow cytometry. 
 
6.1.3 Echocardiographic Measures 
The ultimate determinant of outcome in subjects with PAH is RV function which will 
measured by transthoracic echocardiography. Thus, we have focused on TAPSE, which 
reflects RV shortening and is a strong predictor of survival in PAH. We will also assess RV 
systolic pressure, stroke volume index, RV fractional area change and other parameters. 
  
6.1.4 Six minute walk distance 
Walking is the most basic form of exercise and is integral to daily activities. The 6MWT is 
a standardized, timed submaximal test of unencouraged, self-determined distance 
walked which is reliable and valid. We will use standardized test methods as well as 
scripted and timed statements that have been established in prior studies of PAH that 
have been recommended by the American Thoracic Society in 2002. The 6WMT is also 
non-invasive and safe. 
 
The subject will be instructed to wear comfortable clothing and shoes. The test will be 
performed at approximately the same time of day at each visit. The Borg score for 
dyspnea and oxygen saturation will be recorded at the beginning and conclusion of each 
test. 
 
6.1.5 Plasma NT-pro BNP 
Plasma NT-proBNP reflects right ventricular function in PAH and is a very strong 
predictor of outcome in PAH.  
 
6.1.6 WHO functional class 
The WHO functional classification for PAH has been modified from the well-known New 
York Heart Association functional classification. This functional classification is based on 


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symptoms, with Class I being defined by no symptoms with physical activity, Class II as 
having mild limitation in physical activity and are comfortable at rest, Class III as having 
markedly limited physical activity and are comfortable at rest, and Class IV as being 
unable to perform any physical activity without symptoms. The WHO functional class 
will be assessed at baseline, Week 4 and Week 9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Chapter 7. Statistical Considerations 
 
7.1 Study design 
 
To address the aims of this study, we will conduct an open-label, single-arm trial.  Blood 
sampling, echocardiography and 6MWT will be performed at baseline and nine weeks.  
 
7.2 Disposition of subjects and baseline summaries 
 
Summaries of all subjects screened and recruited, and the number who complete visits 
at baseline, week two, week four, week eight, and week nine will be provided, according 
to the CONSORT guidelines.  
 
7.3 Statistical procedures  
 
7.3.1 Data analysis 
Prior to the formal analysis, the distributions of the key variables to be used in the 
analyses will be examined using summary statistics and graphical tools.  
 
Outcomes of interest will be evaluated with a per-protocol analysis. Subjects who are not 
compliant or stop the treatment portion of the study will be replaced (although their 
data will also be considered in secondary analyses). Outcomes include estradiol levels, 
TAPSE and other echocardiographic measures, 6MWD, plasma NT-proBNP level, and 
other variables as well as safety and side effects. 
 
These measures will be assessed both at baseline and nine weeks. Summary statistics 
will be produced with both the repeated measures as well as the calculated differences 
from the baseline. We will summarize demographics and other predictors of clinical 
status. Continuous variables will be summarized by the mean, median, standard 
deviation, and range, as appropriate. We will use contingency tables for discrete and 
dichotomous variables. 
 
Hypothesis testing will use two-sided α= 0.05. All statistical analyses will be performed 
using SAS and R. 
 
7.3.2 Univariate analysis 
Univariate analyses will be performed for all variables of interest. These will be carried 
out by comparing the changes from baseline using signed rank tests for continuous 
variables and McNemar’s test for categorical variables. 
 
7.3.3 Missing data and dropouts 
Patients who drop out from treatment or assessment plan will be replaced. 
 


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7.4 Sample size and power calculations  
 
Formal power calculations have not been performed. This study is intended for 
hypothesis generation and to show feasibility.  
 
7.5 Interim monitoring guidelines 
 
We have not planned for formal interim analyses for efficacy. 
 
7.6 Protocol violations 
 
Serious protocol violations such as discontinuation of experimental treatment unrelated 
to AEs will be carefully recorded and regularly reviewed by the Principal Investigator at 
each site and by the lead site. Remedial changes in procedure will be recommended 
where feasible to reduce the incidence of such violations. The causes and circumstances 
of all violations will be documented where known for purposes of future secondary 
analyses and interpretation. 
 
