Conditions: Heart Failure
Keywords: Heart Failure
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This study is being conducted to determine safety and effectiveness of transplanting hearts from Hepatitis C-positive donors into Hepatitis C-negative patients on the heart transplant waitlist, who will then be treated with Zepatier after transplantation.

Detailed description:
Open-labelled pilot clinical trial of Zepatier (MK-5172 and MK-8742/Grazoprevir + Elbasvir) in at least 20 HCV-negative subjects receiving a heart transplant from a HCV-positive donor. Eligible subjects will receive a heart transplant from a deceased-donor with genotype 1 or 4 HCV, and then will receive 12 weeks of Zepatier after heart transplantation when infection with HCV is confirmed in these heart transplant recipients. Treatment will be complete after 12 weeks.

Arms:
arm 1: None

Interventions: intervention 1: Zepatier
Intervention descriptions: intervention 1: Zepatier (grazoprevir 100mg and elbasvir 50 mg once daily) is taken by mouth for 12 weeks unless a genetic variation is detected. In this case treatment with Zepatier will be extended to 16 weeks. Study subjects with treatment failure will be provided open-label Zepatier + sofosbuvir (sovaldi) 400mg + Ribavirin (generic), renally dosed based on creatinine clearance per the manufacturer guidelines.

Protocol document:
ICF_001.pdf: 
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UNIVERSITY OF PENNSYLVANIA RESEARCH 
SUBJECT INFORMED CONSENT AND HIPAA 
AUTHORIZATION FORM 
Protocol Title:  Open-labeled trial of Zepatier for treatment of hepatitis 
C negative patients who receive heart transplants from 
hepatitis C positive donors (USHER) 
Sponsor: 
University of Pennsylvania 
Funder: 
Merck & Co. 
Principal 
Investigator: 
David Goldberg, MD, MSCE 
(215) 746-8598
Co-Principal 
Investigator: 
Peter Reese, MD, MSCE 
(215) 900-3782
Rhondalyn Forde-McLean, MD, MHS
(215) 662-2727
Study 
Coordinator:
Anna Sicilia, BS 
(215) 746-7105
Emergency 
Contact: 
24 Hour Emergency Numbers 
Dr. Reese: (215) 900-3782 | Dr. Goldberg: (646) 242-6349 
(215) 662-6200 -  Ask for Heart Transplant Coordinator on Call
Why am I being asked to volunteer? 
You are being asked to participate in this trial because you are expected to have 6-12 
months, or more, before you receive a heart transplant.   
We are asking you to consider joining a study where hearts with hepatitis C will be 
offered to people like you who do not have hepatitis C. Hepatitis C is a virus that infects 
your liver, and over many years (10-30), can lead to scarring of your liver, which can 
develop into end-stage scarring (called cirrhosis), which could lead to liver failure, 
cancer, or death. Rarely, hepatitis C can cause inflammation in other parts of your body, 
including your skin or kidneys. 
If you receive a heart with hepatitis C, we would give you free medicine to treat the 
hepatitis C virus. The treatments for hepatitis C are highly effective. In other studies, 
these medicines have cured more than 95% of patients with chronic hepatitis C. 
However, we do not know whether these medicines will be as effective for someone 
who becomes infected with hepatitis C after a heart transplant. 
Your participation is voluntary which means you can choose whether or not you want to 
participate. If you choose not to participate, your care at Penn and your priority on the 
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heart transplant waiting list will not change. You will receive the usual care for someone 
on the transplant waiting list. 
 
Before you can make your decision, you will need to know what the study is about, the 
possible risks and benefits of being in this study, and what you will have to do in this 
study. The research team is going to talk to you about the research study, and they will 
ask you to read this consent form carefully. You may also decide to discuss it with your 
family, friends, or family doctor. You may find some of the medical language difficult to 
understand. Please ask the study doctor and/or the research team about this form. If 
you decide to participate, you will be asked to sign this form. 
 
What is the purpose of this research study? 
Currently there are over 4,000 people waiting for a heart transplant in the United 
States, but there are only about 2,800 heart transplants from deceased donors 
performed each year. Because there are not enough hearts available for all the people 
who need them, average waiting times for heart transplantation can be more than 6-12 
months, especially for patients with blood types A, B, or O, or for patients who are 
“bigger” (either height or weight).  
 
One potential option to increase the number of available hearts is to allow patients 
without hepatitis C to accept a heart from a donor with hepatitis C. In almost all cases, 
hearts from donors with hepatitis C are not given to patients without hepatitis C.  
 
The purpose of this study is to determine whether it is safe to give recipients without 
hepatitis C, a heart from a donor with hepatitis C. Additionally, this study will evaluate 
whether treatments given after transplant, can cure hepatitis C in individuals who 
receive hearts from donors with hepatitis C.  
 
In this study, recipients who receive a heart infected with hepatitis C will be treated 
with a pill made of Grazoprevir + Elbasvir (Zepatier) after the transplant. These two 
medications are combined in one pill that has recently been approved by the FDA in 
the US for the treatment of chronic hepatitis C in adults. 
 
This study is funded by Merck, the company that makes Zepatier. 
 
How long will I be in the study? How many other people will be in the 
study? 
Participants will be in the study while they wait for a heart transplant (estimated to 
be ~3-6 months but could be shorter or longer) and for approximately 1 year after 
they get a heart transplant to allow us to follow-up the subjects’ health before and 
after transplant. Upon receiving a heart transplant from a hepatitis C-positive 
donor, subjects will be followed until their hepatitis C level is positive.  Treatment 
will commence, with the hepatitis C treatment duration between 12 and 16 weeks 
depending on the exact HCV subtype.  
 
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This study will enroll around 30 patients at the Hospital of the University of 
Pennsylvania (HUP). Of those 30, we anticipate that ten patients will receive a heart 
transplant with hepatitis C. We believe that all the patients who get a transplant will 
become infected with hepatitis C virus and therefore need treatment for hepatitis C 
virus. 
  
What am I being asked to do? 
Your participation in the study involves multiple visits to the Hospital of the University 
of Pennsylvania over a period of up to 6 months after heart transplant (each study visit 
will usually coincide with a regular post-heart transplant visit), and an additional visit 12 
months after your heart transplant. While you are on the waiting list, we will also 
monitor your health. Many of these visits will require collection of blood to be used for 
safety labs (such as blood counts and liver tests), as well as labs to determine the 
amount of hepatitis C virus in your blood (hepatitis C viral load), and special ultrasound 
tests to measure how stiff your liver is.  
 
This study involves three (3) phases: 
 
Phase 1: Screening 
The screening period is the period of time when it is determined if you are eligible to be 
in the study. This will take place before you receive a heart transplant with hepatitis C 
and before you begin treatment with the study drug. During screening, you will review 
and sign this consent prior to any study procedures. Some of the exams, tests, or 
procedures may have already been done as part of your routine care. If you have had 
some of these tests done already, they may not need to be repeated. This decision will 
be up to your study doctor. The screening procedures may take up to 5 hours and 
includes the following: 
• A complete physical exam  
• Review medications 
• Assessment of current health status 
• Blood sample collection 
- to measure blood counts and to test the function of your organs such as 
your hearts and liver  
- for a  pregnancy test (for women who are able to have children) 
- for research purposes (this may include tests to your immune responses) 
 
Phase 2: Waiting List 
Following screening, if you are determined to be eligible for the study, we will change 
your transplant records to show that you are willing and eligible to receive offers for 
hearts from donors with hepatitis C. You will remain on the heart transplant waiting list. 
During that time, you will still be able to receive offers of hearts from donors without 
hepatitis C.  
 
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If you do get an offer of a heart with hepatitis C, we will test the donor to see what 
hepatitis C genotype the donor has. We are only accepting hearts from donors that 
have hepatitis C genotype 1 and 4, because this type of hepatitis C virus is easier to 
treat. The test for hepatitis C genotype is not perfectly accurate, although studies have 
shown that it is >95% accurate. However, all genotypes of hepatitis C can be treated, 
although some genotypes are more difficult to treat than others (although with current 
available therapies, cure rates of ≈90% can be achieved with all genotypes). 
 
If you do get an offer of a heart, you can decide with your doctor whether or not you 
want to accept the heart.  
 
If you do not get a heart transplant from a donor with hepatitis C during the study 
period, or if you get a heart transplant without hepatitis C, then you will not need any 
study related treatments or treatment-related study visits. We will review your medical 
records to monitor your health.  
 
If you do get a heart transplant with hepatitis C, then you will need to come to study 
visits that take place the same day as your regular visit with your doctor. We will closely 
monitor your health. If we detect hepatitis C virus in your blood, then we will treat you 
for the infection. Then you will enter Phase 3 of the study, which we describe next. 
 
Phase 3: Transplantation 
We will monitor your blood for hepatitis C infection. It is possible that some people who 
are infected with hepatitis C from a heart transplant will be able to rid themselves of 
the virus through their own immune system. However, we expect that almost everyone 
in the study who receives a hepatitis C infected heart transplant will become 
chronically infected with the virus. We will begin treatment for hepatitis C as soon as 
we detect the virus in your blood. 
 
Study Drug 
After transplantation, study participants with hepatitis C will receive 12 weeks of 
Zepatier treatment. The study drug includes Grazoprevir + Elbasvir and is given as a 
single combination pill each day. We will supply enough study drugs at each visit to last 
until your next visit. Also, prior to starting the medication, we will check to see if there are 
mutations in the virus. If by chance certain mutations are found, your treatment may be 
lengthened to 16 weeks, instead of the original 12 weeks, in addition to receiving an 
additional medication, Ribavirin, if your heart function allows for it. 
 
If by chance your hepatitis C is not cured after receiving Zepatier for 12 weeks, then you 
will be provided with a second treatment that includes Zepatier, plus 2 additional 
medications which have been used to treat Hepatitis C (Sofosbuvir and Ribavirin) to try 
to cure your hepatitis C infection.  
 
Zepatier works by blocking the hepatitis C virus from multiplying in your body. In studies 
of patients with hepatitis C who had not received a heart transplant, cure rates using 
these medications have been over 95%.  
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The drug will be provided by the manufacturer who is sponsoring the study. 
 
The cure rate of Zepatier has not been established in patients who undergo heart 
transplantation and become infected with hepatitis C from the heart. The safety and 
tolerability of Zepatier after heart transplantation have also not been studied.  However, 
in the event dialysis is needed after your transplant due to acute kidney injury, we do 
know that the cure rates for patients with known hepatitis C and chronic kidney  disease 
(including being on dialysis) are similar to rates of patients without kidney disease.  
 
Zepatier has been approved by the Food and Drug Administration. This drug regimen 
was chosen as first-line therapy for this study rather than other approved agents 
because this investigational agent is unique in that it can be safely used in patients with 
abnormal heart function. As a result, if your heart function has not fully recovered when 
treatment is initiated after transplant, the investigational agents can be safely given to 
you. 
 
Other Medications 
You will continue to take all the other medications prescribed by your doctor during 
the study. Your medication list will be reviewed during the screening visit and 
approved if you are eligible for the study. It is extremely important to provide an 
accurate list of all your medications (prescribed, over-the-counter, and herbal) at each 
visit and to take them as directed. However, we will not supply other medications. 
 
 
Study Visits 1 – 4: The first visit will take place in the hospital during your recovery 
from surgery. Visits 2 – 4 will take place approximately every week - on the same days 
as your heart transplant clinic visits. 
 
Someone from the research team will attempt to contact you before each appointment 
to remind you where to go and relay any special instructions.  
 
During these visits, the following may be performed: 
• Phlebotomy (drawing a blood sample), to measure for presence of the 
hepatitis C virus and to test the virus for mutations (NS5A Resistance 
Testing) that would lead to longer treatment. 
o NS5A Resistance testing is a type of blood test to check for 
mutations in the virus. This test is not approved by the Food and 
Drug Administration (FDA), but is validated by the Clinical 
Laboratory Improvement Amendments (CLIA). CLIA is a 
certification that allows clinical laboratory results to be shared with 
patients. This test is part of routine clinical care, and it is 
“recommended” by the FDA to be used to help guide treatment 
decisions in patients with genotype 1a (a subtype of genotype 1) 
hepatitis C who are being treated with Zepatier. 
• Talk to you about how you feel and perform a physical examination, if 
necessary 
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• Review your medications 
 
If your blood tests show hepatitis C in your blood, we will call you and make 
arrangements for you to start treatment for hepatitis C. We will also notify your 
medical team that you are beginning treatment for hepatitis C. 
 
Study Visits 5 – 9: These visits will take place every two to four weeks - on the same 
days as your heart transplant clinic visits.  
 
Someone from the research team will attempt to contact you before each appointment 
to remind you where to go and relay any special instructions.  
 
You may receive phone calls from research staff in between appointments to confirm 
that you are taking the study drug as prescribed. 
 
The following procedures may be performed:  
• Obtain blood samples to measure for presence of the hepatitis C virus 
• Talk to you about how you feel and perform a physical examination, if 
necessary 
• Review your medications 
• Assess side effects and potential adverse events 
• Count study pills and review drug diary for compliance 
• Provide additional study pills 
 
Research blood samples: Throughout the study, we will collect blood samples to 
measure for presence of the hepatitis C virus. This will be coordinated with blood tests 
for the transplant team. 
 
Additional visits: These will only be necessary if the treatment does not cure you of 
hepatitis C. In that case, we will provide you Zepatier for an additional 12 weeks, and 
add two other hepatitis C  medications (Sofosbuvir and Ribavirin), provided by the 
study investigators. These additional medications should increase the chance of curing 
you of hepatitis C. 
 
Follow-Up Period 
The Follow-up Period is after you have stopped taking the study drug. It is important 
that you return for all follow-up visits so that your health can be reviewed.   
 
Study Visit 10: This will be about 6 months after your transplant. The following 
procedures may be performed: 
 
Obtain blood samples 
 
Review your medications 
 
Assess side effects and adverse events 
 
Assess current health status 
 
Transient elastography (FibroScan®) 
 
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During this visit, your study results will be discussed with you, and as your test results 
become available, someone from the study team will keep you up to date on the status 
of your hepatitis C infection, after treatment 
 
Study Visit 11: This will be about 12 months after your transplant. The following 
procedures may be performed: 
 
Obtain blood samples 
 
Review you medications 
 
Assess current health status 
 
Transient elastography (FibroScan®) 
 
What are the possible risks or discomforts?  
The main risk of this study is that you will become infected with hepatitis C. The main 
potential benefit of this study is that you could get a heart transplant sooner than if you 
only accept offers of hearts from donors without hepatitis C infection. 
 
