Conditions: Hepatopulmonary Syndrome
Keywords: Randomized Controlled Trial Clinical Trial sorafenib Hepatopulmonary Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
The main purpose of this clinical trial is to determine the safety and effects of the study drug, sorafenib, in adults diagnosed with hepatopulmonary syndrome (HPS). The study will evaluate how well the drug is tolerated and its effect on the level of oxygen in the blood and the function of the lung vessels.

Detailed description:

Arms:
arm 1: 400 mg (2 capsules) taken by mouth once a day arm 2: 2 capsules taken by mouth once a day

Interventions: intervention 1: Sorafenib intervention 2: Placebo
Intervention descriptions: intervention 1: Sorafenib is a kinase inhibitor indicated for the treatment of:

* Unresectable hepatocellular carcinoma
* Advanced renal cell carcinoma
* Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
1 
 
SORAFENIB IN PATIENTS WITH HEPATOPULMONARY SYNDROME:  
A DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL 
  
Test drug: 
Sorafenib   
Clinical study phase: 
II 
Version no.: 
2.3 
Date: 
10 June 2016 
Sponsor: 
NHLBI 
Principal Investigator: 
Steven M. Kawut, MD, MS 
Perelman School of Medicine at the University of Pennsylvania 
215-573-0258 
Co-Principal Investigator: 
Michael Fallon, MD 
University of Texas-Houston 
Statistician: 
Susan Ellenberg, PhD 
Perelman School of Medicine at the University of Pennsylvania 
 
 
 
 
 
 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the guidance of 
the clinical investigation.  Reproduction or disclosure of this document - whether in part or in full - to parties 
not associated with the clinical investigation, or its use for any other purpose, without the prior written consent 
of the Principal Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  Hence, the appearance of 
product names without these symbols does not imply that these names are not protected. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
2 
 
Synopsis 
 
Title  
SORAFENIB IN PATIENTS WITH HEPATOPULMONARY SYNDROME: A 
DOUBLE-BLIND RANDOMIZED CLNICAL TRIAL 
Clinical study phase 
II 
Study objectives 
This study is being conducted to determine whether sorafenib may be effective at 
treating hepatopulmonary syndrome (HPS) compared to placebo. 
 
Primary Aim: 
 
1. To determine whether sorafenib affects alveolar-arterial oxygen gradient 
(AaPO2) at 12 weeks in patients with HPS 
 
Secondary Aims: 
 
2. To determine whether sorafenib affects intrapulmonary shunting at 12 
weeks 
 
3. To determine whether sorafenib affects hematopoietic progenitor cell 
(HPC) and other biomarker levels at 8 and 12 weeks 
 
4. To determine whether sorafenib affects SF-36 questionnaire scores and 
Mahler dyspnea index at 8 and 12 weeks 
 
5.  To determine whether sorafenib affects the distance walked in six minutes 
at 8 and 12 weeks 
 
6. To determine whether sorafenib affects AaPO2  and PaO2 at 8 and 12 weeks 
in patients with HPS 
 
7.  To determine whether sorafenib affects oxygen saturation from pulse 
oximetry at 8 and 12 weeks in patients with HPS 
 
8. To determine whether sorafenib affects functional class at 8 and 12 weeks 
 
9.  To determine the safety and side effects associated with sorafenib 
administration in patients with HPS  
Indication 
Hepatopulmonary syndrome 
Diagnosis and main criteria 
for inclusion 
Inclusion Criteria 
• 
Diagnosis of HPS: 
- 
AaPO2 ≥ 15 mm Hg (≥ 20 mm Hg for age > 64 yrs)  
- 
Intrapulmonary shunting  
- 
Absence of significant restriction (TLC < 70%) or obstruction 
(FEV1 < 80% & FEV1/FVC < 70%)  
- 
Presence of cirrhosis/hepatic fibrosis and/or portal hypertension 
• 
Child-Pugh class A or B liver disease 
• 
Platelet count ≥ 30×109 per liter 
• 
Hemoglobin ≥ 8.5 g per deciliter 
• 
International normalized ratio ≤ 2.3 
• 
Albumin ≥ 2.8 g per deciliter 
• 
Total bilirubin ≤ 5 mg per deciliter 
• 
Alanine aminotransferase and aspartate aminotransferase ≤ 5 times the 
upper limit of the normal range  
• 
Serum creatinine ≤ 1.5 times the upper limit of the normal range and not 


Sorafenib in HPS 
Protocol V2.3 
 
3 
 
receiving dialysis 
• 
Negative pregnancy test (for women of childbearing potential) at both 
screening and baseline visits. Post-menopausal women (defined as no 
menses for one year) and surgically sterilized women are not required to 
undergo a pregnancy test. 
• 
Subjects (men and women) of childbearing potential must agree to use 
medically acceptable contraception beginning at the signing of the ICF 
until at least 14 days after the last dose of study drug. 
• 
Age ≥ 21 years 
• 
Ability to provide informed consent 
 
Exclusion Criteria 
• 
Recent chronic heavy alcohol consumption 
• 
Enrollment in a clinical trial or concurrent use of another investigational 
drug or device therapy (i.e., outside of study treatment) during, or within 
28 days of screening visit 
• 
Current hepatic encephalopathy 
• 
Active infection 
• 
Diagnosis of portopulmonary hypertension 
• 
WHO Class IV functional status 
• 
Congenital long-QT syndrome 
• 
Subjects who have used strong CYP3A4 inducers (e.g., phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort [Hypericum perforatum], 
dexamethasone at a dose of greater than 16 mg daily, or rifampin 
[rifampicin], and/or rifabutin) within 28 days before randomization 
• 
Subjects who are currently taking Coumadin®(warfarin)  
• 
Active or clinically significant cardiac disease, including: 
-Active coronary artery disease 
-Unstable angina (anginal symptoms at rest), new-onset angina within 12 
weeks before randomization, or myocardial infarction within 24 weeks 
before randomization 
• 
Liver or other solid organ transplant recipients 
• 
Expectation of liver transplant within four months of randomization 
• 
Hepatocellular carcinoma that does not meet all of the following criteria: 
a. 
Single lesion ≤ 3 cm documented by LIRADS criteria 
b. Complete response to ablative therapy (TACE, RFA, alcohol 
ablation) using the modified RECIST criteria one month after 
therapy with no more than two treatments 
c. 
No other lesions develop after initiation of HCC therapy 
• 
Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic 
pressure > 90 mm Hg on repeated measurement) despite optimal medical 
management. 
• 
Any hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or higher 
within 4 weeks before randomization 
• 
Presence of a non-healing wound, non-healing ulcer, or bone fracture 
• 
Women who are pregnant or breast-feeding 
• 
Major surgery 28 days prior to randomization 
• 
Subjects with any previously untreated or concurrent cancer except 
cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder 
tumor.  Subjects surviving a cancer that was curatively treated and 
without evidence of disease for more than 3 years before randomization 
are allowed. All cancer treatments (chemotherapy, radiation therapy, 
surgery, immunotherapy, biologic therapy, or tumor embolization) must 
be completed at least 3 years prior to study entry (i.e., signature date of 


Sorafenib in HPS 
Protocol V2.3 
 
4 
 
the informed consent form).  
• 
Inability to comply with the protocol and/or not willing or not available 
for follow-up assessments  
Study design 
Randomized, double-blind, placebo-controlled parallel trial of 30 subjects with 
HPS. Eligible subjects will be randomly assigned 1:1 to receive either sorafenib 
(400 mg QD) or placebo for 12 weeks. 
Study observations 
Subjects evaluated at screening, baseline, and every 2 weeks until the end of the 
study 
• 
Laboratory tests including a complete blood count with diff, routine 
chemistry tests, and coagulation studies at screening 
• 
Chemistries, complete blood count with diff, and coagulation studies 
monthly while subject is taking study drug 
• 
HPC levels at baseline and 8 and 12 weeks 
• 
Electrocardiogram, spirometry, and lung volumes at screening 
• 
Arterial blood gas at screening/baseline and 12 weeks (8 weeks optional) 
• 
Contrast echocardiogram at screening/baseline and 12 weeks 
• 
Six minute walk testing at baseline, 8, and 12 weeks 
• 
SF-36 and dyspnea index measures at baseline, 8 and 12 weeks 
Type of control 
Placebo 
Number of subjects 
30 
Plan for statistical analysis 
Primary endpoint: 
• 
Difference in changes in AaPO2 between sorafenib and placebo groups at 
12 weeks 
 
Secondary endpoints: 
• 
Difference in changes in intrapulmonary shunting between sorafenib and 
placebo groups at 12 weeks 
• 
Difference in changes in HPC and other biomarker levels between 
sorafenib and placebo groups at 8 and 12 weeks 
• 
Difference in changes in SF36 scores and Mahler dyspnea index scores 
between sorafenib and placebo groups at 8 and 12 weeks 
• 
Difference in changes in distance walked in six minutes between 
sorafenib and placebo groups at 8 and 12 weeks 
• 
Difference in changes in PaO2 and oxygen saturation by pulse oximetry 
between sorafenib and placebo groups at  8 and 12 weeks  
• 
To assess the effect of sorafenib vs. placebo on AaPO2 at 8 and 12 weeks 
(for those with available ABG at 8 weeks)  
• 
Differences in changes in functional class between sorafenib and placebo 
groups at 8 and 12 weeks 
• 
Safety and side effects associated with sorafenib administration in 
patients with HPS 
 
Sample size and power: 
A total of 30 patients will be enrolled (15 sorafenib, 15 placebo), which will 
provide 80% power to detect a 11.5 mm Hg difference in changes in  AaPO2 
(α = 0.05). 
 
Data analysis: 
The primary analysis will compare the absolute change from baseline to 12 
weeks in AaPO2 between the blinded treatment arms using a two-sample t-test.  
Incidence of adverse events and secondary endpoints will also be analyzed. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
5 
 
LIST OF ABBREVIATIONS 
 
AaPO2  
Alveolar-arterial oxygen gradient 
ABG  
Arterial blood gas 
AE 
 
Adverse event 
c-KIT  
Stem Cell Factor Receptor Tyrosine Kinase 
CBDL  
Common bile duct ligation 
CCC  
Clinical Coordinating Center 
CTCAE 
Common Terminology Criteria for Adverse Events 
DTC  
Differentiated thyroid carcinoma 
ERK  
Extracellular Signal-Regulated Kinases 
FDA  
Food and Drug Administration (US) 
GCP  
Good Clinical Practice 
GMP  
Good Manufacturing Practice 
HPC  
Hematopoietic progenitor cell 
HCC  
Hepatocellular carcinoma 
HFSR  
Hand-foot-skin reaction 
HPS 
 
Hepatopulmonary syndrome 
IB 
 
Investigator’s brochure 
ICF 
 
Informed consent form 
ICH 
 
International Conference on Harmonisation 
INR 
 
International normalized ratio 
IRB 
 
Institutional Review Board 
MEK  
MAP Kinase / ERK Kinase 1 
MOP  
Manual of Procedures 
NCI 
 
National Cancer Institute 
NM 
 
Nano Molar number 
PaO2  
Partial pressure of oxygen in arterial blood 
PBMCs 
Peripheral blood mononuclear cells 
PDGFR 
Platelet Derived Growth Factor Receptor 
PI 
 
Principal Investigator 
PVCLD 
Pulmonary Vascular Complications of Liver Disease 
QD 
 
quaque die (every day) 
RCC  
Renal cell carcinoma 
SAE 
 
Serious adverse event 
6MWT 
Six-minute walk test 
TLC 
 
Total lung capacity 
TTE 
 
Transthoracic echocardiography 
UPHS  
University of Pennsylvania Health System 
VEGF  
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
WHO  
World Health Organization 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
6 
 