 
7.7 Safety  
 
All subjects will be assessed for toxicity and included in the safety analysis. This analysis 
will include summaries of the incidence and grade of toxicities.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 


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Chapter 8. Quality Control 
 
Design strategies and monitoring activities throughout the study will ensure the 
integrity and high quality of the data. Design strategies training and certification of 
personnel. The monitoring program includes data queries over the time of the trial.  
 
8.1 Personnel training  
 
Prior to enrollment of the first subject in the study protocol, the PI will ensure that staff 
has completed appropriate training and that all documentation including IRB approval is 
completed and available. The purpose of training is to ensure that study personnel are 
carrying out the protocol in a consistent way and are adhering to good clinical practice 
guidelines. Staff will have current Human Subjects Training Certification on file at the 
IRB office. Before enrollment begins, study coordinators and research assistants who 
will perform the outcome assessments will be trained in all procedures, including 
completion of case-report forms (CRFs).  
 
The PI and research staff will constitute the first line of monitoring of the safety of the 
human participants. Surveillance for AEs will consist of questioning subjects about 
potential AEs at every study contact, having subjects report any adverse event to the 
study team, and having subjects undergo vital sign checks and physical exams during 
each study visit. Laboratories will be performed and checked at screening before 
enrolling the subject in the study. 
 
All study personnel are required to read the consent form and the protocol.  
 
8.2 Data quality  
 
The PI will perform continuous monitoring of data quality and completion of CRFs. 
The PI will review database forms and source documents to ensure that the information 
on the forms is complete and consistent with the source documents.  
 
 
 
 
 
 
 
 
 
 
 


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Chapter 9. Participant Safety and Confidentiality 
 
9.1 Consent 
 
Consent will be obtained for enrollment from participants. For each consent process, 
study personnel will discuss the details of the study, the risks and benefits, and the 
subject’s rights and responsibilities if they choose to participate in the trial and their 
right to refuse to participate.  It will be made clear that their clinical care will not be 
affected by their decision.   
 
9.2 Institutional Review Board process  
 
IRB approval must be obtained and on file before enrolling participants into the clinical 
trial.  
 
9.3 Laboratory values 
 
The following clinical laboratory tests will be measured at screening (or baseline for known 
postmenopausal women) and nine week visits and as clinically indicated. 
 
9.3.1 Hematology 
Complete blood count will be performed at screening.  
 
9.3.2 Hepatic function panel 
Hepatic function panel will be performed at screening.  
 
9.3.3 Coagulation studies 
Prothrombin time, INR will be performed at screening.  
 
9.3.4 Follicle-stimulating hormone 
FSH will be performed at screening.  
 
9.4 Fulvestrant-related laboratory abnormalities and drug interactions 
 
Hypersensitivity reactions including urticarial and angioedema have been reported. Use 
of fulvestrant in patients with a history of bleeding disorders (including 
thrombocytopenia) should be approached with caution. Subjects on anticoagulant 
therapy will not be enrolled in the study. Aspiring is permitted as a concomitant 
medication. Subjects with moderate hepatic impairment will be given a lower dose of 
fulvestrant.  
 
 9.5 Other events 
 


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We will not discontinue study drug for clinical events not thought to be serious drug-
related AEs. For example, a hospitalization for clinical worsening will not result in 
cessation of trial participation. Such events could result in missing data for primary and 
secondary endpoints, comprising the integrity of the analysis. As the trial does not 
prohibit any therapies which is the standard of care in PAH, there is no ethical or safety 
reason to stop trial participation under such circumstances. Even if subjects are 
withdrawn from the study drug outcome assessments will continue. Subjects who are 
not compliant or stop the treatment portion of the study will be replaced. 
 