1. Risks related to transplantation with a hepatitis C heart 
Liver problems 
You should know that it is possible that the treatment for hepatitis C will not work as well 
after a transplant as it has worked in patients who do not have a transplant. It is also 
possible that after heart transplant, a hepatitis C infection could cause you serious 
health problems, including liver failure or death. Hepatitis C can rarely cause severe 
liver inflammation in the first few weeks to months after infection, or the virus can cause 
scarring and failure of your liver over many years.   
 
In the short term, infection with hepatitis C can cause a flu-like illness that includes 
fatigue, nausea, fever, abdominal pain, vomiting, joint pain, and jaundice (yellow skin). 
In very rare circumstances, acute infection with hepatitis C can cause severe 
inflammation or even liver failure, including a condition called fibrosing cholestatic 
hepatitis. The risk of this complication in patients without hepatitis C who receive a 
transplant from a donor with hepatitis C is unknown. This complication can be treated 
and cured in some cases with the medications the investigators will be providing.   
 
Liver failure can cause someone to experience leg swelling, yellow skin, 
uncomfortable feelings of itchiness, bleeding, breathing problems and the abdomen to 
fill with fluid. Liver failure can also cause death. Based on the limited data available, 
we believe that it would be rare for someone in the study to experience liver failure in 
the first months after transplantation, when we would give treatment. However, 
because liver failure is possible, we are only enrolling individuals in this study who 
would potentially be eligible to receive a liver transplant if they developed liver failure 
after a heart transplant, in addition to a clinical evaluation by a liver doctor 
(hepatologist) and liver transplant surgeon, which are not required for a heart 
transplant. 
 
If your hepatitis C cannot be cured with the first-line and second-line treatments 
through this trial, over many years, there may be continued inflammation and scarring 
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of your liver that over many years can lead to cirrhosis and eventually liver failure. 
Longer term infection with hepatitis C increases the risk of developing liver cancer, 
liver failure requiring a liver transplant, or death. 
 
Additional risks of hepatitis C:  
Hepatitis C can cause other types of inflammation in your body, such as arthritis, rash, 
anemia and inflammation damage to your heart transplant. However, these problems 
should respond to effective treatment for the virus. 
 
There may also be a small risk of developing Focal and Segmental Glomerulosclerosis 
(FSGS) after receiving a kidney from a donor with hepatitis C. FSGS is a disease that 
harms the filters of the kidney and causes a patient to lose protein in their urine.  
However, this condition can also develop in patients who do not have hepatitis C. Long 
term, FSGS may cause kidney failure. After transplant, we will monitor all patients for 
conditions like FSGS. We will also offer treatments for FSGS, which can help some 
patients. 
 
Risks of the test used to determine the hepatitis C virus genotype 
In this study, we intend only to transplant organs from patients with a certain type of 
hepatitis C – genotype 1. This type of the virus is easier to cure. There is less than a 
1% chance that the test we use to identify the virus might not be 100% accurate. If the 
test gives the wrong result and you get a heart that has a different genotype of virus in 
it, your chances of being cured may be lower.  
 
2. Risks related to study medication 
Side effects from medication: 
 
When receiving treatment for hepatitis C, you may have side effects. Everyone taking 
part in the study will be watched carefully for any side effects. Side effects may be mild 
or serious. You should talk to your study doctor about any side effects that you 
experience while taking part in the study. If you are injured for any reason while you 
are in the study, you should tell the treating doctor or hospital that you are taking part 
in the study. 
 
Side Effects of Zepatier 
There is a risk of serious and/or life-threatening side effects when non-study 
medications are taken with the study drug. For your safety, you must tell the study 
doctor or nurse about all medications you are taking before you start the study drug 
and also before starting any new medications while in the study. Also, you must tell the 
study doctor or nurse before enrolling in any other clinical trials while in this study. 
In studies, this drug has been generally well tolerated. Risks and side effects related 
to Zepatier include: 
Most Common 
1) Feeling tired or weak, 2) Headache  
 
Less Common 
3) Nausea, 4) Diarrhea, 5) Insomnia, 6) Joint soreness, 7) Itching, 8) Rash,  
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9) Shortness of breath, 10) Anemia (low red blood cell count) 
 
Rare 
11) Abnormal liver function tests suggesting liver inflammation, 12) Abnormal 
pancreas function tests suggesting pancreas inflammation, 13) depression, 14) 
abdominal pain, 15) irritability 
 
Tell your healthcare provider right away if you get any of the following symptoms or if 
they get worse during treatment with Zepatier: 
- 
loss of appetite  
- 
yellowing of your skin or eyes 
- 
nausea and vomiting  
- 
color changes in your stool 
- 
feeling tired or weak 
 
There may be other side effects that have not yet been described including severe 
allergic reaction. It is also possible that taking medications to prevent your immune 
system from rejecting your heart transplant (also known as immunosuppression) at the 
same time as Zepatier might change its effectiveness or side effects. 
 
Resistance of the virus to hepatitis C treatments: 
We do not know how effective Zepatier will be in eliminating hepatitis C after a 
transplant, in your circumstances. Determining the medication’s effectiveness is one 
of the purposes of our study. One of the main risks of participating in this study is the 
possibility that hepatitis C may become resistant to the medication and may limit your 
future treatment options. The likelihood of resistance developing is higher if you skip 
doses or do not follow the study recommendations. If you show possible resistance to 
the study drug by having an increase in your hepatitis C viral load while on treatment, 
you will be asked to return to repeat the hepatitis C viral load test quickly. We may 
change your treatment plan. 
 
Very few people (approximately 5%) have a mutation of a type of hepatitis C that puts 
them at risk for resistance. We will conduct a test to determine if you are at risk for this. 
As with the genotyping test, there is a risk that the test is not 100% accurate. If the test 
gives the wrong result, your chances of being cured may be lower and you may need 
additional treatment. 
 
If you do not respond to treatment with Zepatier after 12 weeks, we will offer you a 
different set of medications (Sofosbuvir and Ribavirin) in addition to another round of 
Zepatier to treat your hepatitis C. It is unknown if this alternative set of medications will 
succeed in curing you of hepatitis C, although the expectation of the investigators is 
that it will likely be successful in curing you of your hepatitis C.  
 
Risks and side effects related to the additional use of Sofosbuvir and Ribavirin include: 
Most Common 
1) Feeling tired or weak, 2) Headache, 3) Nausea/stomach pain, 4) Anemia, 5) 
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Insomnia,  
6) Rash, 7) Itchiness, 8) Shortness of breath 
 
Less Common 
9) Cough, 10) Dry skin, 11) Diarrhea, 12) Vomiting, 13) Low appetite,  
14) Indigestion, 15) Sore muscles, 16) Feeling irritable/depressed, 17) Sore joints, 
18) Nasal irritation, 19) Abnormal liver function tests, 20) Abnormal pancreas 
function tests, 21) Low white blood cell counts, which can increase vulnerability to 
infection, 22) Low platelet counts, which can increase vulnerability to bleeding, 23) 
birth defects from Ribavirin when either the man or woman is currently taking 
Ribavirin at the time of contraception, or had used Ribavirin in the preceding 6 
months. 
 
3. Risks related to study procedures and tests 
Blood Drawing  
The potential risks of the needle stick to draw blood include pain, bruising, 
bleeding, fainting, and infection. Discomfort from this procedure is generally short 
lasting, and serious side effects are extremely rare. Some people experience 
feelings of lightheadedness or dizziness after having blood drawn. The amount of 
blood drawn will be within the limits allowed for adult participants. 
 
Genetic Testing 
Some of the blood drawn from you as part of this study will be used for genetic tests. 
Genetic tests can help researchers learn about potential relationships between 
response to HCV treatment and genetic factors. Human leukocyte antigen (HLA) 
testing will also be completed. This is a genetic test of markers of the immune system.  
We will not release any information about you or your family to relatives, any 
insurance company, employer, or your primary care physician without your written 
permission. There may be a risk that genetic information obtained as a result of 
participation in research could be misused for discriminatory purposes. However, state 
and federal laws provide some protections against genetic discrimination. 
Researchers who will have access to genetic information about you will take 
measures to maintain the confidentiality of your genetic information. Although we are 
committed to confidentiality, a court could still subpoena your medical records. All of 
these issues should be carefully considered before joining the study. 
 
Risk of Stored Samples (Optional) 
If you agree to have samples stored for future research use, there may be 
confidentiality risks associated with the storage and analysis of your samples or the 
information resulting from the analysis of your samples. For example, if future research 
involves genetic testing there's a potential risk associated with the release of private 
health information, though every effort will be made to maintain your confidentiality. 
 
Discovery of health problems during screening 
During screening for this study, we will examine you and perform studies as apart of 
screening. It is possible that by doing these studies, we will identify new health 
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problems that you weren’t aware of. If we discover new health problems, we will answer 
your questions and try to arrange appropriate treatment if any is needed. If new health 
problems are discovered, it is possible that you would not be able to enter this study. It 
is also possible that you would no longer be eligible for heart transplantation based on 
the results.  
 
 
Reproductive risks 
If you do become pregnant, Zepatier may cause problems to your fetus. The risks to a 
fetus or a nursing child are not known at this time, so women who are pregnant or 
nursing a child may NOT join the study.  
 
All women who can have children must have a test that shows they are not pregnant 
before the study drug is given and will be counseled regarding the importance of 
avoiding pregnancy during study treatment, including the use of highly effective 
methods of birth control. Women who can have children must engage in a highly 
effective form of birth control while in the study and six weeks afterwards. We define 
highly effective birth control the same way that the transplant program does. Notably, 
the use of transplant anti-rejection drugs can cause birth defects.  
 
Examples include: 
1) sexual abstinence, or  
2) a vasectomized partner, or   
3) an intrauterine device (IUD), or 
4) a hormonal method such as oral contraceptive pill PLUS a barrier method such as 
a condom, or 
5) Diaphragm with spermicide PLUS a condom 
 
Even if you use birth control there is a small chance that you could become pregnant. 
If you suspect that you have become pregnant, you must notify the study doctor 
immediately. If you become pregnant during the study, it is important that you tell us 
right away.  
 
All men and women in the study who are sexually active must ALSO use a barrier 
method of contraception – such as condoms - while they are in the study and while they 
have hepatitis C. Although it is rare, hepatitis C can sometime be spread through sex. 
Barrier contraception during any sexual activity is important to keep your partner from 
getting infected with the virus.  
 
All men and women who require Ribavirin therapy will be required to use two forms of 
contraceptive therapy while on Ribavirin therapy, and for up to 6 months after the last 
dose of the study drug due to the risk of birth defects from the use of Ribavirin.  Men are 
required to also use birth control because Ribavirin can affect the sperm in a manner 
that can lead to birth defects.  
 
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What if new information becomes available about the study? 
In addition to the risks described above, there may be unknown risks, or risks that were 
not anticipated, associated with being in this study. If new information becomes 
available about the study drug that might affect your willingness to continue participation 
your study doctor will inform you immediately and will discuss with you whether you 
want to continue to participate in the clinical study. 
 
You may be asked to sign a revised consent form if this occurs. You have the right to 
decide either to continue with the clinical study or to withdraw. 
 
What are the possible benefits of the study?  
The main benefit of the study is that you may receive a heart transplant earlier than you 
would have if you chose to wait for a heart without hepatitis C. Receiving a heart 
transplant earlier will lead to clinical benefits as your heart function improves as well as 
improve your quality of life. Also, receiving a heart may increase your overall lifespan 
by decreasing your risk of dying while waiting for a transplant.  
 
What other choices do I have if I do not participate?  
We encourage you to discuss this study with your physician and to explore other 
treatment options. Other treatment options include not enrolling in this study and 
waiting for a heart transplant from a heart donor who does not have hepatitis C. 
 
However, if you decide not to join the study, you may instead remain on the waitlist for 
a longer period of time and suffer health consequences, including death or additional 
complications. 
 
Will I be paid for being in this study? 
You will not receive any form of payment for your participation in this study. 
 
Will I have to pay for anything? 
The heart transplant itself will be paid for by your insurance carrier, and does not require 
any additional pre-authorization because of the potential to receive a heart from a 
hepatitis C-positive donor.  The costs of all visits and tests described above will be billed 
to you or your insurance carrier, except for the blood draw for research purposes (which 
includes the hepatitis C genotype test which is based on a laboratory-developed test 
using materials purchased from the commercial entity that developed this test, and will 
be paid for by the research team), and the study drug, which will be paid for by the 
study funder. You are still responsible for any deductibles or applicable co-pays for 
routine office visits, blood work and procedures. Please talk to your doctor and study 
team about putting you in touch with a financial counselor to determine exactly what the 
deductible and co-pay will be for you; this is highly variable depending on your type of 
insurance.  
 
What happens if I am injured from being in the study?   
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If you become sick or injured as a direct result of taking the study product(s) the 
Hospital of the University of Pennsylvania will provide you with medical treatment.  The 
Sponsor, the University of Pennsylvania, will reimburse you for the reasonable and 
necessary costs of such medical treatment.  No other form of reimbursement for study-
related injury or illness is offered by the Sponsor.  You should immediately contact your 
Study Doctor at the contact information shown on the first page of this form, in the event 
you experience any study-related illness or injury. 
 
If you receive Medicare benefits, the Sponsor, the University of Pennsylvania, is 
required by law to report payments made to you for treatment, complications, and 
injuries that arise from this Study.  Information that you are taking part in the Study, 
medical treatments received, Medicare claims, and other personal information about 
you such as your name, social security number, and date of birth, will be provided to the 
Centers of Medicare and Medicaid Services and its agents and/or contractors for this 
purpose. 
 
You do not give up your legal rights by signing this form.   
 
If you think you have been injured as a result of taking part in this research study, tell 
the person in charge of the research study as soon as possible. The researcher’s name 
and phone number are listed at the beginning of the consent form. 
 
We are committed to offering you with treatment for hepatitis C infection during the 
study. We expect that these treatments are likely to cure you of the infection. However, 
it is possible that treatment will not cure the infection and that you would develop health 
complications. Once the study ends, we would expect you to seek appropriate 
treatments for hepatitis C infection through your insurance or private means. 
 
When is the Study over? Can I leave the Study before it ends? 
This study is expected to end after all participants have completed all visits, and all 
information has been collected. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely. It is 
important to tell the study doctor if you are thinking about stopping so that your doctor 
can evaluate any risks and discuss what alternative follow-up care and testing could be 
most helpful for you. 
 