Brief Table of Contents   
 
 
ABSTRACT 
11 
 
CHAPTER 1: Background and Significance 
12 
 
CHAPTER 2: Objectives and Specific Aims 
16 
 
CHAPTER 3: Screening, Subject Selection and Randomization 
17 
 
CHAPTER 4: Treatments 
20 
 
CHAPTER 5: Data Collection 
23 
 
CHAPTER 6: Assessment of Efficacy and Outcome Measures 
33 
 
CHAPTER 7: Statistical Considerations 
35 
 
CHAPTER 8: Quality Control and Data Handling 
38 
 
CHAPTER 9: Participant Safety and Confidentiality 
40 
 
REFERENCES: 
58 
 


Sorafenib in HPS 
Protocol V2.3 
 
7 
 
Detailed Table of Contents 
 
Synopsis 
2 
 
List of Abbreviations 
5 
 
Brief of Contents 
6 
 
Detailed Table of Contents  
7 
 
ABSTRACT 
11 
 
CHAPTER 1: Background and Significance 
12 
 
1.1 Background 
12 
 
1.2 Rationale of the Study 
14 
 
1.3 Sorafenib 
14 
1.3.1 Preclinical 
14 
1.3.2 Clinical Experience 
14 
 
CHAPTER 2: Objectives and Specific Aims 
16 
 
2.1 Objectives 
16 
 
2.2 Specific Aims 
16  
 
CHAPTER 3: Screening, Subject Selection and Randomization 
17 
 
3.1 Recruitment: Identification and Screening Process 
17 
 
3.2 Subject Selection Criteria 
17 
3.2.1 Inclusion Criteria 
17 
3.2.2 Exclusion Criteria 
18 
 
3.3 Randomization 
19 
 
3.4 Maintenance of Treatment Randomization Codes and Procedures for 
Breaking the Code 
19 
 
CHAPTER 4: Treatments 
20 
 
4.1 Sorafenib 
20 
 
4.2 Placebos and Packaging of Study Medication 
21 


Sorafenib in HPS 
Protocol V2.3 
 
8 
 
 
4.3 Administration of Study Medication 
21 
4.4 Management of Other Medical Therapies during the Trial 
21 
 
4.5 Treatment Masking 
22 
 
4.6 Drug Logistics and Accountability 
22 
4.6.1 Accountability 
22 
4.6.2 Destruction and Return 
22 
 
CHAPTER 5: Data Collection 
23 
 
5.1 Study Visits 
23 
5.1.1 Informed Consent 
23 
5.1.2 Visit 0 (Screening) 
23 
5.1.3 Visit 1 (Baseline) 
24 
5.1.4 Visit 2 (Week 2 ± 3 days) 
25 
5.1.5 Visit 3 (Week 4 ± 3 days) 
26 
5.1.6 Telephone Contact 1 & 2 (Week 6 ± 3 days, Week 10 ± 3 days) 
26 
5.1.7 Visit 4 (Week 8 ± 3 days) 
27 
5.1.8 Visit 5 (Week 12 ± 3 days) 
28 
5.1.9 Telephone Contact 3 OR Visit 6: Two Week  
         Follow Up (Week 14 ± 3 days) 
29 
5.1.10 Future Research 
 
30 
 
5.2 Study Schedule of Procedures 
31 
 
5.3 Subject Retention and Drug Compliance 
32 
 
CHAPTER 6: Assessment of Efficacy and Outcome Measures 
33 
 
6.1 Assessments of Efficacy 
33 
6.1.1 Alveolar-Arterial Oxygen Gradient (AaPO2) 
33 
 
6.2 Secondary Outcome Measures 
33 
6.2.1 Hematopoietic Progenitor Cell (HPC) Levels 
33 
6.2.2 Intrapulmonary Shunting 
33 
6.2.3 Six-Minute Walk Distance 
34 
6.2.4 SF-36 / Mahler Dyspnea Index 
34 
 
CHAPTER 7: Statistical Considerations 
35 
 
7.1 Study Design 
35 
 
7.2 Disposition of Subjects and Baseline Comparisons 
35 
 


Sorafenib in HPS 
Protocol V2.3 
 
9 
 
7.3 Statistical Procedures 
35 
7.3.1 Data Analysis 
35 
7.3.2 Univariate Analysis 
35 
7.3.3 Analyses of Treatment Assignment and Outcome Measures 
35 
7.3.4 Survival Analysis 
36 
7.3.5 Missing Data and Dropouts 
36 
 
7.4 Sample Size and Power Calculations 
36 
 
7.5 Interim Monitoring Guidelines 
36 
 
7.6 Protocol Violations 
37 
 
7.7 Safety and Masking Analysis 
37 
 
CHAPTER 8: Quality Control and Data Handling 
38 
 
8.1 Personnel Training 
38 
 
8.2 Data Quality 
38 
 
8.3 Audit and Inspection 
39 
 
8.4 Archiving 
39 
 
CHAPTER 9: Participant Safety and Confidentiality 
40 
 
9.1 Consent 
40 
 
9.2 Institutional Review Board Process 
40 
 
9.3 Laboratory Values 
41 
9.3.1 Hematology 
41 
9.3.2 Chemistry 
41 
9.3.3 Coagulation Studies 
41 
9.3.4 Pregnancy Testing 
41 
 
9.4 Sorafenib-Related Laboratory Abnormalities and Drug Interactions 
41 
 
9.5 Dose Modification for Management of Adverse Events 
42 
9.5.1 Dose Reduction Levels 
42 
9.5.2 Dose Modification for Hematologic Toxicities 
43 
9.5.3 Dose Modification for Non-Hematologic Toxicities 
44 
9.5.4 Hand-Foot-Skin Reaction 
44 
9.5.5 Treatment-Emergent Hypertension 
45 
 


Sorafenib in HPS 
Protocol V2.3 
 
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9.6 Other Events 
46 
 
9.7 Safety and Adverse Events 
46 
9.7.1 Definitions 
46 
9.7.2 Classifying Adverse Events 
48 
9.7.3 Interpretation of Definitions 
49 
9.7.4 Reporting Procedures for Adverse Events 
50 
9.7.5 Subject Withdrawal 
54 
 
9.8 Confidentiality of Study Data 
55 
 
9.9 Potential Risks 
56 
 
9.10 Potential Benefits 
57 
 
9.11 Alternatives 
57 
 
9.12 Ethical Considerations 
57 
 
REFERENCES 
58 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
11 
 
ABSTRACT 
 
Cirrhotic liver disease afflicts nearly 3 million Americans, and complications of cirrhosis are the 
fourth leading cause of death between ages 45 and 65. Hepatopulmonary syndrome (HPS) is one 
such complication which results when pulmonary microvascular dilations lead to an increased 
alveolar-arterial oxygen gradient (AaPO2) determined by arterial blood gas (ABG) analysis and 
intra-pulmonary transit of microbubbles visualized by echocardiography after injection of 
agitated saline in a peripheral vein. 
 
Recently, the tyrosine kinase-inhibitor sorafenib has been shown to reverse aberrant angiogenesis 
in the lungs, resolve gas exchange abnormalities, and reduce intrapulmonary shunting in the HPS 
animal model. Sorafenib has been studied extensively in patients with cirrhosis with 
hepatocellular carcinoma and is FDA-approved in this population. 
 
The primary aim of this randomized, double-blind, parallel-arm, placebo-controlled, phase II 
trial of 30 patients is to determine whether sorafenib affects AaPO2 at twelve weeks in patients 
with HPS. The study will also examine the effect of sorafenib on biomarkers of angiogenesis, 
including circulating hematopoietic progenitor cells, as well as its impact on six-minute walk 
distance and health-related quality-of-life. Ultimately, the feasibility and safety of the use of 
sorafenib as a novel therapeutic for the treatment of HPS will be determined. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
12 
 
Chapter 1. Background and Significance 
 
1.1 Background 
 
Cirrhotic liver disease afflicts nearly 3 million Americans, and complications of cirrhosis are the 
fourth leading cause of death between ages 45 and 65.1  Hepatopulmonary syndrome (HPS) is 
one such complication that results when pulmonary microvascular dilations lead to an increased 
alveolar-arterial oxygen gradient (AaPO2) and intra-pulmonary transit of bubbles visualized by 
echocardiography after injection of agitated saline. HPS occurs in 33% of patients with cirrhosis 
and portal hypertension evaluated for liver transplantation (LT),2 amounting to several hundreds 
of thousands of Americans with HPS. HPS (even without resting hypoxemia) has been shown to 
worsen quality of life and double the already significantly elevated risk of death of the cirrhotic 
patient. Although LT can resolve HPS, it is limited by donor availability and cost, and patients 
with HPS still have a worse survival rate after transplant compared to others with cirrhosis, in 
part due to delayed resolution in some. Unfortunately, the significant public health implications 
of HPS are magnified by the lack of any medical therapies for this lung disease. 
 
Definition, assessment, and mechanisms of gas exchange abnormalities in HPS 
 
The definition of HPS has been established by the Task Force on Pulmonary-Hepatic Disease.3  
A diagnosis of HPS requires documentation of shunting of the lungs and an increased AaPO2 in 
the absence of parenchymal lung disease. Shunting (or more correctly, pulmonary capillary 
dilation) is assessed by contrast transthoracic echocardiography (TTE), in which agitated saline 
microbubbles are injected via a peripheral vein during imaging. Normally, these microbubbles 
appear in the right side of the heart and then are trapped in the pulmonary microvasculature 
without reappearing in the left atrium. With vascular dilations, bubbles transit through the lung 
microcirculation and appear in the left side of the heart three or more cardiac cycles after 
appearing in the right side (“delayed transit”). 
 
The mechanisms for increased AaPO2 in HPS include: arteriovenous malformations (shunt), 
ventilation/perfusion mismatch, and capillary enlargement (diffusion impairment). Arteriovenous 
malformations and vascular engorgement are seen in post mortem lung samples from affected 
patients.4 
 
Vascular alterations in portal hypertension: A paradigm for HPS? 
 
Cirrhosis and portal hypertension trigger widespread cardiovascular alterations, and studies have 
shown a critical role for vascular remodeling. In the liver, angiogenesis, inflammation, and 
fibrosis create a “wound healing” response, worsening the disease, and vascular endothelial 
growth factor-A (VEGF-A) and platelet-derived growth factor are overexpressed. Tyrosine 
kinase inhibition in animal models not only decreases hepatic angiogenesis, liver fibrosis, and 
intrahepatic resistance but also directly inhibits variceal and collateral formation in the 
splanchnic vasculature, showing that angiogenesis is integral to vascular sequelae and outcomes 
in portal hypertension.5-8 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
13 
 
Mechanisms of HPS 
 
Early reports in HPS focused on decreased pulmonary vascular tone, increased cardiac output, 
and elevated pulmonary nitric oxide (NO), which normalized after NO inhibition or LT. More 
recently, it is recognized that reduction in NO does not treat HPS and HPS typically requires 
weeks to months to resolve after LT, indicating that structural vascular alterations are critical. 
Animal models have shown that HPS 1) occurs early in the course of induced cirrhosis via 
common bile duct ligation (CBDL), 2) is associated with increased pulmonary capillary density 
and growth, and 3) may be prevented by overexpression of the anti-angiogenic molecules 
endostatin and angiostatin or administration of sorafenib.9-10 Macrophages have been linked to 
angiogenesis in a variety of diseases. 
 
Single nucleotide polymorphisms in angiogenic genes are associated with HPS in humans11 and 
there are increased circulating hematopoietic progenitor cells (HPCs) in HPS [unpublished data]. 
While alternative mechanistic pathways have been investigated, the most consistent “signals” in 
human and animal models point to pulmonary angiogenesis as key to the pathogenesis of HPS. 
 
Physiologic and mechanistic endpoints 
 
The diagnosis of HPS is predicated on measures of gas exchange and intrapulmonary vascular 
dilation, and these are both improved (and in fact normalized) within 3-6 months after LT, 
justifying them as end points in this Phase II trial. While there are controversies surrounding 
HPCs, it is clear that HPCs 1) indicate and contribute to ongoing angiogenesis, 2) are identifiable 
by their cell surface expression profile, 3) can be reliably measured in multicenter human studies, 
and 4) may be increased in patients with HPS. HPCs also respond to therapeutic interventions 
which affect angiogenic potential, making them attractive biomarkers. 
 
Definition and epidemiology of HPS 
 
HPS patients are defined by: 
    1. AaPO2 ≥ 15 mmHg (≥ 20 mmHg for age > 64 yrs) 
    2. Intrapulmonary shunting by contrast TTE 
    3. Absence of significant restriction (TLC < 70%) or obstruction (FEV1 < 80% and 
FEV1/FVC < 70%) on spirometry 
    4. Presence of cirrhosis/hepatic fibrosis and/or portal hypertension 
 
Sorafenib improves AaPO2 and decreases intrapulmonary shunting in CBDL animal model 
 
We administered sorafenib 5mg/kg daily for two weeks to 3-week CBDL animals to assess 
effects on the onset of HPS (which develops < 2 weeks after CBDL). Treatment resulted in a 
significant decrease in lung angiogenesis, and improvement in AaPO2 relative to controls. These 
findings demonstrate that sorafenib has direct anti-angiogenic effects in the lung which result in 
improvement in HPS. 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
14 
 
1.2 Rationale of the Study 
 
This trial targets a clinically significant pulmonary complication of cirrhosis that affects almost 1 
million Americans and dramatically shortens survival, yet has no available medical therapy. HPS 
is treatable only with LT, but LT is a demanding surgical procedure limited by donor availability 
with complicated post-operative management and inferior outcomes in patients with HPS. Many 
patients do not have another indication for LT beyond HPS, so it is not an appropriate 
therapeutic option for the vast majority of HPS patients. Thus there is an urgent need to study 
effective medical therapies. 
 
Sorafenib has potent anti-angiogenic effects and treats HPS in the animal model of the disease. 
The goal of this study is to determine if sorafenib is beneficial and safe in patients with HPS. 
 