9.6 Safety and Adverse events 
 
9.6.1 Definitions 
Unanticipated Problem (UP): Any incident, experience, or outcome that meets all of the 
following criteria:  
 
1) unexpected (in terms of nature, severity, or frequency) given a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and b) the characteristics 
of the subject population being studied;  
 
2) related or possibly related to participation in the research; and  
 
3) 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.    
 
Possibly related to participation in the research: There is a reasonable possibility that 
the AE, experience, or outcome may have been caused by the procedures involved in 
the research. 
 
Adverse event (AE):  Any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study.  Intercurrent illnesses or injuries should be 
regarded as AEs.  Abnormal results of diagnostic procedures are considered to be AEs if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious AE 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious adverse event (SAE): Adverse reactions are classified as serious or non-serious.  
A serious adverse event is any AE that is:  
• fatal 
• life-threatening 


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• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance. They may jeopardize the subject, and may 
require intervention to prevent one of the other serious outcomes noted above.  For 
example, drug overdose or abuse, a seizure that did not result in in-subject 
hospitalization or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious.  
 
All AEs that do not meet any of the criteria for serious should be regarded as non-
serious AEs.  
 
9.6.2. Classifying AEs 
Severity 
 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the CRF. 
 
If the intensity of an AE worsens during study drug administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
 
The three categories of intensity are defined as follows: 
• Mild - The event may be noticeable to the subject. It does not influence daily 
activities, and usually does not require intervention. 
 
• Moderate - The event may make the subject uncomfortable. Performance of 
daily activities may be influenced, and intervention may be needed. 
 
• Severe - The event may cause noticeable discomfort, and usually interferes with 
daily activities. The subject may not be able to continue in the study, and 
treatment or intervention is usually needed. 
 
Expectedness 
 
AEs must be assessed as to whether they were expected to occur or were unexpected, 
meaning not anticipated based on current knowledge found in the protocol, investigator 
brochure, product insert, or label. 
 
Expected: an AE known to be associated with the intervention or condition under study. 
 


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OHRP defines an unexpected AE as any AE occurring in one or more subjects 
participating in a research protocol, the nature, severity, or frequency of which is not 
consistent with either: 
1) the known or foreseeable risk of AEs associated with the procedures involved in the 
research that are described in a) the protocol-related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and b) other relevant sources of information, 
such as product labeling and package inserts; or 
2) the expected natural progression of any underlying disease, disorder, or condition of 
the subject(s) experiencing the AE and the subject’s predisposing risk factor profile for 
the AE. 
 
Relatedness 
 
1) Definite: the AE is clearly related to the intervention 
 
2) Probably: the AE is likely related to the intervention 
 
3) Possible: the AE may be related to the intervention 
 
4) Unlikely: the AE is doubtfully related to the intervention 
 
5) Unrelated: the AE is clearly not related to the intervention 
 
For each identified AE, an AE form will be completed. Reporting procedures should be 
started immediately upon learning of a SAE.  
 
9.6.3 Interpretation of definitions 
AE Reporting Period 
The study period during which AEs must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up 
at week 12.   
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an AE if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an AE must also be recorded and documented as an AE.  
 
Post-study AE 
All unresolved AEs should be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the AE is otherwise explained.  At the last scheduled 
visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be 
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any death or AE occurring at any time after a subject has discontinued or terminated 
study participation that may reasonably be related to this study.  The sponsor should 
also be notified if the investigator should become aware of the development of cancer 
or of a congenital anomaly in a subsequently conceived offspring of a subject that has 
participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an AE if any one of the 
following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious AE unless specifically instructed otherwise in this 
protocol.  Any condition responsible for surgery should be documented as an AE if the 
condition meets the criteria for an AE.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an AE in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an AE if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of 
the study, unless it is a worsening or increase in frequency of hospital admissions 
as judged by the clinical investigator. 
 