Reasons for Stopping Study Medication 
If you are not responding to the study medication (checked frequently by measuring 
the levels of hepatitis C in your blood) or develop a potential life threatening 
complication from the medication, we will stop the study medications completely. 
However, you will still be followed but less frequently. Regardless of the stage of liver 
disease, the recommendations are to treat hepatitis C if medically possible, however 
some physicians might choose to wait and not treat in the immediate future. 
 
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Reasons for Withdrawal or Study Discontinuation 
Your involvement in this study is entirely up to you. You may leave the study at any 
time and for any reason. Withdrawal will not interfere with your future care. If 
you decide to leave, we may ask you to return for a final visit to perform tests and 
exams to ensure safety. However, you will not be required to return for this visit. 
 
You may be discontinued from the study (taken off the study without our asking for your 
permission) if: 
• You become pregnant while undergoing treatment with Zepatier. Therapy will be 
stopped as there are no safety data of Zepatier during pregnancy.  Patients will 
continue with the regularly scheduled study visits, but will not be eligible to 
receive continued Zepatier therapy. 
• We cannot locate you, or if you miss multiple visits or study drug doses. 
• You develop a condition that it is life threatening or any other significant risk as 
judged by the Investigators. 
• We or your primary care provider believe that it is in your best interest to 
stop taking the study medications even if the criteria required for stopping 
treatment have not been met. 
• Zepatier is no longer produced by the company, or if a decision is made to stop 
the study. 
 
Who can see or use my information? How will my personal 
information be protected?   
Your medical records will be kept confidential to the extent allowed by the law. Your 
name or any other data that might identify you will not be used in any reports or 
publications resulting from this study. Because of your consent to participate, your 
medical records may be reviewed by the study Sponsor and by Penn’s Institutional 
Review Board (the group that is responsible for making sure that the study follows 
the guidelines for the protection of human research subjects) with the understanding 
that these records will be used only in connection with carrying out obligations relating 
to this clinical study. We will also give information about you to your personal doctors. 
You may change doctors whenever you like, but we need to have a doctor with whom 
we can communicate about you. We would not ask your permission for each of these 
contacts. 
 
Data from this study will be entered into a computerized database through a secured 
website. Only authorized personnel using a password will be permitted to enter and 
access data. You will not be identified by name, social security number, or medical 
record number in the study database. Each patient will be assigned a unique study ID 
code for identification. Records linking the study ID code with any personal identification 
information will be kept by the study team in a locked area. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as 
required by the U.S. Law. This web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this web 
site at any time. 
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Electronic Medical Records and Research Results  
What is an Electronic Medical Record?  
An Electronic Medical Record (EMR) is an electronic version of the record of your care 
within a health system. An EMR is simply a computerized version of a paper medical 
record.   
 
If you are receiving care or have received care within the University of Pennsylvania 
Health System (UPHS) (outpatient or inpatient) and are participating in a University of 
Pennsylvania research study,  results of research-related procedures (i.e., laboratory 
tests, imaging studies, and clinical procedures) may be placed in your existing EMR 
maintained by UPHS.   
 
Once placed in your EMR, these results are accessible to appropriate UPHS workforce 
members that are not part of the research team. Information within your EMR may also 
be shared with others who are determined by UPHS to be appropriate to have access to 
your EMR (e.g., health insurance company, disability provider).  
 
What information about me may be collected, used, or shared with 
others?   
The following personal health information will be collected, used for research, and may 
be disclosed during your involvement with this research study:  
• Personal medical history 
• Current and past medications or therapies 
• Information from a physical examination that generally also includes your weight,  
blood pressure reading, heart rate, breathing rate and temperature 
• Results of tests and procedures you will undergo during this research study as 
described in the informed consent form. 
• Social security number for the purpose of reimbursement for certain expenses 
such as parking 
• Medical record number 
• Any other unique identifying number (such as study ID number linked with your 
medical records in a separate research file) 
• Dates directly related to you, such as your birthdate, dates of hospitalizations, 
tests, and procedures 
• Name, telephone number, fax number, and email addresses may be collected in 
order to contact you 
 
Why is my information being used? 
Your information is used by the research team to contact you during the study. Your 
information and results of tests and procedures are used to: 
• Do the research 
• Oversee the research 
• To see if the research was done the right way. 
 
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Who may use and share information about me?   
The following individuals may use or share your information for this research study: 
• The Principal Investigators and the Investigators’ study team  
• Authorized members of the workforce of the UPHS and the School of Medicine, 
and University of Pennsylvania support offices, who may need to access your 
information in the performance of their duties (for example: for research oversight 
and monitoring, to provide treatment, to manage accounting or billing matters, 
etc.).  
 
Who, outside of the School of Medicine, might receive my 
information? 
As part of the study, the Principal Investigator, the study team and others listed above, 
may disclose your personal health information, including the results of the research 
study tests and procedures. This information may be disclosed to those listed below: 
 
Individuals or organizations responsible for administering the study:  
• Your information will be sent to Merck, its authorized representatives, and the FDA. 
Merck and its study representatives monitoring the study will periodically review 
medical and research records to insure integrity of the data being collected. Your 
information will also be sent to labs performing analyses for the study. 
• All research centers participating in the study, even if they are not a part of the 
School of Medicine, may receive information about your medical record but this 
information will not include any confidential identifying information about you. 
 
Regulatory and safety oversight organizations 
• The Food and Drug Administration 
• The Office of Human Research Protections 
 
Once your personal health information is disclosed to others outside the School of 
Medicine, it may no longer be covered by federal privacy protection regulations.   
 
The Principal Investigators or study staff will inform you if there are any additions to the 
list above during your active participation in the trial. Any additions will be subject to 
University of Pennsylvania procedures developed to protect your privacy. 
 
City of Philadelphia Health Department/PA Department of Health 
If you test positive for Hepatitis C, by law we have to report the infection to the City of 
Philadelphia Health Department/PA Department of Health. We would report your name, 
gender, racial/ethnic background, and the month and year you were born. This is to 
keep track of how many people in the U.S. have HCV infection. It is also to make sure 
that states get enough money from the federal government to support the medical care 
of people living with HCV. The Health Department does not share the names of HCV 
infected people with anyone else. It removes all personal identifiers, such as your name, 
before giving information on the number of HCV infections to the federal government. 
 
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How long may the School of Medicine use or disclose my personal 
health information?   
Your authorization for use of your personal health information for this specific study 
does not expire.  
 
Your information may be held in a research database. However, the School of Medicine 
may not re-use or re-disclose information collected in this study for a purpose other than 
this study unless: 
• You have given written authorization  
• The University of Pennsylvania’s Institutional Review Board grants permission 
• As permitted by law  
 
Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose your health 
information at any time. You do this by sending written notice to the investigators for the 
study. If you withdraw your permission, you will not be able to stay in this study. 
 
What if I decide not to give permission to use and give out my health 
information? 
Then you will not be able to be in this research study. You will be given a copy of this 
Research Subject HIPAA Authorization describing your confidentiality and privacy rights 
for this study.  
 
By signing this document, you are permitting the School of Medicine to use and disclose 
personal health information collected about you for research purposes as described 
above. 
 
Who can I call with questions, complaints or if I’m concerned about 
my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this 
research study or if you have any questions about your rights as a research subject, you 
should speak with the Principal Investigators listed on page one of this form. If a 
member of the research team cannot be reached or you want to talk to someone other 
than those working on the study, you may contact the Office of Regulatory Affairs with 
any question, concerns, or complaints at the University of Pennsylvania by calling 
(215) 898-2614. 
 
 
 
 
 
 
 
 
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When you sign this form, you are agreeing to take part in this research study. This 
means that you have read the consent form, your questions have been answered, and 
you have decided to volunteer. Your signature also means that you are permitting the 
University of Pennsylvania to use your personal health information collected about you 
for research purposes within our institution. You are also allowing the University of 
Pennsylvania to disclose that personal health information to outside organizations or 
people involved with the operations of this study. 
 
A copy of this consent form will be given to you.  
 
 
_____________________________    ___________________________   _________ 
Printed Name of Subject 
 
         Signature of Subject 
 
 
 
Date 
 
 
 
_____________________________     ___________________________   _________ 
Printed Name of Person Obtaining Consent 
Signature 
 
 
 
 
Date 
   
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Stored Samples and Future Research (Optional) 
If you agree to participate in this study, you may also agree to let us store your 
samples for future research. These stored samples may help us learn more about 
hepatitis C. We will label your stored samples with a code that only the study team 
can link to you. We will keep any information that can be traced back to you as 
private as possible. If you change your mind and decide you do not want us to store 
your samples, please contact us. We will do our best to comply with your request, but 
cannot guarantee that we will always be able to destroy all your samples. 
 
We might send your samples to other investigators for their research, without any 
information that can identify you. We might also share information such as your sex, 
age, health history, or ethnicity. We will not sell your samples and you will not be paid 
for any products that result from the research. Some future studies may need health 
information (such as smoking history or present health status) that we don’t already 
have. If so, our study team will contact you. Future research that uses your samples 
will probably not help you, but it may help us learn more about how to treat or prevent 
hepatitis C and other health problems. In general, the research tests we perform are 
not like routine medical tests, and may not relate directly to your medical care. 
        
 
 
Check box if you are willing to allow the study team to take and store a 
sample of your blood for future genetic testing. 
 
Check box if you are willing to allow the study team to share your blood 
samples with other research teams to learn about hepatitis C virus. The 
blood samples, if shared, would not be labelled with your personal 
information. 
 
 
_____________________________    ___________________________   _________ 
Printed Name of Subject 
 
         Signature of Subject 
 
 
 
Date 
 
 
 
_____________________________     ___________________________   _________ 
Printed Name of Person Obtaining Consent 
Signature 
 
 
 
 
Date 
 
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FORMULARIO DE AUTORIZACIÓN EN VIRTUD 
DE HIPAA (LEY DE TRANSFERENCIA Y 
RESPONSABILIDAD DE LOS SEGUROS DE 
SALUD) Y CONSENTIMIENTO INFORMADO 
PARA SUJETOS DE INVESTIGACIÓN DE LA 
UNIVERSIDAD DE PENSILVANIA 
 
Título del 
protocolo:   
Estudio abierto de Zepatier para el tratamiento de 
pacientes que no padecen de hepatitis C y reciben 
trasplantes cardíacos de donantes que padecen de 
hepatitis C (USHER) 
Patrocinador: 
Universidad de Pensilvania (University of Pennsylvania) 
Proveedor de 
fondos: 
Merck & Co. 
Investigador 
principal: 
David Goldberg, MD, MSCE 
(215) 746-8598 
Coinvestigador 
principal: 
Peter Reese, MD, MSCE 
(215) 900-3782 
Rhondalyn Forde-McLean, MD, MHS 
(215) 662-2727 
Coordinadora 
del estudio: 
Anna Sicilia, BS 
(215) 746-7105 
Contacto de 
emergencia: 
Números de teléfono de emergencia las 24 horas 
Dr. Reese: (215) 900-3782 | Dr. Goldberg: (646) 242-6349 
(215) 662-6200. Solicite hablar con el coordinador de trasplante 
cardíaco de guardia. 
 
¿Por qué me solicitan ser voluntario? 
Se le solicita que participe en este estudio debido a que se estima que usted debe 
esperar de 6 a 12 meses o más para recibir un trasplante cardíaco.   
 
Le solicitamos que considere participar en un estudio en el que se ofrecerán corazones 
con hepatitis C a personas como usted, que no tienen hepatitis C. La hepatitis C es un 
virus que infecta el hígado, y en el transcurso de muchos años (de 10 a 30) puede 
causar fibrosis cicatricial hepática y derivar en fibrosis hepática en fase terminal 
(llamada “cirrosis”), lo que podría ocasionar insuficiencia hepática, cáncer o la muerte. 
En raras ocasiones, la hepatitis C puede causar inflamación en otras partes del cuerpo, 
incluso en la piel o en los riñones. 
 
Si usted recibiera un corazón con hepatitis C, le daríamos medicamentos gratis para 
tratar el virus de la hepatitis C. Los tratamientos para la hepatitis C son sumamente 
eficaces. En otros estudios, estos medicamentos han curado a más del 95 % de los 
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pacientes con hepatitis C crónica. Sin embargo, no sabemos si esos medicamentos 
serán tan eficaces para una persona que se infecta con hepatitis C después de un 
trasplante cardíaco. 
Su participación es voluntaria, lo que significa que usted puede decidir si desea 
participar o no. Si decide no participar, su atención en Penn y su prioridad en la lista de 
espera de trasplante cardíaco no se verán afectadas. Recibirá el tratamiento habitual 
para una persona que se encuentra en la lista de espera de un trasplante. 
 
Antes de tomar su decisión, necesitará saber de qué se trata el estudio, los posibles 
riesgos y beneficios de participar en este estudio, y qué tendrá que hacer durante el 
estudio. El equipo de investigación hablará con usted sobre el estudio de investigación 
y le solicitarán que lea con atención este formulario de consentimiento. También puede 
decidir conversarlo con su familia, sus amigos y su médico de cabecera. Es posible que 
algunos términos médicos le resulten difíciles de entender. Pregúntele al médico del 
estudio o al equipo de investigación sobre el contenido de este formulario. Si decide 
participar, se le solicitará que firme este formulario. 
 
¿Cuál es el propósito de este estudio de investigación? 
Actualmente, hay más de 4000 personas en los Estados Unidos que esperan un 
trasplante cardíaco, pero solo se realizan 2800 trasplantes cardíacos por año con 
donantes fallecidos. Debido a que no hay suficientes corazones disponibles para 
todas las personas que los necesitan, el tiempo de espera promedio para un 
trasplante cardíaco puede ser de 6 a 12 meses o más, especialmente para pacientes 
con grupos sanguíneos A, B u O, o para pacientes de más estatura o peso.  
 
Una posible opción para aumentar la cantidad de corazones disponibles es permitirles 
a los pacientes sin hepatitis C aceptar un corazón de un donante con hepatitis C. En la 
mayoría de los casos, los corazones de donantes con hepatitis C no se dan a 
pacientes sin hepatitis C.  
 
El propósito de este estudio es determinar si es seguro dar un corazón de un donante 
con hepatitis C a un receptor sin hepatitis C. Además, este estudio evaluará si los 
tratamientos administrados después del trasplante pueden curar la hepatitis C en 
personas que han recibido el corazón de un donante con hepatitis C.  
 