1.3 Sorafenib 
 
1.3.1 Preclinical 
 
Sorafenib is a multikinase inhibitor which affects specific targets that are imperative for tumor 
cell proliferation, including the serine/threonine kinases C and B isoforms of Rapidly 
Accelerated Fibrosarcoma protein (C-RAF and B-RAF) (IC50 6 and 25 nM respectively) and the 
receptor tyrosine kinase RET, Flt-3 and stem cell factor receptor tyrosine kinase (c-KIT) (IC50 
47, 33 and 68 nM respectively).  Sorafenib has potent activity against receptor tyrosine kinases 
important in tumor angiogenesis, including the vascular endothelial growth factor receptor 
family (VEGFR1, -2, -3; IC50 26, 90 and 20 nM respectively) and platelet derived growth factor-
beta (PDGFR-ί; IC50 57 nM). In cellular mechanistic (on target) assays, sorafenib was found to 
be a potent inhibitor of VEGFR-2, VEGFR-3, and PDGFR and Flt-3 receptor phosphorylation. 
The anti-tumor activity of sorafenib in vivo is driven by its direct effects on tumor growth 
through its inhibition of the Raf/MEK/ERK pathway and on the anti-angiogenic activity of the 
compound.  Sorafenib demonstrates broad anti-tumor activity in human tumor xenograft models 
of liver, kidney, lung, prostate, breast and leukemia. In human hepatocellular tumor cell lines, 
sorafenib potently inhibited cellular proliferations and Raf/MEK/ERK signaling and induced 
apoptosis. Sorafenib has potent activity against the human tumor xenograft model of 
hepatocellular carcinoma with tumor stabilization seen at moderate doses and partial tumor 
regressions observed at higher doses. 
 
1.3.2 Clinical Experience 
 
Sorafenib as a single agent has been evaluated globally in multiple Phase I and II trials in various 
malignancies. Three pivotal Phase III, international, multi-institutional, single-agent, 
randomized, placebo-controlled trials led to sorafenib’s approval for renal cell carcinoma (RCC) 
(US 2005, EU 2006) worldwide,hepatocellular carcinoma (HCC) (2007) worldwide, and  locally 
recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) (US 2013). 
 
TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial) used a randomized, 
double-blind, placebo-controlled design to assess the efficacy of sorafenib in 903 subjects with 
advanced RCC who received one prior systemic regimen.12  The formal analysis of progression 


Sorafenib in HPS 
Protocol V2.3 
 
15 
 
free survival using data available as of January 28, 2005, demonstrated a statistically significant 
doubling of progression free survival in subjects treated with sorafenib as well as a favorable 
safety profile of sorafenib in advanced RCC subjects.  This trial supported the US and European 
Union approvals of sorafenib in RCC, followed by regulatory approvals around the world, the 
first approved agent for this disease in over a decade. 
 
Clinical results in Phase I studies of sorafenib as a single agent were suggestive of a therapeutic 
effect in HCC and led to the design of a single-arm Phase II study (10874), in which 137 subjects 
with advanced, inoperable HCC Child-Pugh classes A and B were treated.  The results of this 
study provided the basis for the randomized, placebo-controlled Phase III study in subjects with 
advanced HCC (SHARP, Sorafenib HCC Assessment Randomized Protocol).13 This large (602 
subjects) study was the first international, randomized, double-blind, placebo-controlled study to 
demonstrate a statistically significant and clinically meaningful improvement in overall survival 
in advanced HCC subjects treated with sorafenib over placebo.  The median overall survival was 
10.7 months in the 299-patient sorafenib group and 7.9 months in the 303-subject placebo group 
(hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.87; p<0.001).  Thus sorafenib had a 
statistically significant effect on prolonging overall survival versus placebo, representing a 31% 
relative reduction in risk of death. 
 
The DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive 
Iodine refractory thyrOid caNcer) trial was an international, multicenter, placebo-controlled 
study. A total of 417 patients with locally advanced or metastatic, RAI-refractory, differentiated 
thyroid cancer who had received no prior chemotherapy, tyrosine kinase inhibitors, monoclonal 
antibodies that target VEGF or VEGF receptor, or other targeted agents for thyroid cancer were 
randomized to receive 400 mg of oral sorafenib twice daily (207 patients) or matching placebo 
(210 patients).14 Ninety-six percent of randomized patients had metastatic disease.  Sorafenib 
significantly extended progression-free survival (PFS), the primary endpoint of the study, 
compared to placebo. The median PFS was 10.8 months among patients treated with sorafenib, 
compared to 5.8 months among patients receiving placebo (HR=0.587 [95% CI, 0.454-0.758]; 
p<0.0001). Safety and tolerability in the study were generally consistent with the known profile 
of sorafenib. 
 
As of December 31, 2013, over 10,000 cancer patients with various malignancies have been 
exposed to sorafenib either as single agent or in combination with other chemotherapeutic agents 
in Phase I/II/III studies.  Sorafenib has been generally well tolerated at doses up to 400 mg p.o. 
twice daily (BID).  The most common drug-related adverse events have included hand-foot skin 
reaction (HFSR), diarrhea, fatigue, hypertension, pain and rash.  Grade 3 and 4 drug-related 
adverse events are uncommon.  There was no evidence of cumulative toxicity and the majority of 
the adverse events were reversible. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
16 
 
Chapter 2. Objectives and Specific Aims 
 
2.1 Objectives 
 
This study is being conducted to determine whether sorafenib may be effective at treating HPS. 
The hypothesis is that sorafenib will effectively reverse the physiologic abnormalities which 
characterize HPS, decreasing AaPO2 and reducing intrapulmonary shunting. A variety of 
biomarkers will be included to confirm the mechanism of activity, as well as a number of 
quality-of-life, functional, and clinical outcome endpoints to support the primary analyses. The 
goals of this study are 1) to provide evidence of a significant effect of sorafenib on HPS 
physiology, 2) to determine whether there are positive “signals” for sorafenib in terms of how 
these patients feel or function, 3) to demonstrate the feasibility of performing an NIH-funded 
clinical trial in HPS, and 4) to find treatment effect sizes for clinical endpoints in order to plan a 
Phase III trial. This randomized, placebo-controlled trial of 30 patients addresses the following 
specific aims. 
 
2.2 Specific Aims 
 
Primary Aim:  
 
1. To determine whether sorafenib affects AaPO2 at 12 weeks in patients with HPS 
 
Secondary Aims: 
 
2. To determine whether sorafenib affects intrapulmonary shunting at 12 weeks 
3. To determine whether sorafenib affects HPC and other biomarker levels at 8 and 12 
weeks 
4. To determine whether sorafenib affects SF-36 questionnaire scores and Mahler dyspnea 
index at 8 and 12 weeks 
5.  To determine whether sorafenib affects the distance walked in six minutes at 8 and 12 
weeks 
6.  To determine whether sorafenib affects AaPO2 and PaO2 at 8 and 12 weeks in patients 
with HPS 
7.  To determine whether sorafenib affects oxygen saturation from pulse oximetry at 8 and 12 
weeks in patients with HPS 
8. To determine whether sorafenib affects functional class at 8 and 12 weeks 
9.  To determine the safety and side effects associated with sorafenib administration in 
patients with HPS  
 
Other aims include demonstrating the feasibility of studying a novel therapeutic in HPS and 
determining the sample size necessary to conduct a Phase III study. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
17 
 
Chapter 3. Screening, Subject Selection and Randomization 
 
3.1 Recruitment: Identification and Screening Process 
 
Thirty subjects with HPS will be recruited at the University of Texas - Houston, the Mayo 
Clinic-Rochester, MN, Mayo Clinic - Phoenix, AZ), Columbia University Medical Center, the 
Medical University of South Carolina, Northwestern University, and the University of 
Pennsylvania Health System (UPHS) and randomized to either sorafenib or placebo in a double 
blind fashion. Patients will be identified by the medical staff in the liver and pulmonary clinics 
and liver transplant programs.  Recruitment efforts will also expand to additional clinics and 
health systems in the surrounding areas of the previously mentioned sites.  Phone calls to local 
pulmonologists and hepatologists seeking referrals and/or letters describing the study and 
seeking referrals for this study will be sent to pulmonologists and hepatologists in these 
surrounding clinics.   
 
For screening, we will perform computerized searches at the sites for patients with an ICD-9 or 
ICD-10 code for HPS (573.5 or K76.81) or with late shunting by contrast echo with an abnormal 
arterial blood gas (ABG). In addition, an active recruitment effort will be mounted by sending 
emails to pulmonologists and hepatologists at the recruiting centers and surrounding centers. 
 
We expect to screen approximately 3,000 patients (including both “new evals” for LT and 
prevalent cirrhotic patients at each center) providing ~900 patients with HPS over approximately 
3 years between the seven centers. Of these, we expect approximately 20% (180) to meet 
inclusion/exclusion criteria. Using our current study numbers as a guide, we expect 
approximately 80-90 patients to consent and approximately 32%-35% to meet inclusion and 
randomize, leaving 30 in the final study sample.  
 
3.2 Subject Selection Criteria 
 
3.2.1 Inclusion Criteria 
 
• Diagnosis of HPS: 
– 
AaPO2 ≥ 15 mm Hg (≥ 20 mm Hg for age > 64 yrs)  
– 
Intrapulmonary shunting determined by echo core (bubbles appear ≥ 3 beats after 
appearance of bubbles in the right atrium on contrast TTE) 
– 
Absence of significant restriction (TLC < 70%) or obstruction (FEV1 < 80% & 
FEV1/FVC < 70%) (If TLC is not measurable, then FVC may be used to meet this 
criterion) 
– 
Presence of cirrhosis/hepatic fibrosis and/or portal hypertension 
• Child’s class A and B liver disease 
• Platelet count ≥ 30×109 per liter 
• Hemoglobin ≥ 8.5 g per deciliter 
• International normalized ratio ≤ 2.3 
• Albumin ≥ 2.8 g per deciliter 
• Total bilirubin ≤ 5 mg per deciliter 


Sorafenib in HPS 
Protocol V2.3 
 
18 
 
• Alanine aminotransferase and aspartate aminotransferase ≤ 5 times the upper limit of the 
normal range  
• Serum creatinine ≤ 1.5 times the upper limit of the normal range and not receiving 
dialysis  
• Negative pregnancy test (for women of childbearing potential) at both screening and 
baseline visits. Post-menopausal women (defined as no menses for at least 1 year) and 
surgically sterilized women are not required to undergo a pregnancy test. 
• Subjects (men and women) of childbearing potential must agree to use medically 
acceptable contraception beginning at the signing of the ICF until at least 14 days after 
the last dose of study drug. 
• Age ≥ 21 years 
• Ability to provide informed consent 
 
3.2.2 Exclusion Criteria 
 
 
• Recent chronic heavy alcohol consumption 
• Enrollment in a clinical trial or concurrent use of another investigational drug or device 
therapy (i.e., outside of study treatment) within 28 days of screening visit 
• Current hepatic encephalopathy 
• Active infection 
• Diagnosis of portopulmonary hypertension 
• WHO Class IV functional status 
• Congenital long-QT syndrome 
• Subjects who have used strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, 
phenobarbital, St. John’s Wort [Hypericum perforatum], dexamethasone at a dose of 
greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days before 
randomization 
• Subject who are currently taking Coumadin®(warfarin)  
• Active or clinically significant cardiac disease, including: 
– 
Active coronary artery disease 
– 
Unstable angina (anginal symptoms at rest), new-onset angina within 12 weeks before 
randomization, or myocardial infarction within 24 weeks before randomization 
• Liver or other solid organ transplant recipients 
• 
Expectation of liver transplant within four months of randomization 
• 
Hepatocellular carcinoma that does not meet all of the following criteria: 
a. 
Single lesion ≤ 3 cm documented by LIRADS criteria 
b. Complete response to ablative therapy (TACE, RFA, alcohol ablation) using the modified RECIST 
criteria one month after therapy with no more than two treatments 
c. 
No other lesions develop after initiation of HCC therapy 
• 
Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm 
Hg on repeated measurement) despite optimal medical management 
• Any hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or higher within 4 weeks 
before randomization 
• Presence of a non-healing wound, non-healing ulcer, or bone fracture 
• Women who are pregnant or breast-feeding 
• Major surgery within 28 days of randomization. 


Sorafenib in HPS 
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19 
 
• Subjects with any previously untreated or concurrent cancer except cervical cancer in-
situ, treated basal cell carcinoma, or superficial bladder tumor.  Subjects surviving a 
cancer that was curatively treated and without evidence of disease for more than 3 years 
before randomization are allowed. All cancer treatments (chemotherapy, radiation 
therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) must be 
completed at least 3 years prior to study entry (i.e., signature date of the informed consent 
form) 
• Inability to comply with the protocol and/or not willing or not available for follow-up 
assessments  
 
3.3 Randomization  
 
Randomization will incorporate Field Center as a stratification variable, and will be blocked to 
ensure balance over time. The Research Pharmacy at the University of Pennsylvania will prepare 
numbered drug kits which will be shipped and stored at each Field Center. At the baseline visit, 
when the research coordinator registers the patient as meeting all inclusion/exclusion criteria, the 
number of the kit for use by that patient will be provided by the web-based database. 
 