9.6.4 Reporting procedures for AEs 
The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those 
events related to study participation that are unforeseen and indicate that participants 
or others are at increased risk of harm.  The Penn IRB requires researchers to submit 
reports of the following problems within 10 working days from the time the investigator 
becomes aware of the event: 
• Any non-fatal, non-life threatening AE (regardless of whether the event is serious 
or non-serious, on-site or off-site) that occurs any time during or after the 
research study, which in the opinion of the principal investigator is: 
Unexpected 


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AND 
Related to the research procedures (An event is “related to the research 
procedures” if in the opinion of the principal investigator or sponsor, the event 
was more likely than not to be caused by the research procedures.) 
 
Non-fatal, non-life threatening unexpected suspected serious adverse reactions will be 
reported to the NHLBI within 15 calendar days. Any fatal or life-threatening unexpected, 
suspected serious adverse reactions will be reported to the Penn IRB within 3 days. 
Serious and unexpected AEs which are fatal or life-threatening must be reported within 
7 days to the NHLBI. 
 
UPs that are not SAEs must be reported within two weeks to the NHLBI.  All UPs that are 
not SAEs must be reported within 30 days to OHRP by the Penn IRB.  
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be 
reported to the Penn IRB using the institution required form or as a written report of the 
event (including a description of the event with information regarding its fulfillment of 
the above criteria, follow-up/resolution and need for revision to consent form and/or 
other study documentation). 
The Primary Investigator is expected to provide as much of the following information as 
is available: 
• 
Protocol name and number 
• 
Subject identifiers 
• 
Demographic data 
• 
Nature of the event 
• 
Severity of the event 
• 
Probable relationship (causality) of AE to study procedure 
• 
Date and time of AE onset 
• 
Date and time of AE resolution, if available 
• 
Concomitant medications that the participant was taking for an 
underlying medical condition or disease and the therapeutic 
agents used for the treatment of the adverse event 
• 
Clinical assessment of participant conducted at time of SAE/AE 
• 
Results of any laboratory and/or diagnostic procedures, and 
treatment 
• 
Follow-up plan 
• 
Outcome 
• 
Autopsy findings (if appropriate) 
 


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The Principal Investigator and research coordinator will provide details about the AE as 
they become available. If additional information cannot be obtained for whatever 
reason, this will be documented. 
 
The Principal Investigator should promptly determine an assessment of causality. 
 
The Principal Investigator/designee should keep originals or photocopies of all relevant 
documentation, including facsimile confirmations and email exchanges, and file them in 
the participant's file. 
The Principal Investigator/designee should file copies of all correspondence with the IRB 
in the appropriate section of the Regulatory Master File or site study file. 
Other Reportable events: 
The following events are also reportable to the Penn IRB: 
• Any adverse experience that, even without detailed analysis, represents an 
unexpected SAE that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
• Any AE that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to 
assure protection of human subjects. 
• Information that indicates a change to the risks or potential benefits of the 
research, in terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response 
to treatment than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or 
more frequent than initially expected. 
– A paper is published from another study that shows that an arm of your 
research study is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
• Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the 
subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more 
participants at increased risk, or affects the rights or welfare of subjects. 


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9.6.5 Subject withdrawal  
A subject has the right to withdraw from the study entirely at any time for any reason 
without prejudice to future medical care by the investigator or other physician. The 
investigator also has the right to withdraw subjects from the study in the event of 
concurrent illness, AEs, or other reasons deemed to be in the subject’s best interest. 
 
A subject should be withdrawn from the study if there is: 
 
• Withdrawal of consent 
• Termination of the study by the funding agency  
 
In order to preserve the integrity of the study, even if the subject is withdrawn from the 
treatment portion of the protocol (either due to subject, physician, or investigator 
decision), we will continue with the scheduled follow-up assessments both for the 
safety of the subject and for completeness of data collection. This will be explained to 
potential subjects at the time of informed consent. The importance of compliance with 
study visits will be reinforced throughout the trial. If the both treatment is permanently 
withdrawn, the subject will return to the center for safety assessment (history, physical 
examination, and clinical laboratories, if necessary). In the event of clinical worsening, 
subjects will be continued on their assigned study medication. If a subject develops an 
indication for fulvestrant therapy (such as breast cancer), the subject will be withdrawn 
from receiving study drug in this clinical trial but will continue to be assessed per 
protocol. 
 