En este estudio, a las personas que reciban un corazón infectado con hepatitis C se 
les dará como tratamiento un comprimido de grazoprevir + elbasvir (Zepatier) después 
del trasplante. Esos dos medicamentos combinados en un comprimido han recibido 
recientemente la aprobación de la Administración de Alimentos y Medicamentos (Food 
and Drug Administration, FDA) en los EE. UU. para el tratamiento de la hepatitis C 
crónica en adultos. 
 
Este estudio está financiado por Merck, la compañía que elabora Zepatier. 
 
¿Cuánto tiempo tendré que participar en el estudio? ¿Cuántos 
participantes habrá en el estudio? 
Los participantes permanecerán en el estudio durante el tiempo de espera de un 
trasplante cardíaco (se estima un período aproximado de 3 a 6 meses, pero puede ser 
más breve o más prolongado) y durante aproximadamente 1 año después de haber 
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recibido el trasplante, a fin de permitir el seguimiento de su estado de salud antes y 
después del trasplante. Una vez que los sujetos reciban un trasplante cardíaco de un 
donante con hepatitis C, se les realizará un seguimiento hasta que su nivel de 
hepatitis C sea positivo. En ese momento comenzará el tratamiento para la hepatitis C, 
que durará entre 12 y 16 semanas según el subtipo específico del virus de la 
hepatitis C que tengan.  
 
En este estudio se inscribirá aproximadamente a 30 pacientes en el Hospital de la 
Universidad de Pensilvania (Hospital of the University of Pennsylvania, HUP). 
Prevemos que, de esos 30 pacientes, diez recibirán un trasplante de corazón con 
hepatitis C. Consideramos que todos los pacientes que reciban un trasplante se 
infectarán con el virus de la hepatitis C y, por consiguiente, necesitarán tratamiento 
para el virus de la hepatitis C. 
  
¿Qué me piden que haga? 
Su participación en el estudio implicará varias visitas al Hospital de la Universidad de 
Pensilvania durante un período de hasta 6 meses después del trasplante cardíaco 
(cada visita del estudio generalmente coincidirá con una visita habitual posterior al 
trasplante cardíaco), y una visita adicional a los 12 meses de haber recibido el 
trasplante cardíaco. Mientras usted esté en la lista de espera, también controlaremos 
su estado de salud. Muchas de esas visitas requerirán la obtención de sangre para 
realizar análisis de seguridad (como análisis de sangre y hepáticos) y análisis para 
determinar el nivel del virus de la hepatitis C en la sangre (carga viral de la 
hepatitis C), así como pruebas especiales con ultrasonido para medir la rigidez del 
hígado.  
 
Este estudio comprende tres (3) fases: 
 
Fase 1: Selección 
En el período de selección se determina si usted reúne los requisitos necesarios para 
participar en el estudio. Esta fase tiene lugar antes de que usted reciba un trasplante de 
corazón con hepatitis C y antes de que comience el tratamiento con el medicamento 
del estudio. En la selección, usted deberá leer y firmar este consentimiento antes de 
iniciar cualquier procedimiento del estudio. Es posible que ya le hayan hecho algunos 
de los exámenes, análisis o procedimientos como parte de su atención habitual. Si ya 
le han hecho algunos de esos estudios, es posible que no tengan que repetirse. La 
decisión dependerá del médico del estudio. Los procedimientos de la selección pueden 
durar hasta 5 horas e incluyen lo siguiente: 
• Un examen físico completo.  
• Revisión de los medicamentos. 
• Evaluación del estado actual de salud. 
• Obtención de muestras de sangre: 
- para medir los recuentos sanguíneos y evaluar la función de órganos 
como el corazón y el hígado;  
- para una prueba de embarazo (en las mujeres que pueden tener hijos); 
- con fines de investigación (esto podría incluir análisis para evaluar las 
respuestas inmunitarias). 
 
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Fase 2: Lista de espera 
Después de la selección, si se determina que usted cumple con los requisitos 
necesarios para participar en el estudio, modificaremos sus registros de trasplante 
para establecer que usted acepta y es elegible para recibir ofrecimientos de 
corazones de donantes con hepatitis C. Usted permanecerá en la lista de espera para 
el trasplante cardíaco. Durante ese período, aún podrá recibir ofrecimientos de 
corazones de donantes sin hepatitis C.  
 
Si recibe el ofrecimiento de un corazón con hepatitis C, haremos análisis para 
determinar el genotipo de la hepatitis C del donante. Solamente aceptamos corazones 
de donantes que tengan los genotipos 1 y 4 de hepatitis C, porque esos tipos del virus 
de la hepatitis C son más fáciles de tratar. El análisis del genotipo de la hepatitis C no 
es totalmente exacto; sin embargo, los estudios han demostrado que tiene una 
precisión >95 %. No obstante, todos los genotipos de la hepatitis C pueden tratarse, 
aunque algunos genotipos son más difíciles de tratar que otros (pero con los 
tratamientos disponibles en la actualidad, pueden lograrse tasas de curación de 
aproximadamente el 90 % con todos los genotipos). 
 
Si usted recibe el ofrecimiento de un corazón, puede decidir con el médico si desea 
aceptarlo o no.  
 
Si usted no recibe un trasplante cardíaco de un donante con hepatitis C durante el 
período del estudio, o si recibe un trasplante de corazón sin hepatitis C, no necesitará 
ningún tratamiento relacionado con el estudio ni ninguna visita del estudio relacionada 
con el tratamiento. Revisaremos sus registros médicos para controlar su salud.  
 
Si recibe un trasplante de corazón con hepatitis C, deberá asistir a las visitas del 
estudio que tienen lugar el mismo día que su visita habitual con el médico. 
Supervisaremos con atención su estado de salud. Si detectamos el virus de la 
hepatitis C en su sangre, le daremos un tratamiento para la infección. En ese 
momento ingresará a la fase 3 del estudio, que se describe a continuación. 
 
Fase 3: Trasplante 
Le controlaremos la sangre para detectar la infección por hepatitis C. Es posible que 
algunas personas infectadas con hepatitis C por un trasplante cardíaco puedan 
eliminar el virus por sí solas mediante el sistema inmunitario. Sin embargo, prevemos 
que casi todas las personas del estudio que reciban un trasplante de corazón 
infectado con hepatitis C se infectarán con el virus de manera crónica. Iniciaremos el 
tratamiento para la hepatitis C tan pronto como detectemos el virus en su sangre. 
 
Medicamento del estudio 
Después del trasplante, los participantes del estudio que tengan hepatitis C recibirán un 
tratamiento de 12 semanas con Zepatier. El medicamento del estudio consiste en 
grazoprevir + elbasvir y se administra en un único comprimido combinado por día. En 
cada visita, le proporcionaremos una cantidad suficiente del medicamento del estudio 
para que le dure hasta su próxima visita. Asimismo, antes de comenzar con el 
medicamento, le haremos un control para determinar si hubo mutaciones del virus. Si 
se hallan ciertas mutaciones, su tratamiento podría extenderse hasta 16 semanas en 
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lugar de 12, y además recibirá un medicamento adicional, ribavirina, si su función 
cardíaca lo permite. 
 
Si la hepatitis C no se cura tras haber recibido Zepatier durante 12 semanas, recibirá 
un segundo tratamiento que incluye Zepatier más 2 medicamentos adicionales que se 
utilizan para tratar la hepatitis C (sofosbuvir y ribavirina) a fin de curar la infección  
por hepatitis C.  
 
Zepatier actúa evitando que el virus de la hepatitis C se multiplique en el organismo. En 
estudios de pacientes con hepatitis C que no han recibido un trasplante cardíaco, las 
tasas de curación con dichos medicamentos han sido superiores al 95 %.  
 
El medicamento será provisto por el fabricante que patrocina el estudio. 
 
La tasa de curación de Zepatier no se ha establecido en pacientes que se someten a 
un trasplante cardíaco y se infectan con hepatitis C por el corazón. Tampoco se ha 
estudiado la seguridad y tolerabilidad de Zepatier después de un trasplante cardíaco. 
Sin embargo, en caso de que necesite diálisis después del trasplante debido a una 
insuficiencia renal aguda, sabemos que las tasas de curación en pacientes con 
hepatitis C y enfermedad renal crónica (incluso en diálisis) conocidas son similares a 
las tasas de pacientes sin enfermedad renal.  
 
Zepatier ha sido aprobado por la Administración de Alimentos y Medicamentos (FDA). 
Se eligió este régimen farmacológico como tratamiento de primera línea para este 
estudio, en lugar de otros medicamentos aprobados, debido a que este medicamento 
en investigación es único en cuanto a que puede usarse de manera segura en 
pacientes con funcionamiento cardíaco anormal. En consecuencia, si su 
funcionamiento cardíaco no se ha recuperado plenamente al inicio del tratamiento 
después del trasplante, podrá recibir de manera segura los medicamentos en 
investigación. 
 
Otros medicamentos 
Durante el estudio, seguirá tomando todos los otros medicamentos indicados por el 
médico. En la visita de selección, se revisará la lista de medicamentos que toma y se 
aprobará si usted cumple con los requisitos necesarios para participar en el estudio. 
Es sumamente importante que en cada visita proporcione la lista exacta de todos los 
medicamentos que toma (con receta, de venta libre y de hierbas) y que tome su 
medicación según lo indicado. Sin embargo, no proporcionaremos otros 
medicamentos. 
 
 
Visitas 1 a 4 del estudio: La primera visita tendrá lugar en el hospital durante su 
recuperación de la cirugía. Las visitas 2 a 4 tendrán lugar aproximadamente cada 
semana, los mismos días que sus visitas a la clínica por el trasplante cardíaco. 
 
Un integrante del equipo de investigación intentará comunicarse con usted antes de 
cada cita para recordarle dónde debe ir y proporcionarle las instrucciones especiales 
que correspondan.  
 
Durante esas visitas, es probable que se realice lo siguiente: 
• Flebotomía (obtención de una muestra de sangre), para medir la 
presencia del virus de la hepatitis C y determinar si hubo mutaciones del 
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virus (análisis de resistencia a NS5A), lo que podría requerir un 
tratamiento más prolongado. 
o Los análisis de resistencia a NS5A son un tipo de análisis de 
sangre para detectar mutaciones del virus. Este análisis no está 
aprobado por la Administración de Alimentos y Medicamentos 
(FDA), pero está validado por las Enmiendas para la Mejora de 
los Laboratorios Clínicos (Clinical Laboratory Improvement 
Amendments, CLIA). Las CLIA son una certificación que permite 
que los resultados de los laboratorios clínicos se compartan con 
los pacientes. Este análisis es parte de la atención clínica de 
rutina, y está recomendado por la FDA para que se utilice con el 
fin de orientar las decisiones sobre el tratamiento en pacientes 
con hepatitis C de genotipo 1a (un subtipo del genotipo 1) que 
reciben tratamiento con Zepatier. 
• Le preguntarán cómo se siente y le realizarán un examen físico, si es 
necesario. 
• Revisión de sus medicamentos. 
 
Si los análisis de sangre demuestran que usted tiene hepatitis C, lo llamaremos y 
haremos arreglos para que inicie el tratamiento contra la hepatitis C. También le 
notificaremos a su equipo médico que usted va a comenzar el tratamiento contra la 
hepatitis C. 
 
Visitas 5 a 9 del estudio: Estas visitas tendrán lugar aproximadamente cada dos a 
cuatro semanas, los mismos días que sus visitas a la clínica por el trasplante 
cardíaco.  
 
Un integrante del equipo de investigación intentará comunicarse con usted antes de 
cada cita para recordarle a dónde debe ir y proporcionarle las instrucciones 
especiales que correspondan.  
 
Es posible que, entre las citas, reciba llamadas telefónicas del personal de 
investigación para confirmar que usted está tomando el medicamento del estudio 
según lo indicado. 
 
Es probable que se realicen los siguientes procedimientos:  
• Obtención de muestras de sangre para medir la presencia del virus de la 
hepatitis C. 
• Le preguntarán cómo se siente y le realizarán un examen físico, si es 
necesario. 
• Revisión de sus medicamentos. 
• Evaluación de efectos secundarios y posibles eventos adversos. 
• Recuento de los comprimidos del medicamento del estudio y revisión del 
registro diario de medicamentos, con fines de cumplimiento. 
• Provisión de comprimidos adicionales del medicamento del estudio. 
 
Muestras de sangre con fines de investigación: Durante todo el estudio, 
obtendremos muestras de sangre para medir la presencia del virus de la hepatitis C. 
Esto se coordinará con los análisis de sangre para el equipo de trasplante. 
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Visitas adicionales: Las visitas adicionales solo serán necesarias si el tratamiento no 
cura la hepatitis C. En ese caso, le proporcionaremos Zepatier durante 12 semanas 
adicionales, y añadiremos otros dos medicamentos para la hepatitis C (sofosbuvir y 
ribavirina), provistos por los investigadores del estudio. Esos dos medicamentos 
adicionales deberían aumentar las probabilidades de curar la hepatitis C. 
 
Período de seguimiento 
El período de seguimiento comenzará cuando usted haya dejado de tomar el 
medicamento del estudio. Es importante que asista a todas las visitas de seguimiento 
para que puedan revisar su estado de salud. 
 
Visita 10 del estudio: Tendrá lugar 6 meses después del trasplante. Es probable que 
se realicen los siguientes procedimientos: 
 
Obtención de muestras de sangre. 
 
Revisión de sus medicamentos. 
 
Evaluación de efectos secundarios y eventos adversos. 
 
Evaluación del estado de salud actual. 
 
Elastografía de transición (FibroScan®). 
 
Durante esta visita, se analizarán con usted los resultados del estudio y, a medida que 
los resultados de sus análisis estén disponibles, un integrante del equipo del estudio lo 
mantendrá al corriente sobre el estado de la infección por hepatitis C después del 
tratamiento. 
 
Visita 11 del estudio: Tendrá lugar aproximadamente 12 meses después del 
trasplante. Es probable que se realicen los siguientes procedimientos: 
 
Obtención de muestras de sangre. 
 
Revisión de sus medicamentos. 
 
Evaluación del estado de salud actual. 
 
Elastografía de transición (FibroScan®). 
 
¿Cuáles son los posibles riesgos o molestias?  
El riesgo principal de este estudio es que usted se infecte con hepatitis C. El posible 
beneficio principal de este estudio es que usted podría recibir un trasplante cardíaco 
con menos demora que si solo aceptara ofrecimientos de donantes sin hepatitis C. 
 