3.4 Maintenance of Treatment Randomization Code and Procedures for Breaking the Code 
 
Unblinding may only occur for emergency purposes which would affect clinical care.  
Investigators should note that the occurrence of a serious adverse event or progressive disease 
should not routinely precipitate the immediate unblinding of the label.  If unblinding is necessary 
for the treatment of a subject for a serious adverse event, every attempt should be made to 
contact the Principal Investigator (PI) prior to unblinding.  If this is not feasible, then the 
Principal Investigator must be contacted within 24 hours of unblinding. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
20 
 
Chapter 4. Treatments 
 
4.1 
Sorafenib 
 
Sorafenib tablets are purchased from Bayer HealthCare.  The 200-mg tablet formulation contains 
sorafenib tosylate and the excipients croscarmellose sodium, microcrystalline cellulose, 
hypromellose, sodium lauryl sulfate, and magnesium stearate.  The tablets have a film coating 
comprised of hypromellose, polyethylene glycol, titanium dioxide, and red ferric oxide, which 
has no effect on the release rate of the active ingredient, sorafenib tosylate.  The tablets are un-
debossed, salmon colored, weigh approximately 350 mg each, and are 10 mm (millimeter) round 
in shape. 
The chemical name for sorafenib tosylate is 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-
ureido] -phenoxy}-pyridine-2-carboxylic acid methylamide-4-methylbenzene-sulfonate, and its 
molecular weight is 637 daltons.  The structure of sorafenib is depicted in Figure 0-1. 
 
Figure 0-1: Structure of Sorafenib (BAY 43-9006) 
 
Sorafenib tablets do not need to be protected from light.  They are sufficiently stable with regard 
to light, oxidation, thermal stress, and hydrolytic degradation.  The formulation is presented as an 
immediate release dosage form, i.e., the active ingredient is completely dissolved under in vitro 
test conditions within a short period of time. 
 
Sorafenib 400 mg QD by mouth or an identically encapsulated placebo will be administered 
daily as the starting dose. This dosage is significantly above the effective weight-based dose in 
the HPS animal experiments and is a commonly attainable dose in clinical practice.   
 
Subjects will be instructed on the proper administration of sorafenib.  Sorafenib tablets should be 
taken at approximately the same time each day preferably in the morning.  Sorafenib tablets 
should be taken without food, at least 1 hour before and at least 2 hours after a meal, and with up 
to 240 mL (approximately 1 cup or 8 oz) of water.  
 
 


Sorafenib in HPS 
Protocol V2.3 
 
21 
 
4.2 Placebos and Packaging of Study Medication 
 
Sorafenib and placebo tablets will be over-encapsulated by the Research Pharmacy at the 
University of Pennsylvania. At the Research Pharmacy, capsules will be packaged into HDPE 
bottles with a liner, cotton, and childproof cap.  Bottles will be fully labeled to meet state and 
FDA requirements, and packaged into labeled kits. There will be one bottle of drug product 
dispensed to study subjects at the Baseline Visit, Visit# 3 (Week 4), and Visit # 4 (Week 8) 
during the treatment phase. Study drug must be stored at room temperature and protected from 
moisture. Subjects will be asked to bring bottles to each study visit to allow for tracking of 
compliance and medication control. At the end of the study, after accountability has been 
completed and notification by the Clinical Coordinating Center (CCC) has been sent, study 
product can be destroyed at each Field Center’s Research Pharmacy. 
 
4.3 Administration of Study Medication 
 
The occurrence of planned or unplanned procedures may warrant holding study medication from 
a patient safety standpoint (surgery, etc.). As holding such therapy when these procedures are 
planned or occur is part of normal usage (and required to maximize patient safety in the trial), the 
patient’s physician will be allowed to temporarily stop the sorafenib/placebo and restart therapy 
when considered safe from standard clinical practice. The timing and duration of such events 
will be recorded. Temporary interruption of sorafenib prior to major surgical procedures is 
recommended.  The decision to resume sorafenib should be based on clinical judgment of 
adequate wound healing, which will be the recommended strategy in this study. Patients will be 
instructed to inform all treating physicians of their participation in the trial and the possibility of 
sorafenib use, and we will alert the patient’s primary medical doctor and HPS clinician of 
participation in this trial. 
 
4.4 Management of Other Medical Therapies during the Trial 
 
All concomitant medications (including start/stop dates and indication) must be recorded in the 
subject’s source documentation. 
 
Permitted prior and concomitant therapy 
 
• Treatment with non-conventional therapies (e.g., herbs [with the exception of St. John’s 
Wart], acupuncture) and vitamin/mineral supplements is acceptable. 
• Subjects may receive standard of care for any underlying illness. 
• In the event of neutropenia, anemia, or thrombocytopenia, subjects may receive 
appropriate supportive care (e.g., transfusion, prophylactic antibiotics, antifungals and/or 
antivirals, hematopoietic growth factors).  This supportive care should not substitute a 
recommended dose modification. 
• Caution is recommended when administering substrates of CYP2B6 and CYP2C8 with 
sorafenib.  Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to 
increase when these are co-administered with sorafenib. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
22 
 
Excluded concomitant therapy 
 
• Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with heparins 
and heparinoids. 
– 
However, prophylactic anticoagulation as described below is allowed: 
o Low dose aspirin (≤ 100 mg daily). 
o Prophylactic doses of heparin. 
 
4.5 Treatment Masking 
 
All study personnel and subjects will be masked for the duration of the study until the last 
subject completes follow-up assessments. The University of Pennsylvania Research Pharmacist 
will be unmasked, the statistical analyst, and the DSMB will be unmasked; the Research 
Pharmacist will supply the DSMB and analyst with the drug/placebo identifier. 
4.6 Drug Logistics and Accountability 
Each Field Center will have limited supply of study drug kits available on study, which will be 
replenished by the University of Pennsylvania Research Pharmacy as they are dispensed to study 
subjects. All study drugs dispensed to the Field Centers will be stored in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements and the 
instructions given by the clinical supplies department of the Institution and will be inaccessible 
to unauthorized personnel. 
4.6.1 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the investigational agent using the drug accountability 
form. 
4.6.2 Destruction and Return 
At the end of the study, unused supplies of sorafenib should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record Form. 


Sorafenib in HPS 
Protocol V2.3 
 
23 
 
Chapter 5. Data Collection 
 
5.1 Study Visits   
 
5.1.1  Informed Consent 
 
Potentially eligible subjects will be referred if there is interest in enrolling. The following 
procedures will be performed during the screening process: 
• Sign and date the ICF and HIPAA release 
• Review of inclusion/exclusion criteria 
• Schedule Screening Visit 
 
After the subject has consented, the subject will be scheduled for a screening visit within 56 days 
if the subject meets inclusion/exclusion criteria thus far.  The research coordinator will call the 
subject 1-2 days prior to the screening visit and send a reminder letter as well if the screening 
visit is not conducted within the 2 weeks following consent. The coordinator will instruct the 
subject to not eat or drink (except water) and to avoid heavy exercise for 12 hours prior to the 
study visit. The coordinator will also request that the subject refrain from smoking for 12 hours 
prior to the study visit. Subjects will be instructed to hold their routine medications on the 
morning of the visit and to bring their medications and a snack with them to the visit to take at 
the center after blood draw.  
 
5.1.2  Visit 0: (Screening) 
 
The following procedures will be performed during the screening process: 
 
• Review medical history 
• Vital signs 
• Physical exam 
• WHO functional capacity assessment 
• Review current medications 
• Labs/Phlebotomy: complete blood count with differential, including hemoglobin, 
hematocrit, and platelet count, clinical chemistries, and coagulation studies 
• Serum HCG pregnancy test (for women of childbearing potential) 
• Electrocardiogram (ECG) 
• Spirometry and lung volumes 
• ABG (seated while breathing room air) 
• Contrast echocardiogram 
• Provide instructions on recording of new medications and dose changes 
• Instruct subjects to bring routine medications to baseline visit and to avoid heavy exercise 
and smoking for 12 hours before the baseline visit 
 
After the consent and screening visits, the subject will be scheduled for a baseline study visit 
within 28 days at the study center if all inclusion/exclusion criteria are met. The research 


Sorafenib in HPS 
Protocol V2.3 
 
24 
 
coordinator will call the subject and send a follow-up letter more than two weeks before the 
baseline visit as a reminder. 
 
5.1.3 Visit 1: (Baseline) 
 
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 heavy exercise 
for 12 hours before the study day assessment. The coordinator will also request that the subject 
refrain from smoking for 12 hours prior to the study visit.  Lastly, subjects will be instructed to 
hold their routine medications on the morning of the visit and to bring their medications and a 
snack with them to the visit to take at the center after blood draw.   
 
Baseline information will be used to characterize the participants and to compare the 
experimental groups with regards to demographics and other variables. Safety laboratories, 
ABG, and contrast TTE obtained at the screening visit will be used as baseline measurements. 
Eligibility criteria will be reviewed prior to randomization to treatment group. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will be 
performed: 
 
• Review of inclusion/exclusion criteria 
• Phlebotomy (HPC levels, angiogenesis biomarkers, etc.) 
• Urine collection for pregnancy test (for women of childbearing potential) 
• Eat a small snack 
• Interim medical history 
• Vital signs 
• Physical exam 
• WHO functional class assessment 
• Review current medications 
• Complete SF36 
• Complete Mahler Baseline Dyspnea Index (BDI) 
• Six minute walk testing with Borg scores 
• Randomization to treatment group 
• Dispense supply of study drug  
• Dispense study supply of moisturizing cream 
• Reinforce instructions on recording of new medications and dose changes 
• Reinforce instructions on bringing the subject’s routine and study medications to all visits 
 
Blood samples for study assays will be processed and banked or shipped, and urine pregnancy 
test will be performed (for women of child-bearing potential). 
 
After the labs have been drawn, the subject will eat a snack. The investigator or research nurse 
will take an interim medical history and perform a physical examination including vitals, review 
current medications, and complete the BDI.  The subject will complete the SF36. 
 


Sorafenib in HPS 
Protocol V2.3 
 
25 
 
The subject will then perform the six-minute walk test (6MWT). 
 
After confirming a negative pregnancy test (for subjects of child-bearing potential) and other 
inclusion criteria, the subject will be randomized to a treatment group using the Web-based 
database. A pre-packaged 4 week supply of study medication (encapsulated sorafenib 200 mg or 
placebo capsules) will be given to the subject. Subjects will be instructed on the proper 
administration of the study medication.  Study medication capsules should be taken at 
approximately the same time each day preferably in the morning.  Study medication capsules 
should be taken without food, at least 1 hour before or at least 2 hours after a meal and with up to 
240 mL (approximately 1 cup or 8 oz) of water.   
 
After study drug dispensing and instruction, the study coordinator should supply the subject with 
study moisturizing cream and instruct the subject to apply twice daily to hands and feet upon 
starting study drug.   
 
Because diarrhea and fatigue are also common side effects, preventive/management strategies for 
diarrhea and fatigue should be consistent with local standards (e.g., anti-diarrheals and optimized 
hydration status for diarrhea). 
 
Once instruction has been given to the subject and the subject expresses understanding, the 
research coordinator will thank the subject for their attendance and reinforce compliance with the 
study medication and protocol. The subject’s medical doctors will be alerted to the subject’s 
participation in the clinical trial. 
 
5.1.4  Visit 2: (Week 2 ± 3 days) 
 
 
 
The research coordinator will call the subject 1-2 days before the visit as a reminder. Subjects 
will be encouraged to take their routine medication and study medication as they usually would 
prior to the visit, but subjects will still be instructed to bring their routine and study medications 
with them to each visit. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will be 
performed: 
 
• Interim medical history 
• Vital signs 
• Physical exam 
• Review current medications 
• Study drug accountability 
• Reinforce instructions on recording of new medications 
• Reinforce instructions on bringing the subject’s routine and study medications to all visits 
 
 
The research coordinator will reinforce instructions on bringing the subject’s routine and study 
medications to each visit and will also perform a pill count. The investigator or research nurse 
will take an interim medical history and perform a physical examination, and assess side effects. 


Sorafenib in HPS 
Protocol V2.3 
 
26 
 
 
The research coordinator will thank the subject for their attendance and reinforce compliance 
with the study medication and protocol.  
 