9.7 Confidentiality of study data 
 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization. For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
 
Several mechanisms will be in place to maintain confidentiality. Patient names will not 
be abstracted and all of the data will be reported in aggregate. Each subject in all phases 


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of the study will be assigned a unique identifier to be used on all data forms, study 
records, and blood samples. A list of patient names and code numbers will be 
maintained separately in locked file cabinets or on password protected computers. Only 
the investigators and project staff will have access to this information. No other 
personally identifiable information will be available.  
 
9.7.1 Global unique identifier 
 
In order to share detailed medical and other information with researchers while 
protecting the subject’s privacy in the future, a global unique ID (GUID) number will be 
generated for use in this study. The subject’s name, birth date, and other “identifying” 
information from the subject’s medical information will be removed before providing 
data to researchers. This information is “de-identified” because it has had all personal 
identifiers removed. The subject’s information will be labeled with the GUID and stored 
on secured computers and servers and protected with encryption and passwords. Only 
authorized people will have access to the key to the code and will be able to identify the 
subject if needed.  
 
9.8 Potential risks 
 
The most common side effects for fulvestrant (greater than 10%) reported are injection 
site pain, back pain, nausea, and increased liver enzymes.  Less common side effects 
(less than 10%) were headaches, fatigue, weakness, pain in arms or legs (extremities), 
hot flashes, vomiting, loss of appetite, constipation, bone, joint and muscle pain, cough, 
and shortness of breath. Very uncommon side effects (less than 1%) were rapid swelling 
of the under the skin (angioedema), skin rash, inflammation of the liver (hepatitis), liver 
failure, hypersensitivity, leukopenia, osteoporosis, blood clots, elevation of bilirubin 
levels, elevation of gamma GT, and vaginal bleeding. Because the drug is processed and 
broken down mostly in the liver, subjects with moderate liver disease will receive a 
lower dose of the medication (250 mg instead of 500mg).  
 
Women of child-bearing potential or breast-feeding mothers will not be enrolled in this 
study therefore there are no risks to unborn children or children who are being breast-
fed.  
 
We will obtain several blood samples from each subject. There is a risk of bruising, 
hematoma, and infection after phlebotomy, which are possible but not considered 
serious AEs. Fainting although unlikely, may occur.  
 
The probe used during the echocardiogram may lead to mild soreness in the area for 
about a day. 
 
The 6MWT may cause light-headedness, chest pain, or musculoskeletal discomfort; 
however the risks of this study to subjects are minimal. In addition, subjects with PAH 


ERA PAH 
 
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 39 
routinely undergo 6MWT for clinical indications, so this study procedure does not 
increase risk above usual clinical care.  
 
As subjects will be allowed to continue their other therapy, there are no alternative 
therapies to the ones being studied. 
 
9.9 Potential benefits 
 
The results from the study could be applied in the future to subjects (including those in 
the study) who stand to benefit from the information. There may be clinical benefits to 
the use of fulvestrant in subjects with PAH. As the study involves the risks of 
administration of fulvestrant, phlebotomy, exercise testing, and loss of confidentiality, 
and there is a potential for future benefit for both subjects in the study and for future 
subjects, the risk/benefit ratio is favorable. 
 
9.10 Alternatives 
 
The use of the medications for this study requires that other medications including 
hormone therapy not be used. Therefore, the alternative is to not participate in this 
study and to continue having the option to take these medications.  
 
9.11 Ethical Considerations 
 
This study is to be conducted accordance with applicable US government regulations 
and international standards of Good Clinical Practice, and applicable institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
Institutional Review Board (IRB) in agreement with local legal prescriptions for formal 
approval of the study conduct.  The decision of the IRB concerning the conduct of the 
study will be made in writing to the investigator and a copy of this decision will be 
provided to the NIH before commencement of this study.   
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for 
review and approval by the IRB for the study.  The formal consent of a subject, using the 
IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
 


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 40 
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