1. Riesgos relacionados con el trasplante de un corazón con hepatitis C 
Problemas hepáticos 
Usted debe saber que es posible que el tratamiento para la hepatitis C después de un 
trasplante no sea tan efectivo como lo ha sido en pacientes que no tienen un trasplante. 
También es posible que, después del trasplante cardíaco, la infección por hepatitis C le 
cause problemas graves de salud, que incluyen insuficiencia hepática o la muerte. En 
raras ocasiones, la hepatitis C puede causar inflamación hepática grave durante las 
primeras semanas o meses posteriores a la infección, u ocasionar fibrosis e 
insuficiencia hepática después de muchos años. 
 
A corto plazo, la infección por hepatitis C puede causar una enfermedad similar a la 
gripe, que causa fatiga, náuseas, fiebre, dolor abdominal, vómitos, dolor en las 
articulaciones e ictericia (piel amarillenta). En muy raras circunstancias, la infección 
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aguda por hepatitis C puede ocasionar inflamación hepática grave o, incluso, 
insuficiencia hepática, incluido un trastorno llamado “hepatitis colestásica fibrosante”. 
Se desconoce el riesgo de padecer esta complicación en pacientes sin hepatitis C que 
reciben un trasplante de un donante con hepatitis C. En algunos casos, esta 
complicación puede tratarse y curarse con los medicamentos que le proporcionarán los 
investigadores. 
 
La insuficiencia hepática puede ocasionar hinchazón de las piernas, piel amarillenta, 
sensación molesta de picazón, sangrado, problemas respiratorios y acumulación de 
líquido en el abdomen. La insuficiencia hepática también puede causar la muerte. 
Sobre la base de los datos limitados disponibles, consideramos que sería inusual que 
un participante del estudio presentara insuficiencia hepática en los primeros meses 
posteriores al trasplante, mientras esté recibiendo el tratamiento que nosotros 
proporcionamos. Sin embargo, dada la posibilidad de una insuficiencia hepática, 
solamente inscribimos en este estudio a personas que podrían ser posibles 
receptoras de un trasplante de hígado en caso de que presentaran insuficiencia 
hepática después de un trasplante cardíaco; además, un médico especialista en el 
hígado (hepatólogo) y un cirujano de trasplantes hepáticos le realizarán una 
evaluación clínica que no se requiere para un trasplante cardíaco. 
 
Si la hepatitis C no puede curarse con los tratamientos de primera y de segunda línea 
durante este estudio, al cabo de muchos años podría producirse una inflamación 
continua y fibrosis cicatricial del hígado, que con el trascurso de muchos años puede 
derivar en cirrosis y, posteriormente, en insuficiencia hepática. La infección por 
hepatitis C a largo plazo aumenta el riesgo de cáncer de hígado, de insuficiencia 
hepática que requiere un trasplante de hígado, o de muerte. 
 
Riesgos adicionales de la hepatitis C:  
La hepatitis C puede causar otros tipos de inflamación en el cuerpo, como artritis, 
erupción, anemia y daño inflamatorio en el corazón trasplantado. Sin embargo, esos 
problemas deben responder a un tratamiento eficaz para el virus. 
 
También podría existir un pequeño riesgo de que se presente glomeruloesclerosis 
focal y segmentaria (Focal and Segmental Glomerulosclerosis, FSGS) después de 
recibir un riñón de un donante con hepatitis C. La FSGS es una enfermedad que daña 
los filtros del riñón y provoca la pérdida de proteína en la orina. Sin embargo, esta 
enfermedad también puede presentarse en pacientes que no tienen hepatitis C. A 
largo plazo, la FSGS puede causar insuficiencia renal. Después del trasplante, 
controlamos a todos los pacientes para detectar posibles afecciones como la FSGS. 
También ofreceremos tratamientos para la FSGS, lo que puede ayudar a algunos 
pacientes. 
 
Riesgos del análisis utilizado para determinar el genotipo del virus de la 
hepatitis C 
En este estudio, solamente trasplantamos órganos de pacientes con un determinado 
tipo de hepatitis C: la de genotipo 1. Ese tipo del virus es más fácil de curar. Existe 
una probabilidad inferior al 1 % de que el análisis que utilicemos para identificar el 
virus no tenga una precisión del 100 %. Si el análisis arroja un resultado erróneo y 
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usted recibe un corazón con un genotipo diferente del virus, las probabilidades de 
cura podrían ser menores.  
 
2. Riesgos relacionados con el medicamento del estudio 
Efectos secundarios del medicamento: 
 
Cuando reciba tratamiento para la hepatitis C, es posible que sufra efectos 
secundarios. Se controlará rigurosamente a todos los participantes del estudio para 
detectar posibles efectos secundarios. Los efectos secundarios pueden ser leves o 
graves. Debe hablar con el médico del estudio sobre cualquier efecto secundario que 
usted presente durante su participación en el estudio. Si se lesiona por alguna razón 
durante su participación en el estudio, debe comunicarle al médico o al hospital 
tratante que usted está participando en el estudio. 
 
Efectos secundarios de Zepatier 
Si se toman medicamentos que no son del estudio junto con el medicamento del 
estudio, existe el riesgo de que se presenten efectos secundarios graves o que 
pongan en riesgo la vida. Por su seguridad, infórmele al médico del estudio o al 
enfermero del estudio todos los medicamentos que está tomando antes de comenzar 
a tomar el medicamento del estudio y antes de tomar cualquier otro medicamento 
durante su participación en el estudio. Asimismo, debe informarle al médico del 
estudio o al enfermero del estudio antes de inscribirse en otros ensayos clínicos 
durante su participación en este estudio. 
En los estudios, este medicamento ha sido bien tolerado en general. Los riesgos y 
efectos secundarios relacionados con Zepatier incluyen los siguientes: 
Muy frecuentes 
1) Sensación de cansancio o debilidad, 2) dolor de cabeza.  
 
Menos frecuentes 
3) Náuseas, 4) diarrea, 5) insomnio, 6) dolor en las articulaciones, 7) prurito 8) 
erupción, 9) dificultad para respirar, 10) anemia (bajo recuento de glóbulos rojos). 
 
Muy poco frecuentes 
11) Pruebas de la función hepática anormales que sugieren inflamación del 
hígado, 12) pruebas de la función pancreática anormales que sugieren 
inflamación del páncreas, 13) depresión, 14) dolor abdominal, 15) irritabilidad. 
 
Infórmele de inmediato a su proveedor de salud si tiene alguno de los siguientes 
síntomas o si empeoran durante el tratamiento con Zepatier: 
- 
pérdida del apetito;  
- 
color amarillento en la piel o en los ojos; 
- 
náuseas y vómitos;  
- 
cambio de color en las heces; 
- 
sensación de cansancio o debilidad. 
 
Podría haber otros efectos secundarios que aún no se han señalado, incluida una 
reacción alérgica grave. También es posible que la toma de medicamentos para evitar 
que el sistema inmunitario rechace el trasplante cardíaco (también denominado 
“inmunosupresión”) junto con Zepatier modifique la eficacia o los efectos secundarios 
de este medicamento. 
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Resistencia del virus a los tratamientos para la hepatitis C: 
Desconocemos el grado de eficacia de Zepatier para eliminar el virus de la hepatitis C 
después de un trasplante, en sus circunstancias. Determinar la eficacia de los 
medicamentos es uno de los propósitos de nuestro estudio. Uno de los riesgos 
principales de participar en este estudio es la posibilidad de que la hepatitis C sea 
resistente a los medicamentos y pueda limitar sus futuras opciones de tratamiento. La 
probabilidad de que se produzca una resistencia es mayor si se saltea una dosis o si 
no sigue las recomendaciones del estudio. Si usted demuestra una posible resistencia 
al medicamento del estudio al presentar un incremento en la carga viral de la 
hepatitis C, se le solicitará que se vuelva a realizar el análisis de carga viral de la 
hepatitis C cuanto antes. Podríamos cambiar su plan de tratamiento. 
 
Muy pocas personas (aproximadamente el 5 %) tienen una mutación de un tipo de 
hepatitis C que presenta riesgo de resistencia. Llevaremos a cabo un análisis para 
determinar si usted tiene dicho riesgo. Tal como ocurre con el análisis del genotipo, 
existe un riesgo de que el análisis no tenga una exactitud del 100 %. Si el análisis 
arroja un resultado erróneo, las probabilidades de cura podrían ser menores y es 
posible que necesite tratamiento adicional. 
 
Si no responde al tratamiento con Zepatier después de 12 semanas, le ofreceremos 
un conjunto de medicamentos diferentes (sofosbuvir y ribavirina) además de otro 
régimen de tratamiento con Zepatier para tratar la hepatitis C. Se desconoce la 
eficacia de dicho conjunto alternativo de medicamentos para curar la hepatitis C, 
aunque los investigadores prevén que es probable que cure con eficacia la 
enfermedad.  
 
Los riesgos y efectos secundarios relacionados con la administración adicional de 
sofosbuvir y ribavirina incluyen los siguientes: 
Muy frecuentes 
1) Sensación de cansancio o debilidad, 2) dolor de cabeza, 3) náuseas/dolor de 
estómago, 4) anemia, 5) insomnio, 6) erupción, 7) prurito, 8) dificultad para 
respirar. 
 
Menos frecuentes 
9) Tos, 10) piel reseca, 11) diarrea, 12) vómitos, 13) disminución del apetito,  
14) indigestión, 15) dolor muscular, 16) irritabilidad/depresión, 17) dolor en las 
articulaciones, 18) irritación nasal, 19) pruebas de la función hepática anormales, 
20) pruebas de la función pancreática anormales, 21) recuento bajo de glóbulos 
blancos, lo cual podría aumentar la vulnerabilidad a las infecciones, 22) bajo 
recuento plaquetario, lo cual podría aumentar la vulnerabilidad al sangrado, 23) 
anomalías congénitas debido a la ribavirina cuando el hombre o la mujer están 
tomando ribavirina en el momento de la concepción o han tomado ribavirina 
durante los 6 meses anteriores. 
 
3. Riesgos relacionados con los procedimientos y análisis del estudio 
Extracción de sangre  
Los posibles riesgos de la introducción de la aguja para extraer sangre incluyen dolor, 
hematomas, sangrado, desmayo e infección. Las molestias ocasionadas por este 
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procedimiento generalmente son breves, y los efectos secundarios graves son 
extremadamente inusuales. Algunas personas tienen sensación de mareo o vahído 
tras la extracción de sangre. La cantidad de sangre que se extraiga estará dentro de 
los límites permitidos para los participantes adultos. 
 
Pruebas genéticas 
Parte de la sangre que le extraigan como parte de este estudio se utilizará para 
pruebas genéticas. Las pruebas genéticas pueden ayudar a los investigadores a 
conocer las posibles relaciones entre la respuesta al tratamiento contra el virus de la 
hepatitis C y los factores genéticos. También se realizará un análisis de antígenos 
leucocitarios humanos (Human leukocyte antigen, HLA). Es una prueba genética de 
marcadores del sistema inmunitario.  
No divulgaremos ningún tipo de información sobre usted o su familia a parientes, 
compañías de seguros, empleadores o médicos de atención primaria sin su 
autorización por escrito. Podría existir el riesgo de que la información genética 
obtenida como resultado de la participación en la investigación se utilice 
indebidamente con fines discriminatorios. Sin embargo, las leyes federales y estatales 
proporcionan algunas protecciones contra la discriminación genética. Los 
investigadores que tengan acceso a su información genética tomarán medidas para 
mantener la confidencialidad de dicha información. Si bien tenemos el compromiso de 
mantener la confidencialidad, un tribunal podría presentar una orden judicial para 
obtener sus registros médicos. Todas estas cuestiones deben considerarse con 
mucho cuidado antes de tomar la decisión de participar en el estudio. 
 
Riesgo de las muestras almacenadas (opcional) 
Si usted acepta que se almacenen muestras para investigaciones en el futuro, podría 
haber riesgos de pérdida de confidencialidad relacionados con el almacenamiento y 
análisis de sus muestras o de la información obtenida del análisis de sus muestras. 
Por ejemplo, si una investigación futura incluye pruebas genéticas, existe un posible 
riesgo relacionado con la divulgación de información privada de salud a pesar de que 
tomemos todos los recaudos posibles para mantener su confidencialidad. 
 
Hallazgo de problemas de salud durante la selección 
Durante la selección para este estudio, le haremos exámenes y llevaremos a cabo 
estudios como parte del proceso de selección. Es posible que, al realizar dichos 
estudios, detectemos problemas de salud que usted desconocía. Si hallamos 
problemas de salud nuevos, responderemos sus preguntas e intentaremos acordar el 
tratamiento apropiado en caso de ser necesario. Si se hallan problemas de salud 
nuevos, es posible que usted no pueda participar en este estudio. También es posible 
que, según los resultados, usted ya no cumpla con los requisitos necesarios para 
recibir un trasplante cardíaco.  
 
Riesgos para la reproducción 
Si usted queda embarazada, es posible que Zepatier provoque problemas en el feto. 
Actualmente se desconocen los riesgos para el feto o el lactante, de modo que las 
mujeres que están embarazadas o amamantando NO pueden participar en el estudio.  
 
Antes de recibir el medicamento del estudio, todas las mujeres que puedan tener hijos 
deben realizarse una prueba que demuestre que no están embarazadas, y se les 
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aconsejará sobre la importancia de evitar el embarazo, que incluye la importancia del 
uso de métodos anticonceptivos de alta eficacia, durante el tratamiento del estudio. 
Las mujeres que pueden tener hijos deben adoptar un método anticonceptivo de alta 
eficacia durante su participación en el estudio y las seis semanas posteriores. 
Definimos “método anticonceptivo de alta eficacia” del mismo modo en que lo define 
el programa de trasplante. En particular, la toma de medicamentos para evitar el 
rechazo del trasplante puede causar anomalías congénitas.  
 
Los ejemplos incluyen los siguientes: 
1) abstinencia sexual;  
2) pareja con vasectomía; 
3) dispositivo intrauterino (DIU); 
4) un método hormonal, como píldoras anticonceptivas MÁS un método de barrera, 
como preservativos; 
5) diafragma con espermicida MÁS preservativo. 
 
Aun si utiliza un método anticonceptivo, existe una pequeña probabilidad de que 
quede embarazada. Si sospecha que está embarazada, debe informárselo de 
inmediato al médico del estudio. Si queda embarazada durante su participación en el 
estudio, es importante que nos informe de inmediato.  
 