5.1.5  Visit 3: (Week 4 ± 3 days) 
 
The research coordinator will call the subject 1-2 days before the visit as a reminder. Subjects 
will be encouraged to take their routine medication and study medication as they usually would 
prior to the visit, but subjects will still be instructed to bring their routine and study medications 
with them to each visit. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will be 
performed: 
 
• Phlebotomy: complete blood count with differential, including hemoglobin, hematocrit, 
and platelet count, clinical chemistries, coagulation studies.  
• Serum HCG pregnancy test (for women of childbearing potential)  
• Interim medical history 
• Vital signs 
• Physical exam 
• Review current medications 
• Study drug accountability 
• Reinforce instructions on recording of new medications 
• Reinforce instructions on bringing the subject’s routine and study medications to all visits 
• Dispense supply of study drug 
 
Blood samples for safety monitoring will be sent to the field center’s laboratory. 
 
The research coordinator will reinforce instructions on bringing the subject’s routine and study 
medications to each visit and will also perform a pill count. The research coordinator will 
dispense a re-supply of study medication (encapsulated sorafenib 200 mg or placebo capsules) to 
the subject.  The investigator or research nurse will take an interim medical history and perform 
a physical examination, and assess side effects. 
 
The research coordinator will thank the subject for their attendance and reinforce compliance 
with the study medication and protocol. The coordinator will contact the clinician 24 hours after 
the study visit to discuss the clinical lab results. 
 
5.1.6 Telephone Contacts 1 & 2:  (Week 6 ± 3 day, Week 10 ± 3 days) 
The following will be assessed during telephone contacts 1 & 2. 
 
• Review current medications 
• Study drug accountability 
• Reinforce instructions on recording of new medications 
• Reinforce instructions on bringing the subject’s routine and study medications to all visits 


Sorafenib in HPS 
Protocol V2.3 
 
27 
 
and to avoid heavy exercise and smoking for 12 hours before Visits #4 and #5  
 
The research coordinator or nurse will call the subject at Week 6 and at Week 10 to ask about the 
subject’s general health and to review any changes in the medication they are taking.    The 
research coordinator or nurse will also ask about any missed doses or compliance issues the 
subject reports.  
 
The research coordinator will reinforce instructions on bringing the subject’s routine and study 
medications to each visit.  The research coordinator or nurse will also remind the subject of their 
next appointment and any remind the subject not eat or drink (except water) and to avoid heavy 
exercise for 12 hours prior to the next study visit. The coordinator will also request that the 
subject refrain from smoking for 12 hours before the next scheduled visit.  Subjects will be 
instructed to hold their routine medications on the mornings of the visit following these 
telephone contacts (Visits #4 and #5) and to bring their medications and a snack with them to the 
visit to take at the center after blood draw. 
 
 
5.1.7 Visit 4: (Week 8 ± 3 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 heavy exercise 
for 12 hours before the study day assessment. The coordinator will also request that the subject 
refrain from smoking for 12 hours prior to the study visit.  Subjects will be instructed to hold 
their routine and study medication the morning of the visit and to bring a snack as well as their 
routine and study medications with them to the visit to take at the study center after blood draw. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will be 
performed: 
 
• Phlebotomy: complete blood count with differential, including hemoglobin, hematocrit, 
and platelet count, clinical chemistries, coagulation studies, biomarkers, other study labs 
• Serum HCG pregnancy test (for women of childbearing potential)  
• Eat a small snack 
• ABG (seated while breathing room air)(Optional) 
• Interim medical history 
• Vital signs 
• Physical exam 
• WHO functional class assessment 
• Review current medications 
• Complete SF36 
• Complete Mahler Transition Dyspnea Index (TDI) 
• 6MWT with Borg scores 
• Reinforce instructions on recording of new medications and dose changes 
• Reinforce instructions on bringing the subject’s routine and study medications to all visits 
• Dispense supply of study drug 


Sorafenib in HPS 
Protocol V2.3 
 
28 
 
 
Blood samples for study assays will be processed and banked or shipped, whereas samples for 
safety monitoring will be sent to the field center’s hospital laboratory. 
 
After the labs have been drawn, the subject will eat a snack. The investigator or research nurse 
will take an interim medical history and perform a physical examination including vitals, review 
current medications, and complete the TDI.  The subject will complete the SF36. 
 
The subject will then perform the 6MWT. 
 
After the 6MWT, the research coordinator will perform a pill count.  The research coordinator 
will reinforce proper administration of the study medication.  The research coordinator will also 
reinforce instructions on bringing the subject’s routine and study medications to each visit. 
 
The research coordinator will thank the subject for their attendance and reinforce compliance 
with the study medication and protocol. The coordinator will contact the clinician 24 hours after 
the study visit to discuss the clinical lab results. 
 
5.1.8 Visit 5:  (Week 12 ± 3 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 heavy exercise 
for 12 hours before the study day assessment. The coordinator will also request that the subject 
refrain from smoking for 12 hours prior to the study visit.  Subjects will be instructed to hold 
their routine and study medication the morning of the visit and to bring a snack as well as their 
routine and study medications with them to the visit to take at the study center after blood draw. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will be 
performed: 
 
• Phlebotomy: complete blood count with differential, including hemoglobin, hematocrit, 
and platelet count, clinical chemistries, coagulation studies, biomarkers, other study labs 
• Serum HCG pregnancy test (for women of childbearing potential)  
• Eat a small snack 
• ABG (seated while breathing room air) 
• Contrast echocardiogram 
• Interim medical history 
• Review current medications 
• Vital signs 
• Physical exam 
• WHO functional class assessment 
• Complete SF36 
• Complete Mahler Transition Dyspnea Index (TDI) 
• 6MWT with Borg scores 
• Study drug accountability and collection of remaining study drug 
 


Sorafenib in HPS 
Protocol V2.3 
 
29 
 
Blood samples for study assays will be processed and banked or shipped. 
 
After the blood draw the subject will eat a snack.  ABG and contrast echocardiography will then 
be performed. The investigator or research nurse will take an interim medical history and 
perform a physical examination including vitals, review current medications, and complete the 
TDI.  The subject will complete the SF36. 
 
The subject will perform the 6MWT. 
 
After the completion of the walk test, the research coordinator will perform a pill count and 
collect any unused study drug.  The research coordinator will thank the subject for their 
attendance and reinforce compliance with the protocol.  
 
5.1.9 Telephone contact #3 OR Visit 6 – Two Week Follow Up:  (Week 14 ± 3 days) 
 
Week 14 will be conducted as a telephone contact or a clinic visit should the subject have 
moderate to serious unresolved AE’s and/or the local investigator requires a clinic visit.  
 
For a telephone contact, the research coordinator or nurse will call the subject to ask about the 
subject’s general health and changes in the medication they are taking. The research coordinator 
or nurse will also review any unresolved AE’s the subject had ongoing to determine if they have 
resolved.   
    
If the local investigator requires a clinic visit due to moderate to serious unresolved AE’s or 
other concerns, the research coordinator will call the subject 1-2 days before the visit as a 
reminder. Subjects will be instructed to bring their regular medications with them to the visit and 
to take their regular medications before coming to the study center. 
 
The subject will arrive at the study site outpatient clinic. The following procedures will be 
performed: 
 
• Phlebotomy: complete blood count with differential, including hemoglobin, hematocrit, 
and platelet count, clinical chemistries, coagulation studies 
• Interim medical history 
• Vital signs 
• Review current medications 
• Physical exam 
 
The investigator or research nurse will take an interim medical history and perform a physical 
examination including vitals and review current medications.   
 
The research coordinator will thank the subject for his or her participation. 
 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
30 
 
5.1.10 Future Research 
 
In the future, the University of Pennsylvania may conduct candidate gene and/or genome-wide 
analysis (GWAS) for HPS research with research samples provided during the study.  The main 
focus of the blood testing will be HPC and biomarker analysis as described in the aims of this 
study.  However, we may also look for genetic determinants of the disease state or genetic 
predictors of drug efficacy.  Any GWAS results which result from this analysis will be shared for 
research purposes through the National Institutes of Health (NIH) GWAS data repository in 
accordance with their usual policies.  Information about genetic and physical characteristic 
information will be identified by use of a code number to protect privacy.  
 
 


Sorafenib in HPS 
Protocol V2.3 
 
31 
 
5.2 Study Schedule of Procedures 
 
The table below summarizes the study procedures. 
 
Table 1. Study Procedures 
Consent Screen 
Baseline 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
Wk 10 
Wk 12 
Wk 14 
Visit # 
-1 
0 
1 
2 
3 
 
4 
 
5 
(6) § 
Telephone contact # 
 
 
 
 
 
1 
 
2 
 
3 
Day# 
-84 - -28 
-28--1 
0 
14 ± 3 
28 ± 3 
42 ± 3 
56 ± 3 
70 ± 3 
84± 3 
98 ± 3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and physical exam 
 
 
 
 
 
 
 
 
 
 
Medical history  
 
X 
 
 
 
 
 
 
 
 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
 
X 
 
X 
X§ 
Physical exam 
 
X 
X 
X 
X 
 
X 
 
X 
X§ 
 
 
 
 
 
 
 
 
 
 
 
General testing 
 
 
 
 
 
 
 
 
 
 
Chemistry, CBC with diff, LFT 
 
X 
 
 
X 
 
X 
 
X 
X§ 
Prothrombin time / INR 
 
X 
 
 
X 
 
X 
 
X 
X§ 
Pregnancy test (as appropriate) 
 
X 
X* 
 
X 
 
X 
 
X 
  
Electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
Spirometry / Lung Volumes 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoint assessment 
 
 
 
 
 
 
 
 
 
 
ABG 
 
X 
 
 
 
(X)‡ 
 
X 
 
Contrast Echo 
 
X 
 
 
 
 
 
X 
 
HPCs / Biomarkers 
 
 
X 
 
 
 
X 
 
X 
 
Six-minute walk test 
 
 
X 
 
 
 
X 
 
X 
 
SF-36 / MDI (BDI or TDI) 
 
 
X 
 
 
 
X 
 
X 
 
WHO functional capacity 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study procedures 
 
 
 
 
 
 
 
 
 
 
Dispense study med 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess: 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Med compliance 
 
 
 
X 
X 
X 
X 
X 
X 
 
*At Baseline (Visit 1), pregnancy will be assessed by urine testing.  All other pregnancy tests will be 
measured using blood samples. 
(X)‡Optional at this visit. 
§  Week 14 will be conducted as a telephone contact or a clinic visit should the subject have 
moderate to serious unresolved AE’s and/or the local investigator requires a clinic visit. Testing 
marked “§” will be completed if a clinic visit is conducted.   
 
 


Sorafenib in HPS 
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32 
 
5.3 Subject 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. Subjects will be reimbursed for their time participating in the study and for 
reasonable travel expenses necessary for their participation in the study (parking/mileage) in the 
amount of $250 per study visit that they attend (with an additional $25 at Visit 4 for allowing 
optional ABG to be performed). – Participants traveling over 60 miles will be also reimbursed 
for additional travel expenses including, mileage, hotels and meals up to an additional $300 per 
visit.  In order to receive reimbursement, a copy of the original receipts for expenses will be 
required. 
 
An adequate record of receipt, distribution, and return of all study drugs must be kept. 
 
Subject compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol, and to have blood collected for all safety evaluations.   
 
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 him or her by telephone. If this fails, the coordinator will send two certified express 
letters one week apart, to request follow-up. 
 
We have considered how to minimize noncompliance with therapy. We will strongly emphasize 
the importance of complying with the study drug treatment. Nonetheless, we will perform pill 
counts at visits and record episodes when medication is withheld for any reason. If a subject 
wishes to drop-out from the treatment phase of the study or has a serious adverse event (SAE) 
(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. The inclusion of such follow-up data will allow for analysis by intention-to-treat. 
 
If a subject is withdrawn from the treatment portion of the study for any reason, the subject will 
be strongly encouraged to continue with the remainder of the study assessments, as scheduled. If 
a subject does not wish to return for the remainder of the study assessments/visits, subject will be 
asked to attend one more visit at week 12 to complete end of study assessments. 


Sorafenib in HPS 
Protocol V2.3 
 
33 
 
Chapter 6. Assessment of Efficacy and Outcome Measures 
 
6.1 
Assessments of Efficacy 
 
The primary objective of this study is to assess the effect of sorafenib versus placebo on the 
AaPO2 in subjects with HPS at 12 weeks.  
 
6.1.1 Alveolar-Arterial Oxygen Gradient (AaPO2) 
 
The AaPO2  (assessed by seated arterial blood gas sampling while breathing room air) is the 
primary endpoint of this Phase II study for several reasons. The diagnosis of HPS is predicated 
on abnormal gas exchange, which normalizes after LT. We have shown that interventions which 
decrease lung angiogenesis and intrapulmonary shunting in the animal model of HPS also 
improve AaPO2. The AaPO2 is strongly associated with the degree of intrapulmonary shunting 
by contrast TTE in HPS.  
 