Todos los hombres y las mujeres del estudio que sean sexualmente activos deben 
utilizar TAMBIÉN un método anticonceptivo de barrera, como preservativos, durante su 
participación en el estudio y mientras tengan hepatitis C. Si bien es inusual, la hepatitis 
C puede, a veces, contagiarse a través de relaciones sexuales. Es importante usar un 
anticonceptivo de barrera durante cualquier actividad sexual para evitar que su pareja 
se infecte con el virus.  
 
Todos los hombres y las mujeres que necesiten tratamiento con ribavirina deberán usar 
dos tipos de métodos anticonceptivos mientras estén en tratamiento y hasta 6 meses 
después de la última dosis del medicamento del estudio, debido al riesgo de anomalías 
congénitas por el uso de ribavirina. También se requiere que los hombres usen un 
método anticonceptivo porque la ribavirina puede afectar los espermatozoides y 
ocasionar anomalías congénitas.  
 
¿Qué ocurrirá si surge información nueva sobre el estudio? 
Además de los riesgos antedichos, es posible que existan riesgos que se desconocen, 
o riesgos no previstos, relacionados con la participación en el estudio. Si surge nueva 
información sobre el medicamento del estudio que pudiera afectar su decisión de 
continuar participando, el médico del estudio se lo informará de inmediato y analizará 
con usted su decisión de continuar participando en el estudio clínico. 
 
Es posible que le soliciten firmar un formulario de consentimiento revisado en caso de 
que esto ocurra. Usted tiene el derecho de decidir si va a continuar en el estudio clínico 
o si desea retirarse. 
 
¿Cuáles son los posibles beneficios del estudio?  
El beneficio principal del estudio es que usted puede recibir un trasplante con menos 
demora que si decidiera esperar un corazón sin hepatitis C. Recibir un trasplante 
cardíaco sin esperar tanto brindará beneficios clínicos conforme mejore su 
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funcionamiento cardíaco y su calidad de vida. Además, recibir un trasplante cardíaco 
podría aumentar su esperanza de vida al disminuir el riesgo de muerte durante el 
período de espera del trasplante.  
 
¿De qué otras opciones dispongo si no participo?  
Recomendamos que converse con su médico sobre este estudio y que analice otras 
opciones de tratamiento. Las otras opciones de tratamiento incluyen no inscribirse en 
este estudio y esperar un trasplante de corazón de un donante que no tenga 
hepatitis C. 
 
Sin embargo, si decide no participar en el estudio, podría seguir en la lista de espera 
durante un período más prolongado y sufrir consecuencias que afecten su salud, 
incluidas la muerte o complicaciones adicionales. 
 
¿Me pagarán por participar en este estudio? 
Usted no recibirá ninguna remuneración por su participación en este estudio. 
 
¿Tengo que pagar algo? 
El trasplante cardíaco lo pagará su compañía de seguros, y no requiere ninguna 
autorización previa adicional para la posibilidad de recibir un corazón de un donante 
con hepatitis C. El costo de todas las visitas, los análisis y los procedimientos 
antedichos se les cobrará a usted o a su compañía de seguros, excepto la extracción 
de sangre con fines de investigación (que incluye el análisis del genotipo de la 
hepatitis C, que se basa en un análisis desarrollado en laboratorio con materiales 
adquiridos en la entidad comercial que desarrolló el análisis, y que pagará el equipo de 
investigación) y el medicamento del estudio, que pagará el financiador del estudio. 
Usted sigue siendo responsable de todos los deducibles o copagos correspondientes a 
las visitas de rutina en el consultorio, los análisis de sangre y los procedimientos. Hable 
con el médico y el equipo del estudio para que lo comuniquen con un asesor financiero 
a fin de determinar exactamente de cuánto será su deducible y su copago; estos 
montos varían considerablemente según el tipo de seguro.  
 
¿Qué sucede si me lesiono por participar en el estudio? 
Si usted se enferma o se lesiona como resultado directo de ingerir los productos del 
estudio, el Hospital de la Universidad de Pensilvania le proporcionará tratamiento 
médico. El patrocinador, la Universidad de Pensilvania, le reembolsará todos los costos 
necesarios razonables de dicho tratamiento médico. El patrocinador no ofrece ninguna 
otra forma de reembolso por enfermedades o lesiones relacionadas con el estudio. En 
caso de que usted presente una enfermedad o lesión relacionada con el estudio, debe 
comunicarse de inmediato con el médico del estudio según la información de contacto 
que figura en la primera página de este formulario. 
 
Si recibe beneficios de Medicare, la ley requiere que el patrocinador, la Universidad de 
Pensilvania, notifique los pagos que le efectúen a usted por el tratamiento, las 
complicaciones y las lesiones que pudieran surgir de este estudio. A tales efectos, se 
les proporcionará a los Centros de Servicios de Medicare y Medicaid, sus agentes o 
proveedores, la información sobre su participación en el estudio, los tratamientos 
médicos que recibió, los reclamos de Medicare y otra información personal como su 
nombre, su número de seguro social y su fecha de nacimiento. 
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Versión 1.5 del Consentimiento/10 de enero de 2018                
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Al firmar este formulario, usted no renuncia a ninguno de sus derechos legales. 
 
Si considera que se ha lesionado como resultado de su participación en este estudio de 
investigación, infórmeselo cuanto antes a la persona a cargo del estudio de 
investigación. El nombre y el número de teléfono del investigador figuran al comienzo 
del formulario de consentimiento. 
 
Tenemos el compromiso de ofrecerle tratamiento para la infección por hepatitis C 
durante el estudio. Esperamos que dichos tratamientos tengan la probabilidad de curar 
su infección. Sin embargo, es posible que el tratamiento no cure la infección y que 
usted presente complicaciones de salud. Una vez que finalice el estudio, esperamos 
que usted procure tratamientos adecuados para la infección por hepatitis C a través de 
su seguro médico o en forma privada. 
 
¿Cuándo finaliza el estudio? ¿Puedo retirarme del estudio antes de 
que termine? 
Se prevé que este estudio finalice una vez que todos los participantes hayan 
completado todas las visitas, y que se haya recopilado toda la información. Si está 
considerando o ha decidido retirarse del estudio, infórmeselo al médico del estudio. Él 
le dirá cómo retirarse del estudio de manera segura. Si está pensando en retirarse del 
estudio, es importante que se lo informe al médico del estudio, ya que él podrá evaluar 
todos los riesgos y analizar qué tipo de atención y análisis de seguimiento alternativos 
podrían ser los mejores para usted. 
 
Motivos para interrumpir el medicamento del estudio 
Si usted no está respondiendo bien al medicamento del estudio (con controles 
frecuentes de los niveles de hepatitis C en la sangre) o si presenta una complicación 
que podría poner en riesgo su vida debido al medicamento, interrumpiremos de 
inmediato los medicamentos del estudio. No obstante, deberá recibir seguimiento, 
aunque con menos frecuencia. Independientemente del estado de la enfermedad 
hepática, la recomendación es tratar la hepatitis C si es posible en términos médicos; 
sin embargo, algunos médicos podrían elegir esperar y no tratar la enfermedad en el 
futuro inmediato. 
 
Motivos para el retiro o la interrupción del estudio 
La participación en el estudio depende enteramente de usted. Puede retirarse del 
estudio en cualquier momento y por cualquier motivo. Si se retira del estudio, su 
atención futura no se verá afectada. Si decide retirarse del estudio, es posible que le 
solicitemos que asista a una visita final para realizar análisis y exámenes con motivos 
de seguridad. Sin embargo, no se le exigirá que asista a dicha visita. 
 
Es posible que lo retiren del estudio sin solicitarle permiso si ocurre lo que se indica a 
continuación: 
• Queda embarazada mientras está siguiendo el tratamiento con Zepatier. Se 
interrumpirá el tratamiento dado que no existen datos sobre la seguridad de 
Zepatier durante el embarazo. Las pacientes continuarán con las visitas 
programadas del estudio, pero no serán elegibles para continuar el tratamiento 
con Zepatier. 
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• No podemos localizarlo, falta a varias visitas o se saltea varias dosis del 
medicamento del estudio. 
• Usted presenta un trastorno que pone en peligro su vida o existe otro riesgo 
significativo según el criterio de los investigadores. 
• Según nuestra opinión o la de su proveedor de atención primaria, es mejor 
para usted que deje de tomar los medicamentos del estudio, aunque no se 
cumplan los criterios para interrumpir el tratamiento. 
• El fabricante deja de elaborar Zepatier, o si se tomó la decisión de dar por 
terminado el estudio. 
 
¿Quiénes pueden ver o utilizar mi información? ¿Cómo se protegerá 
mi información personal? 
Se mantendrá la confidencialidad de sus registros médicos en la medida de lo 
permitido por la ley. En los informes y publicaciones que se obtengan como resultado 
de este estudio, no se utilizará su nombre ni ningún otro dato que pudiera identificarlo. 
Debido a su consentimiento para participar, el patrocinador del estudio o el Comité de 
Revisión Institucional de la Universidad de Pensilvania ([Penn’s Institutional Review 
Board], el grupo responsable de asegurar que el estudio siga las normas de 
protección de sujetos humanos de investigación) pueden revisar sus registros 
médicos con el conocimiento de que dichos registros solamente se utilizarán para el 
cumplimiento de obligaciones relacionadas con este estudio clínico. También les 
proporcionaremos información sobre usted a sus médicos personales. Usted puede 
cambiar de médico cuando lo desee, pero necesitamos tener los datos de un médico 
con el cual podamos comunicarnos con respecto a usted. No le solicitaríamos su 
permiso para cada uno de esos contactos. 
 
Los datos de este estudio podrán ingresarse a una base de datos computarizada a 
través de un sitio web seguro. Solamente se le permitirá el ingreso y el acceso a los 
datos al personal autorizado, con el uso de una contraseña. En la base de datos del 
estudio, usted no estará identificado por su nombre, su número de seguro social ni su 
número de expediente médico. A cada paciente se le asignará un código de 
identificación único del estudio. El equipo del estudio mantendrá bajo llave los registros 
que vinculen el código de identificación del estudio con la información de identificación 
personal. 
 
Según lo exige la ley de los EE. UU., en el sitio web http://www.ClinicalTrials.gov se 
encuentra disponible una descripción de este estudio clínico. Dicho sitio web no incluye 
información que pueda identificarlo a usted. A lo sumo, el sitio web incluirá un resumen 
de los resultados. Puede realizar búsquedas en ese sitio web en cualquier momento. 
 
Expedientes médicos electrónicos y resultados de la investigación  
¿Qué es un expediente médico electrónico?  
Un expediente médico electrónico (Electronic Medical Record, EMR) es una versión 
electrónica del registro de su atención en un sistema de salud. Un EMR es 
simplemente una versión computarizada de un expediente médico impreso en papel.  
 
Si usted está recibiendo o ha recibido atención en el Sistema de Salud de la 
Universidad de Pensilvania (University of Pennsylvania Health System, UPHS), ya sea 
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Versión 1.5 del Consentimiento/10 de enero de 2018                
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como paciente internado o ambulatorio, y se encuentra participando en un estudio de 
investigación de la Universidad de Pensilvania, los resultados de los procedimientos 
relacionados con la investigación (es decir, análisis de laboratorio, estudios de 
imágenes y procedimientos clínicos) podrían incluirse en su EMR existente que 
mantiene el UPHS. 
 
Una vez ingresados a su EMR, dichos resultados estarán accesibles para los 
integrantes del personal autorizado del UPHS que no formen parte del equipo de 
investigación. La información que contiene su EMR también podría compartirse con 
terceros cuyo acceso a su EMR el UPHS considere apropiado (p. ej., compañías de 
seguro de salud, proveedores de servicios para discapacitados, etc.).  
 
¿Qué información sobre mi persona podría recopilarse, utilizarse y 
compartirse con terceros? 
La siguiente información personal de salud podrá recopilarse, utilizarse para 
investigación y divulgarse durante su vinculación con este estudio de investigación:  
• Historia clínica personal. 
• Medicamentos o tratamientos presentes y pasados. 
• Información de exámenes físicos, que generalmente incluye su peso, presión 
sanguínea, frecuencia cardíaca, frecuencia respiratoria y temperatura. 
• Resultados de análisis y procedimientos que usted se realizó durante este 
estudio de investigación, según se describe en el formulario de consentimiento 
informado. 
• Número de seguro social para el reembolso de determinados gastos, como 
estacionamiento. 
• Número de expediente médico. 
• Otros números de identificación únicos (como el número de identificación del 
estudio vinculado a sus registros médicos en un archivo de investigación por 
separado). 
• Datos directamente relacionados con usted, como su fecha de nacimiento, 
fechas de hospitalizaciones, análisis y procedimientos. 
• Podría recopilarse su nombre, número de teléfono, número de fax y dirección de 
correo electrónico a fin de comunicarse con usted. 
 
¿Por qué se utiliza mi información? 
El equipo de investigación utiliza su información para comunicarse con usted durante el 
estudio. Su información y los resultados de los análisis y procedimientos se utilizan 
para lo siguiente: 
• realizar la investigación; 
• supervisar la investigación; 
• controlar si la investigación se llevó a cabo correctamente. 
 
¿Quiénes podrían utilizar y compartir la información sobre mí? 
Las siguientes personas podrían utilizar o compartir su información para este estudio 
de investigación: 
• Los investigadores principales y el equipo de estudio de los investigadores.  
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• Integrantes autorizados del personal del UPHS y de la Facultad de Medicina, así 
como de las oficinas de apoyo de la Universidad de Pensilvania, quienes podrían 
necesitar el acceso a su información para llevar a cabo sus tareas (por ejemplo, 
para la supervisión y el control de la investigación, para administrar tratamiento, 
para gestionar asuntos contables o de facturación, etc.).  
 
Fuera de la Facultad de Medicina, ¿quiénes podrían recibir mi 
información? 
Como parte del estudio, el investigador principal, el equipo del estudio y otras personas 
antedichas podrían divulgar su información personal de salud, incluidos los resultados 
de los análisis y procedimientos del estudio de investigación. Esta información podría 
divulgarse a quienes se indican a continuación: 
 
Personas o entidades responsables de administrar el estudio:  
• Su información se enviará a Merck, sus representantes autorizados y la FDA. Merck 
y sus representantes que supervisan el estudio llevarán a cabo una revisión 
periódica de los registros médicos y de investigación para garantizar la integridad de 
los datos que se recopilen. Su información también se enviará a los laboratorios que 
realicen análisis para el estudio. 
• Todos los centros de investigación que participen en el estudio, aunque no formen 
parte de la Facultad de Medicina, podrían recibir información sobre sus registros 
médicos, pero dicha información no incluirá ningún dato confidencial de 
identificación sobre usted. 
 