6.2 
Secondary Outcome Measures 
 
There are several secondary objectives of this study. They include: 
 
• To assess the effect of sorafenib vs. placebo on intrapulmonary shunting at 12 weeks 
• To assess the effect of sorafenib vs. placebo on plasma HPC levels and other 
angiogenesis biomarkers  
• To assess the effect of sorafenib vs. placebo on six-minute walk distance at 8 and 12 
weeks 
• To assess the effect of sorafenib vs. placebo on SF-36 questionnaire scores and Mahler 
dyspnea index at 8 and 12 weeks 
• To assess the effect of sorafenib vs. placebo on PaO2 and oxygen saturation by pulse 
oximetry at 8 and 12 weeks  
• To assess the effect of sorafenib vs. placebo on AaPO2 at 8 and 12 weeks (for those with 
available ABG at 8 weeks)  
• To assess the effect of sorafenib vs. placebo on functional class at 8 and 12 weeks 
• To assess the safety and side effects associated with sorafenib administration in subjects 
with HPS 
 
6.2.1 HPC Levels 
 
We will assess the effect of sorafenib on HPC levels as biomarkers of angiogenesis in subjects 
with HPS. 
 
6.2.2 Intrapulmonary Shunting 
 
Intrapulmonary shunting will be assessed using contrast TTE in a standardized fashion. A 
decrease in arterio-venous dilations in the lungs with the administration of sorafenib should be 
associated with a decrease in the degree of intrapulmonary passage of bubbles using agitated 
saline. 


Sorafenib in HPS 
Protocol V2.3 
 
34 
 
6.2.3 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. Standardized test methods and scripted and timed statements have been 
established in prior studies and will be used. The 6WMT is also non-invasive and safe. 
 
The 6MWT will be performed at baseline, 8 weeks and 12 weeks. 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. 
 
6.2.4 SF-36 / Mahler Dyspnea Index 
 
The SF36 is one of the most widely used generic measures of subjective health status. The SF36 
includes one multi-item scale that assesses eight health concepts: 1) limitations in physical 
activities because of health problems; 2) limitations in social activities because of physical and 
emotional problems; 3) limitations in usual role activities because of physical health problems; 
4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in 
usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) 
general health perceptions. Subjects will complete the SF36 at baseline and weeks 8 and 12.   
The Mahler Dyspnea Index (MDI) is an interview-administered instrument that allows patients to 
assess their level of dyspnea. Baseline scores are called the BDI and depend on ratings for three 
different categories: functional impairment, magnitude of task and magnitude of effort. 
Limitation of ability in each of these three categories of dyspnea is graded from 0 (severe) to 4 
(unimpaired) in each category. The ratings for the three categories are added to form the total 
baseline score, ranging from 0 (severe) to 12 (no dyspnea). The TDI score ranges from −3 (major 
deterioration) to +3 (major improvement) for each domain (compared with the same domain of 
the BDI) with the TDI focal score being the sum of scores for the three domains (−9 to +9). 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
35 
 
Chapter 7. Statistical Considerations 
 
7.1 Study Design 
 
The proposed research project involves one primary and several secondary objectives. To 
address these aims, we will conduct a double-blind, randomized, placebo-controlled trial.  Blood 
sampling and 6MWT will be performed at baseline, 8 weeks, and 12 weeks. Contrast TTE and 
ABG will be performed at screening/baseline and at 12 weeks, with an optional ABG at 8 weeks. 
 
7.2 Disposition of Subjects and Baseline Comparisons  
 
Summaries of all subjects screened, recruited, and randomized and the number who complete 
visits at 8 and 12 weeks post-randomization will be provided, according to the CONSORT 
guidelines. The treatment groups will be compared at baseline with respect to demographics and 
baseline measurements related to efficacy and safety without formal statistical testing. 
 
7.3 Statistical Procedures  
 
7.3.1 Data Analysis 
 
The intent-to-treat analysis will include all randomized subjects. Hypothesis testing will use two-
sided α level 0.05 without correction for multiplicity. We will summarize demographics and 
baseline and follow-up endpoints. 
 
7.3.2 Univariate Analysis 
 
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. 
 
7.3.3 Analyses of Treatment Assignment and Outcome Measures 
 
The primary analysis will compare the absolute change from baseline to 12 weeks in AaPO2 
between the blinded treatment arms using a two-sample t-test.  This will be supplemented with 
mixed analysis of variance methods to allow inclusion of the baseline value (fixed) and clinical 
site (random). If the data are not normally distributed, they will be transformed. For dichotomous 
outcomes, logistic regression will be used. For secondary outcomes with additional longitudinal 
assessments, including 8- and 12-week results of the plasma biomarker assessments, 6MWT, SF-
36, ABG, and the Mahler Dyspnea Index, linear mixed effects models or generalized estimating 
equations will be used as appropriate. 
 
All patients will be assessed for toxicity and included in the safety analysis. This analysis will 
include summaries of the incidence and grade of toxicities. Patients will be evaluated for serious 
adverse events. Safety interim analyses will be performed and reported at each DSMB meeting.  
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
36 
 
7.3.4 Survival Analysis 
 
A log-rank statistic will be used to compare time to death, although there are expected to be few 
events. 
 
7.3.5 Missing Data and Dropouts 
 
We will attempt to minimize missing data, however we have planned for its occurrence. For 
subjects lost to follow-up, we will use all of the information available until the end of follow-up. 
This protocol will continue to be followed and test procedures performed as prescribed even if a 
subject drops out of the therapeutic portion of the study. That is, if a subject decides that he/she 
does not wish to continue taking the study drug(s), the subject will stop the investigational 
treatment, but will still be strongly encouraged to continue to follow up with the study personnel 
for all scheduled study procedures (e.g., phlebotomy, echocardiography), so that missing data 
(and assumptions regarding these data) will be minimized. 
 
For patients lost to follow-up, we will use all the information available up to the time of loss to 
follow-up. For the primary end point, we will perform an analysis of completers only. We will 
also perform additional sensitivity analyses using imputation to assess the impact of missing data 
for the primary and secondary end points. 
 
7.4 Sample Size and Power Calculations  
 
We have considered the effects of the intervention (sorafenib) on the primary and secondary 
outcome measures as independent hypotheses, setting α=0.05 for each. We expect 30 patients to 
enroll in the study and anticipate a 10% drop-out rate, accounted for in our power calculations. 
Assuming that 1 standard deviation in AaPO2 is ~10 mm Hg, we have sufficient power to detect 
a difference of 11.5 mm Hg in the change of AaPO2 over 12 weeks between active treatment and 
placebo.  
 
7.5 Interim Monitoring Guidelines 
 
Regular reports of safety will be compiled and presented to the DSMB at six months and then 
yearly; there are no planned formal interim analyses of efficacy using either upper or lower 
boundary or other methods.  Our reason for this choice is based on the relative speed of accrual 
relative to the sample size and length of follow-up. An interim analysis which included enough 
subjects to provide credible data on early stopping for benefit would have to occur so late in 
recruitment so as to have little or no effect on trial conduct. Between meetings of the DSMB, 
information regarding issues deemed critical to the trial or participants’ safety will be provided to 
the Chair of the DSMB by the PI. As this is a Phase II study with multiple secondary end points 
and the first study of sorafenib for this indication, there will be no formal stopping rules for 
futility.  
 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
37 
 
7.6 Protocol Violations 
 
Serious protocol violations such as discontinuation of experimental treatment unrelated to 
adverse events (AEs) will be carefully recorded and regularly reviewed by the Principal 
Investigator. 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. Because all primary 
analyses will be intent-to-treat, it is essential that violations be kept to a minimum, especially 
where it is possible to influence their rate of occurrence. 
 
 
7.7 Safety Analysis 
 
All patients will be assessed for toxicity and included in the safety analysis. This analysis will 
include summaries of the incidence and grade of toxicities. Safety interim analyses will be 
performed and reported at each DSMB meeting. Patients will be evaluated for SAEs.  
 
 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
38 
 
Chapter 8. Quality Control and Data Handling 
 
Design strategies and monitoring activities throughout the study will ensure the integrity and 
high quality of the data. Design strategies include randomization of treatment assignment, 
masking, and training and certification of personnel. The rigorous monitoring program includes 
data queries and performance monitoring over the time of the trial. 
 
8.1 Personnel Training 
 
Prior to randomization of the first subject in the study protocol, the PI will ensure that the 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 adhering to good clinical practice guidelines. Staff will 
have current Human Subjects Training Certification on file. Before enrollment begins, study 
coordinators and research assistants who will perform the outcome assessments will be trained in 
all procedures, including completion of the web-based database. 
 
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 AE to the study team, and having subjects 
undergo vital sign checks and physical exams during each study visit. Laboratories will be 
performed at selected visits and checked. 
 
All study personnel are required to read the consent form, the protocol and the manual of 
procedures. 
 
8.2 Data Quality  
 
The PI will perform continuous monitoring of data quality and completion of CRFs. The Data 
Coordinating Center (DCC) will create computer modules to identify discrepancies and 
incomplete data. These reports are sent to the sites and tracked until each problem is resolved 
and corrected in the database. 
 
On-site audits of each enrollment site will be conducted by CCC staff when 2-4 subjects are 
enrolled at the site. The necessity of further visits will be determined according to study 
performance by each site. During these visits, the monitoring staff reviews all subjects’ 
eligibility criteria, primary end point, SAEs, and a random sample of at least 10% of database 
forms against source documents to ensure that the information on the forms is complete and 
consistent with the source documents. Confirmation of missing visits and documentation will be 
performed, as will the recording of the disposition of participants who complete or exit the study.  
All consent forms and screening logs will be audited.  Summary statistics from the screening 
logs will be sent to the CCC quarterly or as requested. Finally, the CCC staff reviews the 
reporting, documentation and follow-up of SAEs to assure that these events were handled 
according to required study procedures. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
39 
 
8.3 Audit and Inspection 
 
Inspections by regulatory health authority representatives [i.e., FDA and IEC(s)/IRB(s)] are 
possible. 
 
8.4 Archiving 
 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
 
Patient (hospital) files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice. 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
40 
 
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. 
 
Each subject / legal representative or proxy consenter will have ample time and opportunity to 
ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision. 
 
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the ICF 
and has done so, may he/she enter the study.  Additionally, the investigator and other information 
provider (if any) will personally sign and date the form.  The subject / legal representative or 
proxy consenter will receive a copy of the signed and dated form. 
 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
 
1. If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the investigator).  This is to be 
documented by a signature from the informing physician as well as by a signature from the 
witness. 
 
2. For adults under legal protection, consent shall be given by the legal guardian(s).  The 
consent of an adult under legal protection shall also be requested.  His/her refusal or the 
withdrawal of his/her consent may not be disregarded. 
 
The ICF and any other written information provided to subjects / legal representatives or proxy 
consenters will be revised whenever important new information becomes available that may be 
relevant to the subject’s consent, or there is an amendment to the protocol that necessitates a 
change to the content of the subject information and / or the written ICF.  The investigator will 
inform the subject / legal representative or proxy consenter of changes in a timely manner and 
will ask the subject to confirm his/her participation in the study by signing the revised ICF.  Any 
revised written ICF and written information must receive the IEC/IRB’s approval in advance of 
use. 
 
9.2 Institutional Review Board Process  
 
Study staff at each site will obtain IRB approval before any study procedures are initiated. 
 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
41 
 
9.3 Laboratory Values 
 
The following clinical laboratory tests will be measured at screening and repeated  at time points 
specified in schedule of procedures (section 5.2) and as clinically indicated. 
 
9.3.1 Hematology 
 
Complete blood count with differential including hemoglobin, hematocrit, platelets and absolute 
neutrophil count. 
 
9.3.2 Chemistry 
 
Comprehensive metabolic panel including alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, potassium, total and direct bilirubin, albumin, and phosphate.   
 
9.3.3 Coagulation Studies 
 
Prothrombin time, international normalized ratio (INR). 
 
9.3.4 Pregnancy Testing 
 
Blood and urine pregnancy tests will be performed (as appropriate) per the schedule of procedures 
(section 5.2).  
 
9.4 Sorafenib-Related Laboratory Abnormalities and Drug Interactions 
 
Laboratory Abnormalities 
The following laboratory abnormalities were observed in studies done with sorafenib and 
patients with hepatocellular carcinoma and cirrhosis: 
 
Hypophosphatemia was a common laboratory finding, observed in 35% of sorafenib-treated 
patients compared to 11% of placebo patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) 
occurred in 11% of sorafenib-treated patients and 2% of patients in the placebo group; there was 
1 case of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in the placebo group. The 
etiology of hypophosphatemia associated with sorafenib is not known. 
 
Elevated lipase was observed in 40% of patients treated with sorafenib compared to 37% of 
patients in the placebo group.  CTCAE Grade 3 or 4 lipase elevations occurred in 9% of patients 
in each group.  Elevated amylase was observed in 34% of patients treated with sorafenib 
compared to 29% of patient in the placebo group.  CTCAE Grade 3 or 4 amylase elevations were 
reported in 2% of patients in each group.  Many of the lipase and amylase elevations were 
transient and in the majority of cases sorafenib treatment was not interrupted.  Clinical 
pancreatitis was reported in 1 of 297 sorafenib treated patients(Grade 2).  
 
Hypoalbuminemia was observed in 59% of sorafenib-treated patients and 47% of placebo 
patients; no CTCAE Grade 3 or 4 hypoalbuminemia was observed in either group. 


Sorafenib in HPS 
Protocol V2.3 
 
42 
 
 
INR elevations were observed in 42% of sorafenib-treated patients and 34% of placebo patients; 
CTCAE Grade 3 INR elevations were reported in 4% of sorafenib-treated patients and 2% of 
placebo patients; there was no CTCAE Grade 4 INR elevation in either group. 
 
Lymphopenia was observed in 47% of sorafenib-treated patients and 42% of placebo patients. 
 
Thrombocytopenia was observed in 46% of sorafenib-treated patients and 41% of placebo 
patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of sorafenib-treated 
patients and less than 1% of placebo patients. 
 
Effect of Cytochrome P450 Inducers on Sorafenib 
Rifampin, a strong CYP3A4 inducer, administered at a dose of 600 mg once daily for 5 days 
with a single oral dose of sorafenib 400 mg in healthy volunteers resulted in a 37% decrease in 
the mean AUC of sorafenib. Other inducers of CYP3A4 activity (such as, carbamazepine, 
dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort) can increase the 
metabolism of sorafenib and thus, decrease systemic exposure of sorafenib. 
 
Effect of Cytochrome P450 Inhibitors on Sorafenib 
Ketoconazole, a strong inhibitor of CYP3A4 and P-glycoprotein, administered at a dose of 400 
mg once daily for 7 days did not alter the mean AUC of a single oral dose of sorafenib 50 mg in 
healthy volunteers. 
 
Effect of Sorafenib on Other Drugs 
Sorafenib 400 mg twice daily for 28 days did not increase the systemic exposure of 
concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 
substrate), and omeprazole (CYP2C19 substrate). 
 
9.5 Dose Modification for Management of Adverse Events 
 
9.5.1 Dose Reduction Levels 
 
The starting dose of sorafenib is 400 mg once daily.  Study medication will be administered daily 
on a continuous basis.   
 
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines shown in the Dose 
Delays/Dose Modifications table that follows.  Dose modifications will follow predefined dose 
levels. Dose adjustments for hematologic toxicity are based on the blood counts obtained on the 
study visit day. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
43 
 
Table 1. Dose modification levels for sorafenib 
Dose 
Sorafenib 
Starting Dose 
(Baseline) 
400 mg once daily 
-1 
200 mg once daily 
-2 
200 mg every other day 
 
 
9.5.2 Dose Modification for Hematologic Toxicities 
 
Table 2. Recommended dose modification for hematologic toxicities 
Toxicity 
ANC (x 109/L) 
Hemoglobin 
(g/dL) 
Platelets 
(x 109/L) 
Sorafenib 
Grade 1 
< LLN - 1.5 
< LLN – 10.0 
< LLN to 75 
Treat on time 
No change 
Grade 2 
< 1.5 to 1.0   
< 10.0 – 8.0 
< 75 to 50 
Treat on time 
No change 
Grade 3 
< 1.0 to 0.5   
< 8.0 – 6.5 
< 50 to 25 
Treat on time 
Reduce by one dose 
level 
Grade 4 
< 0.5 
Life-threatening 
consequence; 
urgent intervention 
indicated 
< 25 
Delay sorafenib until 
toxicity resolves to 
Grade 2 or less then 
reduce by two dose 
levels 
Febrile 
Neutropenia 
 
 
 
Sorafenib held until 
toxicity has resolved 
to Grade 2 or less; 
when sorafenib is 
restarted, reduce by 
one dose level 
ANC - absolute neutrophil count 
• 
If no recovery after 30 day delay, study treatment should be permanently discontinued. 
 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
44 
 
9.5.3 Dose Modification for Non-Hematologic Toxicities 
 
 
Table 3. Recommended dose modification for non-hematologic toxicity (excluding 
hypertension and HFSR, diarrhea and fatigue) 
Grade 
Dose Interruption 
Dose Modification 
Grade 0-2 
Treat on time 
No Change 
Grade 3 
Interrupt until ≤ Grade 2 
DECREASE one dose level 
Grade 4 
OFF protocol therapy  
OFF protocol therapy 
• 
If no recovery after 30 day delay, treatment will be discontinued. 
 
Prevention/management strategies for diarrhea and fatigue 
 
Diarrhea and fatigue are common side effects of sorafenib.  The same dose-modification 
algorithm used for skin toxicities can be used to address these toxicities.  However, the 
preventive/management strategies for diarrhea and fatigue should be consistent with local 
standards (e.g., anti-diarrheals and optimized hydration status for diarrhea). 
 
9.5.4 Hand-Foot-Skin Reaction 
 
Table 4. Recommended dose modification for HFSR 
Toxicity Grade 
Suggested dose modification 
Grade 1 
Any occurrence 
Maintain dose level and consider topical therapy for 
symptomatic relief 
Grade 2 
1st occurrence 
Maintain dose level and consider topical therapy for 
symptomatic relief 
If no improvement within 7 days, see below 
 
No improvement 
within 7 days or 2nd 
occurrence  
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by one dose 
level 
 
3rd occurrence  
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by one dose 
level 
 
4th occurrence 
Discontinue treatment permanently 
Grade 3 
1st occurrence 
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by one dose 
level 
 
2nd occurrence 
Interrupt until resolved to Grade 0-1 
When resuming treatment, decrease dose by one dose 
level 
 
3rd occurrence 
Discontinue treatment permanently 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
45 
 
Recommended prevention/management strategies for skin toxicities consistent with HFSR are 
summarized below. 
 
Table 5. Recommended prevention/management strategies for skin toxicities consistent 
with HFSR 
Toxicity Grade 
Practical Prevention / Management Strategies for HFSR  
Grade 0 (Preventive strategies) 
• Maintain frequent contact with trial physician to ensure 
early diagnosis of HFSR. 
• Practical prevention strategies 
o Subjects should avoid hot water, and clothing or 
activities that can cause friction on the skin. 
o Subjects will be encouraged to wear appropriately fitted 
shoes with cushioned socks (e.g., tube socks) 
o Urea-based moisturizing cream (supplied by the study) 
should be applied to hands and feet twice daily liberally. 
• Padded gloves and open shoes with padded soles should 
be worn to relieve pressure points. 
Grade 1  
Any occurrence 
• Continue preventive strategies and in addition: 
o Soak hands in cool water. 
o Apply petroleum jelly to moist skin. 
• In the case of hyperkeratotic lesions, exfoliate the hands or 
feet and apply moisturizing cream immediately afterwards. 
Grade 2 Any occurrence or 
Grade 3 Any occurrence 
• Continue supportive/management measures and add 
analgesic(s) for pain. 
 
9.5.5 Treatment-Emergent Hypertension 
 
Hypertension is a known and potentially serious AE associated with sorafenib treatment. 
Subjects will undergo brief physical examinations, including blood pressure monitoring, at each 
clinic visit.  
 
Blood pressure measurements that are out of the normal range must be noted.  Blood 
pressure measurements considered out of the normal range are diastolic pressure > 90 mm Hg 
and/or systolic pressure > 140 mm Hg, or a 20 mm Hg increase in diastolic pressure if the 
previous measurement was within normal limits. 
 
The dose-modification schedule to be followed in the event of treatment-emergent hypertension 
is outlined below.  The choice of anti-hypertensive medication to be used in cases of treatment-
emergent hypertension will be at the investigator's discretion and based on guidelines provided in 
the MOP (amlodipine will be recommended).  All anti-hypertensive medications used for the 
management of treatment-emergent hypertension should be recorded in the subject’s records. 
 
Once a dose-reduction modification has been made for treatment-emergent hypertension, NO 
dose re-escalation will be allowed. 


Sorafenib in HPS 
Protocol V2.3 
 
46 
 
 
Table 6. Management of treatment-emergent hypertension 
Grade of Event (NCI-CTCAE v4.0) 
Management/ Next Dose 
Grade 1 
Consider increasing blood pressure monitoring.  
Continue sorafenib/placebo dosing as scheduled. 
Grade 2 asymptomatic and diastolic 
pressure 90-99 mm Hg  
Begin anti-hypertensive therapy (amlodipine 
recommended).  Continue sorafenib/placebo dosing as 
scheduled. 
Grade 2 (symptomatic/persistent) 
OR 
Grade 2 symptomatic increase by > 
20 mm Hg (diastolic) or to > 140/90 mm 
Hg if previously within normal limits 
OR  
Grade 3 systolic BP >= 160 mm Hg or 
diastolic BP >= 100 mm Hg 
Sorafenib/placebo should be held until symptoms 
resolve and diastolic blood pressure < 90 mm Hg; also 
treat subject with anti-hypertensives and when 
sorafenib/placebo is restarted, reduce by 1 dose level. 
If diastolic blood pressure is not controlled (< 90 mm 
Hg) on anti-hypertensive therapy, reduce another dose 
level. 
Grade 4 life threatening consequences; 
urgent intervention indicated 
Discontinue sorafenib 
 
 9.6 Other Events 
 
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. This trial does prohibit certain therapies, thus there may 
be a reason to stop study drug participation under such circumstances. Even if subjects are 
withdrawn from the study drug, outcome assessments will continue, allowing analysis by intent-
to-treat. 
 
9.7 Safety and Adverse Events 
 
9.7.1 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, 
informed consent document, or investigators brochure; and b) the characteristics of the subject 
population being studied; 
 
2) related or possibly related to participation in the research  (Possibly related to participation in 
the research means there is a reasonable possibility that the AE, experience, or outcome may 
have been caused by the procedures involved in the research.); and 
 


Sorafenib in HPS 
Protocol V2.3 
 
47 
 
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. 
 
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 events are classified as serious or non-serious.  A 
serious adverse event is any AE that is: 
• fatal 
• life-threatening 
• 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. 
 
Suspected adverse reaction: Any adverse event for which there is a reasonable possibility that 
the drug/investigational product caused the adverse event. For reporting purposes, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the 
drug/investigational product and the adverse event.  
Internal adverse event: Adverse events experienced by subjects enrolled by the investigator(s) 
at their own Field Center.  
External adverse event: Adverse events experienced by subjects enrolled by investigators at 
other Field Centers in the clinical trial.  
 
 
 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
48 
 
9.7.2 Classifying Adverse Events 
 
Severity 
 
The intensity of the AE is classified according to the CTCAEv4.0.  Grade refers to the severity 
(intensity) of the AE:  
 
CTCAEv4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
CTCAEv4 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; 
limiting to age-appropriate instrumental activities of daily living (ADL; instrumental 
ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc). 
CTCAEv4 Grade 3: severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization is indicated; disabling; limiting to self 
care ADL (self care ADL refers to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden). 
CTCAEv4 Grade 4: life-threatening consequences; urgent intervention is indicated. 
CTCAEv4 Grade 5: death due to an AE. 
 
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. 
 
Unexpected:  an AE for which the nature or severity is not consistent with information about the 
condition under study or intervention in the protocol, consent form, product brochure, or 
investigator brochure. 
 
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. 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
49 
 
Relatedness 
 
1) Definite: the AE is clearly related to the research procedures 
2) Probably: the AE is likely related to the research procedures 
3) Possible: the AE may be related to the research procedures 
4) Unlikely: the AE is doubtfully related to the research procedures 
5) Unrelated: the AE is clearly not related to the research procedures 
 
For each identified AE, an entry on the AE form will be completed. Reporting procedures should 
be started 
immediately upon learning of a SAE. 
 
9.7.3 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.  For this study, the 
end of study treatment follow-up is Week 14.  
 
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 considered possibly, probably or definitely related to the study drug 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 related to participation in this study.  The investigator should notify 
the study sponsor of 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: 


Sorafenib in HPS 
Protocol V2.3 
 
50 
 
• The laboratory abnormality is considered clinically significant by the local PI and 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 and 
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 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. 
 