Organizaciones de supervisión de la seguridad y de las normas: 
• La Administración de Alimentos y Medicamentos (Food and Drug Administration). 
• La Oficina de Protección de los Seres Humanos en Investigación (Office of Human 
Research Protections). 
 
Una vez que su información personal de salud se divulgue a terceros fuera de la 
Facultad de Medicina, podría dejar de estar cubierta por las normas federales de 
protección de la privacidad. 
 
Los investigadores principales o el personal del estudio le informarán si se realizan 
incorporaciones a la lista antedicha durante su participación activa en el ensayo. Todas 
las incorporaciones estarán sujetas a los procedimientos de la Universidad de 
Pensilvania desarrollados para proteger su privacidad. 
 
Departamento de Salud de la Ciudad de Filadelfia/Departamento de Salud de 
Pensilvania (City of Philadelphia Health Department/PA Department of Health): 
Si usted obtiene un resultado positivo en el análisis de detección de la hepatitis C, la ley 
exige que lo notifiquemos al Departamento de Salud de la Ciudad de 
Filadelfia/Departamento de Salud de Pensilvania (City of Philadelphia Health 
Department/PA Department of Health). Notificaríamos su nombre, sexo, origen 
étnico/racial, y el mes y el año de su nacimiento. Esto se realiza para llevar un registro 
de la cantidad de personas que están infectadas por el virus de la hepatitis C en los 
EE. UU. También se realiza para garantizar que los estados obtengan dinero suficiente 
del gobierno federal para mantener la atención médica de las personas con hepatitis C. 
El Departamento de Salud no comparte con nadie los nombres de las personas 
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Versión 1.5 del Consentimiento/10 de enero de 2018                
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infectadas por el virus de la hepatitis C. Antes de proporcionarle información al 
gobierno federal sobre la cantidad de infecciones por el virus de la hepatitis C, el 
Departamento elimina todos los datos de identificación personal, como los nombres. 
 
¿Durante cuánto tiempo la Facultad de Medicina puede utilizar o 
divulgar mi información personal de salud? 
Su autorización del uso de su información personal de salud para este estudio 
específico no tiene vencimiento.  
 
Su información podría mantenerse en una base de datos de investigación. Sin 
embargo, la Facultad de Medicina podría no volver a utilizar o a divulgar la información 
recopilada en este estudio con fines que sean distintos a los del estudio a menos que: 
• usted otorgue su autorización por escrito;  
• el Comité de Revisión Institucional de la Universidad de Pensilvania (University of 
Pennsylvania’s Institutional Review Board) así lo autorice; 
• esté permitido por la ley.  
 
¿Puedo cambiar de opinión con respecto a mi permiso para que se 
utilice mi información? 
Sí. Usted puede retirar su permiso para usar y divulgar su información de salud en 
cualquier momento. Debe hacerlo enviando una notificación por escrito a los 
investigadores del estudio. Si retira su permiso, ya no podrá seguir participando en este 
estudio. 
 
¿Qué sucede si decido no dar mi permiso para usar y divulgar mi 
información de salud? 
En ese caso, ya no podrá seguir participando en este estudio de investigación. Usted 
recibirá una copia de esta Autorización de la Ley de Transferencia y Responsabilidad 
de los Seguros de Salud (Health Insurance Portability and Accountability Act, HIPAA) 
para Sujetos de Investigación que describe sus derechos de privacidad y 
confidencialidad para este estudio.  
 
Al firmar este documento, usted le permite a la Facultad de Medicina utilizar y divulgar 
la información personal de salud que se recopiló sobre usted con fines de investigación 
según lo descrito anteriormente. 
 
¿A quién puedo llamar para hacer preguntas o presentar quejas, o si 
tengo inquietudes sobre mis derechos como sujeto de investigación? 
Si tiene preguntas, inquietudes o quejas con respecto a su participación en este estudio 
de investigación, o si tiene preguntas sobre sus derechos como sujeto de investigación, 
debe hablar con los investigadores principales, que figuran en primera página de este 
formulario. Si no puede comunicarse con un integrante del equipo de investigación,  
o si desea hablar con una persona que no esté trabajando en el estudio, puede  
hacer preguntas o presentar inquietudes o quejas llamando a la Oficina de Asuntos  
de Regulación (Office of Regulatory Affairs) de la Universidad de Pensilvania al 
(215) 898-2614. 
 
 
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Versión 1.5 del Consentimiento/10 de enero de 2018                
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Al firmar este formulario, usted acepta participar en este estudio de investigación. Esto 
significa que ha leído el formulario de consentimiento, que se han respondido sus 
preguntas y que ha decidido participar en forma voluntaria. Su firma también significa 
que le permite a la Universidad de Pensilvania utilizar la información personal de salud 
que se recopiló sobre usted con fines de investigación dentro de nuestra institución. 
Asimismo, le permite a la Universidad de Pensilvania divulgar dicha información 
personal de salud a organizaciones o personas externas involucradas en las 
operaciones de este estudio. 
 
Se le proporcionará a usted una copia de este consentimiento informado.  
 
 
_____________________________    ___________________________   _________ 
Nombre del sujeto en letra de imprenta      Firma del sujeto  
 
 
 Fecha 
 
 
 
_____________________________     ___________________________   _________ 
Nombre de la persona que obtiene             Firma 
 
 
 
 
  Fecha 
el consentimiento en letra de imprenta   
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Versión 1.5 del Consentimiento/10 de enero de 2018                
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Muestras almacenadas e investigaciones futuras (opcional) 
Si usted acepta participar en este estudio, es posible que también acepte permitirnos 
almacenar sus muestras para investigaciones futuras. Esas muestras almacenadas 
podrían ayudarnos a conocer más sobre la hepatitis C. Rotularemos sus muestras 
almacenadas con un código que solamente el equipo del estudio podrá vincular con 
usted. Mantendremos la privacidad de toda información que pueda identificarlo a 
usted tanto como sea posible. Si cambia de opinión y decide que dejemos de 
almacenar sus muestras, comuníquese con nosotros. Haremos todo lo posible por 
cumplir con su solicitud, pero no siempre podemos garantizar la destrucción total de 
todas sus muestras. 
 
Podemos enviarles sus muestras a otros investigadores con fines de investigación, sin 
ninguna información que pueda identificarlo. También podemos compartir información 
como su sexo, edad, historia clínica u origen étnico. No venderemos sus muestras y 
no recibiremos pago alguno por los productos que se obtengan como resultado de la 
investigación. Algunos estudios futuros podrían requerir información de salud (como 
antecedentes de tabaquismo o estado de salud actual) que actualmente no 
poseemos. En ese caso, el equipo del estudio se comunicará con usted. Las 
investigaciones futuras que utilicen sus muestras probablemente no sean útiles para 
usted, pero podrían ayudarnos a obtener más conocimientos sobre cómo tratar o 
prevenir la hepatitis C y otros problemas de salud. En general, los análisis de 
investigación que llevamos a cabo no son como los análisis médicos de rutina, y 
podrían no estar directamente relacionados con su atención médica. 
        
 
 
Marque la casilla si desea permitir que el equipo del estudio obtenga y 
almacene una muestra de sangre suya para futuras pruebas genéticas. 
 
Marque la casilla si desea permitir que el equipo del estudio comparta sus 
muestras de sangre con otros equipos de investigación para obtener más 
conocimientos sobre el virus de la hepatitis C. Las muestras de sangre, si 
se comparten, no se rotularán con su información personal. 
 
 
_____________________________    ___________________________   _________ 
Nombre del sujeto en letra de imprenta      Firma del sujeto  
 
 
 Fecha 
 
 
 
_____________________________     ___________________________   _________ 
Nombre de la persona que obtiene           Firma 
 
 
 
 
  Fecha 
el consentimiento en letra de imprenta 
 
IRB Approved From: 02/11/2019 To: 02/10/2020

Prot_SAP_002.pdf: 
Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
1 
OPEN-LABELED TRIAL OF ZEPATIER FOR TREATMENT OF HEPATITIS C NEGATIVE PATIENTS WHO RECEIVE 
HEART TRANSPLANTS FROM HEPATITIS C POSITIVE DONORS (USHER) 
  
Test drug: 
Zepatier 
Clinical study phase: II 
Sponsor: 
University of Pennsylvania 
Funder: 
Merck 
IND# 
Exempt 
IRB# 
826708 
NCT# 
 
Co-principal 
Investigators: 
David Goldberg, MD, MSCE 
Perelman School of Medicine at the University of Pennsylvania 
215-746-8598 
Peter Reese, MD, MSCE 
Perelman School of Medicine at the University of Pennsylvania 
215-900-3782 
Rhondalyn Forde-McLean, MD, MHS 
Perelman School of Medicine at the University of Pennsylvania 
215-662-2727 
The study will be conducted in adherence 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. 
 
 
 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
2 
1 SYNOPSIS 
Title  
Open-Labeled Trial Of Zepatier For Treatment Of Hepatitis C-Negative Patients Who 
Receive Heart Transplants From Hepatitis C-Positive Donors 
Clinical study phase 
II 
Study objectives 
This study is being conducted to determine safety and efficacy of transplanting 
hearts from HCV virus (HCV)-positive donors into HCV-negative patients on the heart 
transplant waitlist, who will then be treated with Zepatier status post-single heart 
transplantation. 
Primary aim:  
1. Primary efficacy objective:  to determine sustained virologic response (SVR) 
rates of open-label Zepatier in HCV-negative patients who receive a heart 
transplant from a genotype 1 or 4 HCV-positive donor, leading to post-
transplantation de-novo HCV infection. 
 
2. Primary safety objective:  to determine the safety of administration of open-
label Zepatier among HCV-negative patients who receive a heart transplant 
from a genotype 1 or 4 HCV-positive donor and develop post-transplant HCV 
infection. 
Secondary aims: 
 
3. To determine 1-year graft survival rates of HCV-negative heart transplant 
patients who receive a heart transplant from a genotype 1 or 4 HCV-positive 
donor, including those who spontaneously clear HCV (and those who receive 
open-label Zepatier upon development of de-novo HCV. 
 
4. To evaluate rates of spontaneous clearance of HCV among HCV-negative 
patients who receive a single heart transplant from a genotype 1 HCV-
positive donor. 
 
Indication 
Chronic HCV post-heart transplantation 
Diagnosis and main 
criteria for inclusion 
Inclusion criteria 
• 
 New York Heart Association (NYHA) Class III or IV CHF refractory to maximal 
medical therapy (ACE inhibitor, B-blocker, digoxin and diuretics, 
resynchronization therapy or ICD when applicable) and/or conventional 
surgery  AND/OR  Inoperable coronary artery disease with intractable anginal 
symptoms  AND/OR  Malignant ventricular arrhythmias unresponsive to 
medical or surgical therapy 
• 
40-65 years of age 
• 
Obtained agreement for participation from the transplant cardiology team 
• 
No evident contraindication to liver transplantation other than the underlying 
cardiac disorder 
• 
Able to travel to the University of Pennsylvania for routine post-transplant 
visits and study visits for a minimum of 6 months after transplantation 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
3 
• 
No active illicit substance abuse 
• 
Women must agree to use birth control in accordance with Mycophenolate 
Risk Evaluation and Mitigation Strategy (REMS) following transplant due to the 
increased risk of birth defects and/or miscarriage 
• 
Both men and women must agree to use at least one barrier method of birth 
control or remain abstinent following transplant due to risk of HCV 
transmission 
• 
Inclusion criteria for treatment (not for entry as study patient) will include any 
detectable HCV RNA by week 4 post-heart transplantation 
• 
Able to provide informed consent 
Exclusion criteria 
• 
Hepatocellular carcinoma 
• 
HIV positive 
• 
HCV antibody positive and/or RNA positive 
• 
Hepatitis B surface antigen, core antibody, and/or DNA positive 
• 
Any other chronic liver disease (excluding non-alcoholic fatty liver disease 
(NAFLD) with abnormal liver enzymes 
• 
Persistently elevated liver transaminases 
• 
Congenital heart disease  
• 
Fibrosis by liver biopsy or total bilirubin > 2.5 with associated evidence of 
synthetic dysfunction.  
• 
Pregnant or nursing (lactating) women 
• 
Known allergy or intolerance to tacrolimus that would require post-transplant 
administration of cyclosporine, rather than tacrolimus given the drug-drug 
interaction between cyclosporine and ZEPATIER 
• 
Waitlisted for a multi-organ transplant  
• 
Evidence of end organ damage due to diabetes (e.g. retinopathy, 
nephropathy, ulcerations) and /or brittle diabetes mellitus (e.g. history of 
diabetic ketoacidosis) and/or uncontrolled diabetes as evidence by a HgbA1C 
of 7.5-8.5.  
• 
Chronic bronchitis, chronic obstructive pulmonary disease, inability to stop 
smoking. 
• 
Hematologic: Significant coagulation abnormalities, bleeding diatheses. 
• 
Psychosocial: Profound neurocognitive impairment with absence of social 
support. 
• 
Active mental illness or psychosocial instability  
• 
Inadequate insurance or financial support for post-transplant care.  
• 
Evidence of drug, tobacco or alcohol abuse within the past six months and 
completion of recommended therapy/services or meets satisfied parameters 
as indicated by social work staff and/or consult team.  
• 
History of chronic non-compliance.  
• 
Amyloidosis (restricted to cardiac only, without evidence of extra cardiac 
involvement) 
• 
BMI ≥38  
• 
Active peptic ulcer disease.  
• 
Severe malnutrition.  