9.7.4 Reporting Procedures for Unanticipated Problems and Adverse Events 
 
Participating investigators should notify the local IRB, in an expedited manner, of those events 
related to study participation that are unforeseen and indicate that participants or others are at 
increased risk of harm. Researchers should submit reports of the following problems : 
 
• Any AE or UP (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: 
1.) Unexpected (An event is “unexpected” when its specificity and severity are not 
accurately reflected in the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved 
informed consent document and other relevant sources of information, such as product 
labeling and package inserts.) 
 AND 
2.) 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.) 
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 


Sorafenib in HPS 
Protocol V2.3 
 
51 
 
Serious and unanticipated AEs which are fatal and indicates that participants or others are at 
increased risk of harm must be reported within 24 hours to the CCC, as well as to the local IRB 
per their requirements. 
What Event is Reported 
Internal/ 
External 
By Whom is 
Event Reported 
To Whom is Event 
Reported 
When is Event Reported 
Fatal unexpected, suspected 
serious adverse event 
 
(SAE – death that is unexpected 
and poss/prob/def related to the 
research) 
Internal 
Event 
Local Investigator 
• 
CCC 
Within 24 hours of initial receipt of 
information 
• 
Local IRB 
Within 24 hours of initial receipt of 
information 
 
CCC 
• 
All participating 
Investigators 
Within 24 hours of initial receipt of 
information from Field Center Investigator 
reporting the local event 
• 
NHLBI, DSMB 
Within 7 calendar days of local Field 
Center’s initial receipt of information  
External 
Event 
Field Center 
Investigators 
• 
Field Center IRBs 
Within 3 calendar days of Field Center’s 
initial receipt of information from CCC 
unless otherwise instructed by Field 
Center’s IRB*  
Life-threatening unexpected, 
suspected serious adverse 
reactions 
 
(SAE- life-threatening, 
unexpected, poss/prob/def 
related to the research) 
 
Internal 
Event 
Local Investigator 
• 
CCC 
Within 2 calendar days of initial receipt of 
information  
• 
Local IRB 
Within 5 calendar days of initial receipt of 
information  
 
CCC 
• 
All participating 
Investigators 
Within 2 calendar days of initial receipt of 
information from Field Center Investigator 
reporting the local event 
• 
NHLBI, DSMB 
Within 7 calendar days of Field Center’s 
initial receipt of information  
External 
Event 
Field Center 
Investigators 
• 
Field Center IRBs 
Within 5 calendar days of Field Center’s 
initial receipt of information from CCC 
unless otherwise instructed by Field 
Center’s IRB* 
Non-fatal, non-life-threatening 
unexpected, suspected serious 
adverse reactions 
 
(SAE – unexpected, 
poss/prob/def related, non-life-
threatening hospitalization, 
prolonged hospitalization, 
disability/incapacity/birth 
defects, important medical 
event)  
Internal 
Event 
Local Investigator 
• 
CCC 
Within 2 calendar days of initial receipt of 
information 
• 
Local IRB 
Within 5 calendar days of initial receipt of 
information 
 
CCC 
• 
All participating 
Investigators 
Within 2 calendar days of initial receipt of 
information from Field Center investigator 
• 
NHLBI, DSMB 
Within 15 calendar days of Field Center’s 
initial receipt of information  
External 
Event 
Field Center 
Investigators 
• 
Field Center IRBs 
Within 5 calendar days of Field Center’s 
initial receipt of information from CCC 
unless otherwise instructed by Field 
Center’s IRB* 
Unanticipated Problem that is 
not an SAE 
 
(AE or non-AE, unexpected, 
poss/prob/def related and 
suggests greater risk of harm) 
 
e.g.  Development of moderate 
hypersomnia that resolve after 
discontinuing drug.  This AE although not-
serious, is not listed as an expected event 
in the consent.  Thus it is an AE that is 
unexpected, possibly related (resolved 
after coming off drug), and places 
subject(s) at greater risk of harm than 
previously known 
Internal 
Event 
Local  Investigator 
• 
CCC 
Within 2 calendar days of initial receipt of 
information  
• 
Local IRB 
Within 5 calendar days of initial receipt of 
information 
 
CCC 
• 
All participating 
Investigators 
Within 2 calendar days of initial receipt of 
information from Field Center investigator 
• 
NHLBI, DSMB 
Within 14 days of Field Center’s initial 
receipt of information  
External 
Event 
Field Center 
Investigators 
• 
Field Center IRBs 
Within 5 calendar days of Field Center’s 
initial receipt of information from CCC 
unless otherwise instructed by Field 
Center’s IRB* 


Sorafenib in HPS 
Protocol V2.3 
 
52 
 
Modified from the NHLBI Adverse Event and Unanticipated Problem Reporting Policy. 
*Investigators should also take into account local IRB guidance if reporting timelines for UPs are shorter than the 
above guidance. 
Investigators should follow the below guidance to help determine if an Adverse Event represents 
an UP that should be reported. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
Reporting Process 
 
UPs posing risks to subjects or others as noted above will be reported to the local 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). 
 


Sorafenib in HPS 
Protocol V2.3 
 
53 
 
The participating Investigator is expected to report any serious and unexpected adverse 
experiences, whether or not they are considered related to the CCC, usually within 24 hours. 
 
The participating Investigator is expected to provide as much of the following information as is 
available to the CCC: 
• 
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) 
 
The participating Investigator will provide details about the AE to the CCC as they become 
available. If additional information cannot be obtained for whatever reason, this will be 
documented. The participating Investigator should inform the CCC when no other information is 
expected. The participating Investigator should provide the CCC with a logical, complete, and 
accurate narrative description of the SAE based upon the above information. 
 
The participating Investigator should promptly determine an assessment of causality. 
 
The participating Investigator should communicate to the CCC if the IRB requires revisions to 
the informed consent form or other measures. 
 
The CCC will determine if any corrective actions should be initiated as a result of any known 
specific or collective SAE/AE(s) and inform all participating Investigators of the corrective 
action (e.g., revision of informed consent form, protocol, CRF). 
 
The participating Investigator/designee should keep originals or photocopies of all relevant 
documentation, including facsimile confirmations, and file them in the participant's file.  
 
All participating Investigators should ensure that their sites report all routine AE(s) as part of the 
periodic or annual reporting requirements to the IRB of record. 
 
The CCC and any participating Investigator should file copies of all correspondence with the 
IRB in the appropriate section of the Regulatory Master File or site study file. 


Sorafenib in HPS 
Protocol V2.3 
 
54 
 
 
 
 
Other Reportable events: 
The following events are also reportable to the 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).  
• Any AE that would cause a modification to the investigators brochure, protocol or ICF, 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. 
 
9.7.5 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. 
 
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons:  
• Subject withdraws consent for study treatment and study procedures.  A subject must be 
removed from the trial at his/her own request or at the request of his/her legally 
acceptable representative.  At any time during the trial and without giving reasons, a 


Sorafenib in HPS 
Protocol V2.3 
 
55 
 
subject may decline to participate further. The subject will not suffer any disadvantage as 
a result. 
• Death. 
 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.  
 
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's medical 
records. 
 
In order to preserve the integrity of the intention-to-treat analysis, even if the subject is 
withdrawn from the treatment portion of the protocol (either due to subject, physician, or 
investigator decision), it is imperative to 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 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. 
There is no evidence that the medication under study is effective in subjects with HPS, so that 
there is neither reason to unmask the study therapy nor to initiate treatment with sorafenib in 
such subjects.  
 
9.8 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. 
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
56 
 
9.9 Potential Risks  
 
There are several areas of potential risk in this study.  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 may occur, which is unlikely but considered a 
serious AE. The removal of <70 cc of blood every 2-4 weeks during the twelve-week period is a 
potential risk; however this amount is routinely taken from subjects for clinical indications 
without adverse effect. Study medications will be delayed until after phlebotomy on each study 
day. 
 
Under some circumstances, it can be a risk for genetic information to be known. To help ensure 
confidentiality, samples will be coded and stored in a secured facility. While situations cannot be 
foreseen where potentially sensitive genetic information is revealed or where people who should 
not have this information could obtain it (representing a loss of confidentiality), however, it is 
possible that presently unforeseen situations may arise where this could happen. 
 
The risks of spirometry and lung volumes are minimal.  There is a small risk of temporary 
shortness of breath. The test should not be given to someone who has experienced a recent heart 
attack or who has certain other types of heart disease. 
 
The risks of obtaining an arterial blood sample for the ABG are blood flow problems at puncture 
site (rare), bruising, hematoma, and infection. Some people may feel lightheaded, faint, dizzy, or 
nauseated. On-going bleeding can be a problem for people with bleeding disorders. On rare 
occasions, the needle may damage a nerve or the artery, causing the artery to become blocked. 
 
The risks associated with an electrocardiogram (ECG) are often none or include mild skin 
irritation or rash at the site of electrode placement. 
 
The risks associated with a contrast echocardiogram are that the probe used on the chest during 
the echocardiogram may lead to mild soreness in the area for about a day.  The risks of inserting 
an IV for the saline (salt-water) contrast are the same as for blood draws. The risk of agitated 
normal saline contrast is extremely low. 
The 6MWT may cause light-headedness, chest pain, or musculoskeletal discomfort, however the 
risks of this study to subjects are minimal. 
 
The administration of sorafenib poses a risk of fatigue, weight loss, rash/desquamation, HFSR, 
hair loss (alopecia), diarrhea, anorexia, nausea, vomiting, constipation, hemorrhaging, 
hypertension, infection, and abdominal pain. 
 
Studies have shown some additional and more serious risks of the administration of sorafenib 
such as cardiac ischemia/infarction, GI perforations, drug induced hepatitis, thromboembolism, 
transient ischemic attack, and liver failure. 
 
Studies with sorafenib have shown subjects may have an increased risk for hypertension, 
bleeding, wound healing complications, and myocardial ischemia. Sorafenib can prolong the 
QT/QTc interval. QT/QTc interval prolongation increases the risk of ventricular arrhythmias. 


Sorafenib in HPS 
Protocol V2.3 
 
57 
 
The other risk to the subjects is the potential loss of confidentiality during data collection. 
 
9.10 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 sorafenib 
in subjects with HPS. As the study involves the risks of randomization to sorafenib, phlebotomy, 
echocardiography, 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. 
 
9.11 Alternatives 
 
The use of the medications for this study requires that certain other medications not be used. 
Therefore, the alternative is to not participate in this study and to continue having the option to 
take these medications. 
 
9.12 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 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. 
 
 
 
 


Sorafenib in HPS 
Protocol V2.3 
 
58 
 
10.0 References 
 
1. Deaths: Final Data for 2006. NVSR Volume 57, Number 14. 80 pp. (PHS) 2009-1120 
 
2. Fallon, M. B., et al. (2008). "Impact of hepatopulmonary syndrome on quality of life and 
survival in liver transplant candidates." Gastroenterology 135(4): 1168-1175. 
 
3. Rodriguez-Roisin, R., et al. (2004). "Pulmonary-Hepatic vascular Disorders (PHD)." Eur 
Respir J 24(5): 861-880. 
 
4. Berthelot, P., et al. (1966). "Arterial changes in the lungs in cirrhosis of the liver--lung spider 
nevi." N Engl J Med 274(6): 291-298. 
 
5. Fernandez, M., et al. (2005). "Inhibition of VEGF receptor-2 decreases the development of 
hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal 
hypertensive rats." Journal of Hepatology 43(1): 98-103. 
 
6. Mejias, M., et al. (2009). "Beneficial effects of sorafenib on splanchnic, intrahepatic, and 
portocollateral circulations in portal hypertensive and cirrhotic rats." Hepatology 49(4): 
1245-1256. 
 
7. Tugues, S., et al. (2007). "Antiangiogenic treatment with Sunitinib ameliorates inflammatory 
infiltrate, fibrosis, and portal pressure in cirrhotic rats." Hepatology 46(6): 1919-1926. 
 
8. Yoshiji, H., et al. (2003). "Vascular endothelial growth factor and receptor interaction is a 
prerequisite for murine hepatic fibrogenesis." Gut 52(9): 1347-1354. 
 
9. Zhang, J., et al. (2009). "Pulmonary angiogenesis in a rat model of hepatopulmonary 
syndrome." Gastroenterology 136(3): 1070-1080. 
 
10. Zhang, J., et al. (In Press). "The Role of CX(3)CL1/CX(3)CR1 in Pulmonary Angiogenesis 
and Intravascular Monocyte Accumulation in Rat Experimental Hepatopulmonary 
Syndrome." J Hepatol. 
 
11. Roberts, K. E., et al. (2010). "Genetic risk factors for hepatopulmonary syndrome in patients 
with advanced liver disease." Gastroenterology 139(1): 130-139 e124. 
 
12. Escudier, B., et al. (2009). "Sorafenib for treatment of renal cell carcinoma: Final efficacy 
and safety results of the phase III treatment approaches in renal cancer global evaluation 
trial." J Clin Oncol 27(20): 3312-3318. 
 
13. Llovet, J. M., et al. (2008). "Sorafenib in advanced hepatocellular carcinoma." N Engl J Med 
359(4): 378-390. 
 


Sorafenib in HPS 
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14. Brose, M.S., et al. (2014).  “Sorafenib in radioactive iodine-refractory, locally advanced or 
metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.”  Lancet 
384(9940): 319-328.