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• 
Major chronic disabling illness (e.g. lupus, severe arthritis, neurologic 
diseases, previous stroke with profound residual). 
• 
Pulmonary infarction within the past 6 weeks  
• 
Severe pulmonary hypertension as evidenced by a fixed pulmonary vascular 
resistance of greater than 4 Wood units on appropriate medical therapy.  
• 
Patient refusal to receive blood products or transfusions during heart 
transplant surgery.  
• 
Severe chronic obstructive pulmonary disease 
• 
Current clinical sepsis.  
• 
Symptomatic or severe vascular disease.  
• 
Chronic Kidney Disease Stage IV, GFR <30  
• 
History of Mantle radiation.  
• 
Asymptomatic renal cell carcinoma <1 year from curative treatment.  
• 
Symptomatic renal cell carcinoma <5 years from curative treatment.  
• 
Prostate cancer <2 years from curative treatment.  
• 
Uterine or cervical cancer <2 years from curative treatment.  
• 
Any other cancer other than the above including malignant melanoma, <5 
years from treatment apart from other skin malignancies. 
• 
On mechanical circulatory support maintained on suppressive antibiotics for 
chronic infection. 
Study design 
Open-labelled pilot clinical trial of Zepatier (MK-5172 and MK-8742/Grazoprevir + 
Elbasvir) in at least 20 HCV-negative subjects with heart failure receiving a heart 
transplant from a HCV-positive donor. Eligible subjects will receive a heart transplant 
from a deceased-donor with genotype 1 or 4  HCV, and then will receive 12 weeks of 
Zepatier after heart transplantation when infection with HCV is confirmed in these 
heart transplant recipients. Treatment will be complete after 12 weeks.* 
 
* Patients with Genotype 1a and Genotype 1 with an unknown subtype will have 
baseline NS5A drug resistance assay testing checked at the start of treatment, and if 
patients have polymorphisms at positions M28, Q30, L31, and/or Y93, treatment with 
Zepatier will be extended to 16 weeks, rather than 12 weeks, and renally-adjusted 
Ribavirin at the clinician’s discretion will be initiated, and continued for the remainder 
of therapy (until the 16 week mark).  Such a strategy will provide optimal treatment, 
without delaying therapy prior to receipt of results of NS5A drug resistant testing. 
 
Study observations 
• 
Laboratory tests including hepatic function panel at screening and at 
multiple time points during follow-up.  
• 
HCV RNA prior to treatment, on treatment, and 4 and 12 weeks after 
completing Zepatier. 
Type of control 
None 
Number of subjects 
Estimated 20 HCV-negative subjects transplanted with a heart from an HCV-positive 
donor 
Plan for statistical analysis Primary endpoint: 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
5 
• 
Post-treatment sustained virologic response (SVR)  
Secondary endpoints: 
• 
Determine if there are major adverse events attributable to HCV therapy in 
post-heart transplant patients. 
• 
Evaluate 1-year heart graft survival in HCV-negative patients who receive a 
heart transplant from an HCV-positive donor 
• 
Determine the rates of spontaneous HCV clearance among HCV-negative 
patients with heart failure receiving a heart from an HCV-positive donor 
 
Data analysis: 
The primary analysis will be based on a calculation of SVR rates (number of 
subjects with SVR-12; negative HCV RNA 12 weeks after completing Zepatier 
therapy) / (number of subjects treated with Zepatier post-heart transplantation) 
 
 
 
 
 




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2 TABLE OF CONTENTS 
 
1 
Synopsis ................................................................................................................................................2 
2 
Table of contents ...................................................................................................................................7 
3 
Abstract .................................................................................................................................................9 
4 
Chapter 1: Background And Significance ............................................................................................... 10 
4.1. 
Background ........................................................................................................................................ 10 
Rationale of the study ......................................................................................................................................... 10 
4.2. 
Zepatier .............................................................................................................................................. 11 
5 
Chapter 2: Objectives And Specific Aims ............................................................................................... 12 
5.1. 
Objectives .......................................................................................................................................... 12 
5.2. 
Specific aims ...................................................................................................................................... 12 
6 
Chapter 3: Screening And Subject Selection .......................................................................................... 13 
6.1. 
Recruitment: identification and screening process ........................................................................... 13 
6.2. 
Subject selection criteria ................................................................................................................... 13 
6.3. 
Donor Organ Selection Criteria .......................................................................................................... 15 
7 
Chapter 4: Treatments ......................................................................................................................... 18 
7.1. 
Zepatier (grazoprevir and elbasvir) .................................................................................................... 18 
8 
Chapter 5: Data Collection .................................................................................................................... 21 
8.1. 
Study visits ......................................................................................................................................... 21 
8.2. 
Study schedule of procedures ........................................................................................................... 26 
8.3. 
Subject retention and drug adherence .............................................................................................. 29 
9 
Chapter 6: Assessment Of Efficacy And Outcome Measures .................................................................. 31 
9.1. 
Assessments of Efficacy ..................................................................................................................... 31 
9.2. 
Secondary Outcome Measures .......................................................................................................... 31 
10 
Chapter 7: Statistical Considerations .................................................................................................... 32 
10.1. 
Study Design ...................................................................................................................................... 32 
10.2. 
Disposition of Subjects and Baseline Comparisons ........................................................................... 32 
10.3. 
Analyses of Outcome Measures ........................................................................................................ 32 
10.4. 
Missing Data and Dropouts ............................................................................................................... 32 
10.5. 
Protocol Violations............................................................................................................................. 32 
10.6. 
Safety Analysis ................................................................................................................................... 32 
11 
Chapter 8: Quality Control and Data Handling ....................................................................................... 33 
11.1. 
Personnel Training ............................................................................................................................. 33 
11.2. 
Data Quality ....................................................................................................................................... 33 
11.3. 
Audit and Inspection .......................................................................................................................... 33 
11.4. 
Archiving ............................................................................................................................................ 33 
12 
Chapter 9: Participant Safety and Confidentiality .................................................................................. 34 
12.1. 
Informed Consent .............................................................................................................................. 34 
12.2. 
Institutional Review Board Process ................................................................................................... 34 
12.3. 
Insurance ........................................................................................................................................... 34 
12.4. 
Laboratory Values .............................................................................................................................. 35 
12.5. 
Zepatier Related Laboratory Abnormalities and Drug Interactions .................................................. 35 
12.6. 
Other Events ...................................................................................................................................... 37 
12.7. 
Safety and Adverse Events................................................................................................................. 37 
12.8. 
Subject Withdrawal ........................................................................................................................... 43 
12.9. 
Confidentiality of Study Data ............................................................................................................. 44 


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12.10. 
Potential Risks .................................................................................................................................... 45 
12.11. 
Potential Benefits .............................................................................................................................. 47 
12.12. 
Alternatives ........................................................................................................................................ 47 
12.13. 
Ethical Considerations ....................................................................................................................... 47 
13 
Chapter 11: Good Clinical Practice ........................................................................................................ 48 
14 
Chapter 12: References ........................................................................................................................ 49 
 
 


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3 ABSTRACT 
Since 2006, there has been a 50% increase in the number of adults added to the heart transplant waitlist in the 
US. Yet the persistent organ donor shortage has led to only a 25% increase in the number of transplants, and a 
25% increase in the number of patients removed from the heart transplant waitlist because of death or 
becoming too sick to transplant, reaching nearly 700 patients in 2015. It has been suggested that the donor 
supply could be increased by utilizing hearts from older donors or those with more medical co-morbidities, but 
the increased risk of graft failure prevents their broader use. Despite advances in ventricular assist devices 
(VADs), which can prolong patient survival and improve quality-of-life, they are not a panacea. Long-term 
survival is superior for patients receiving a heart transplant, and VADs are not an option for patients with several 
forms of end-stage heart disease (i.e., arrhythmia disorders). Thus there is a critical need to expand the pool of 
heart donors in order to save more lives from end-stage heart disease.  
 
We will perform a pilot trial to prove feasibility of knowingly using HCV-positive organs for HCV-negative 
recipients, by transplanting 20 HCV-negative subjects with hearts from HCV-positive donors, and then treating 
these subjects’ with Zepatier in the early post-transplant phase in order to cure their HCV. If any subjects clear 
HCV spontaneously within the first four weeks post-transplantation, and do not require treatment, subjects will 
be added until there have been at least 20 HCV-negative subjects who receive a heart transplant from an HCV-
positive donor, develop HCV, and are then treated for their HCV with Zepatier. 
 
 
 


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4 CHAPTER 1: BACKGROUND AND SIGNIFICANCE 
4.1. Background 
Since 2006, there has been a 50% increase in the number of adults added to the heart transplant waitlist in the 
US. Yet the persistent organ donor shortage has led to only a 25% increase in the number of transplants, and a 
25% increase in the number of patients removed from the heart transplant waitlist because of death or 
becoming too sick to transplant, reaching nearly 700 patients in 2015. It has been suggested that the donor 
supply could be increased by utilizing hearts from older donors or those with more medical co-morbidities, but 
the increased risk of graft failure prevents their broader use. Despite advances in ventricular assist devices 
(VADs), which can prolong patient survival and improve quality-of-life, they are not a panacea. Long-term 
survival is superior for patients receiving a heart transplant, and VADs are not an option for patients with several 
forms of end-stage heart disease (i.e., right ventricular dysfunction, hypertrophic cardiomyopathy). Thus there is 
a critical need to expand the pool of heart donors in order to save more lives from end-stage heart disease.  
The current treatment paradigm of HCV has evolved to the point that we should reconsider transplanting hearts 
from HCV-positive donors into HCV-negative patients in order to greatly increase the number of lifesaving heart 
transplants. The potential for liver disease and coronary vasculopathy, coupled with logistical and ethical 
intricacies of transplanting hearts from HCV-positive donors into HCV-negative recipients, highlight the need to 
conduct a controlled study to establish safety and efficacy, while investigating mechanisms of HCV transmission 
and de-novo coronary vasculopathy.  
 
We expect that there will be a high degree of willingness of carefully selected, HCV-negative heart transplant 
patients to accept an organ from an HCV-positive donor, especially given the high HCV cure rates with current 
therapies. After completing this pilot study, the goal is to then apply for federal funding to perform a multi-
center randomized controlled trial using HCV-positive hearts for HCV-negative recipients, with the hope to 
increase utilization of organs that are currently discarded more than 97% of the time. 
 
This study will target cardiac transplant candidates that currently face challenges in receiving an HCV-negative 
transplant and have a substantial probability of health decline while on the waiting list. These capture two broad 
groups of patients: 1) patients with end-stage systolic heart failure with lower probabilities of transplant, and 
higher risk of waitlist mortality; and 2) patients with arrhythmia disorders, as these patients don’t receive the 
highest priority (status 1a) because inotropic support may lead to worsened arrhythmias and/or LVAD support 
may not ease the arrhythmic burden.  With respect to group 1, as one example, patients with blood group O 
have known longer waiting times and lower transplant rates—from 2005-2014, there were 29,488 adults added 
to the heart transplant waitlist in the US, with significantly higher risks of waitlist removal for death or clinical 
deterioration and lower transplant rates in patients with blood group O who were “bigger”:  a) Blood group O, 
height ≥6 feet, weight <100kg: 56.8% transplanted, 17.4% died/too sick; b) Blood group O, height <6 feet, weight 
≥100kg: 43.2% transplanted, 22.2% died/too sick; c) Blood group O, height ≥6 feet, weight ≥100kg: 42.2% 
transplanted, 21.3% died/too sick; d) all other patients on waitlist: 65.3% transplanted, 14.4% died/too sick.  
 
These discrepancies are even more pronounced in certain parts of the country; for example, in UNOS region 2 
(PA, MD, WV, DE, and NJ), 41.1%-56.5% of blood group O patients who are ≥6 feet and/or ≥100kg are 
transplanted, as compared to 70.5% of all other patients on the waitlist during this time period. 
4.2. Rationale of the study 
We will perform a pilot trial to prove feasibility of knowingly using HCV-positive organs for HCV-negative 
recipients, by transplanting 20 HCV-negative subjects with hearts from HCV-positive donors, and then treating 
these subjects with Zepatier in the early post-transplant phase in order to cure their HCV.  


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11 
4.3. Zepatier 
Open-label Zepatier (grazoprevir 100 mg and elbasvir 50 mg) will be administered in this study.3,4 Zepatier is a 
fixed-dose combination tablet without ribavirin. GZR is an HCV NS3/4a inhibitor while EBR is an HCV NS5A 
inhibitor. Both grazoprevir and elbasvir are direct-acting antivirals, which together form an effective therapy for 
HCV and reduce the likelihood and effects of long-term liver-related HCV complications. GZR/EBR exhibits broad 
in vitro activity against most HCV genotypes and in vitro activity against many clinically relevant RAVs.3,4  
 
Zepatier has been evaluated globally in multiple phase I, II, and III trials to treat HCV.3,4  Randomized, placebo-
controlled trials have been carried out, which led to FDA approval for Zepatier as a treatment for genotype 1 
and 4 HCV. 
 
As of July 1, 2015, a diverse population of over 1000 HCV patients has been exposed to Zepatier either as a 
single agent or in combination with ribavirin or sofosbuvir in phase I/II/III studies.  Zepatier has been generally 
well tolerated at doses of 50-100 mg GZR and 50 mg EBR orally once daily.  It has been comparably effective 
across all subgroups it has been tested in, including non-cirrhotic and/or treatment-naïve subjects.3,4 
 
Headaches, fatigue, and nausea represent the most common adverse drug reactions with Zepatier.3,4 Other 
drug-related adverse events have included arthralgia, insomnia, diarrhea, dizziness, pyrexia, and asthenia.3,4 
Drug-related serious adverse events are uncommon, but include allergic reactions, possible adverse interactions 
with other medications, or elevated liver enzymes. In past Zepatier trials, the majority of the adverse events 
were reversible. These adverse events are usually grade 1 or 2 mild or moderate events.  
 
The dosage in our study (100/50 mg daily) is a commonly attainable dose in clinical practice. In the event dialysis 
is needed after transplant, Zepatier has shown to be safe for subjects with chronic heart disease or who are on 
hemodialysis. Less than 1% of Zepatier is excreted renally. In Merck C-SURFER, a phase 1 randomized, controlled 
Zepatier trial, subjects with advanced heart disease tolerated the drug well for the required 12 weeks and had 
no need for dose adjustments.8  
 
Zepatier trials have demonstrated a 94-100% success rate achieving HCV RNA levels of <15 IU/ml after 12 weeks 
of treatment (SVR-12) among genotype 1 HCV patients.3,4  
 
All donor hearts in this trial will come from confirmed genotype 1 or 4 HCV-positive donors. Genotype will be 
confirmed by the standard of care diagnostic test at the Hospital of the University of Pennsylvania.  
 
 


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12 
5 CHAPTER 2: OBJECTIVES AND SPECIFIC AIMS 
5.1. Objectives 
This study is being conducted to determine safety and efficacy of transplanting hearts from genotype 1 
or 4 HCV-positive donors into HCV-negative patients on the heart transplant waitlist, who will then be 
treated with Zepatier post-transplantation. 
5.2. Specific aims 
Primary aim:  
1. Primary efficacy objective:  To determine sustained virologic response (SVR) rates of open-label Zepatier 
in hepatitis C virus (HCV) negative patients who receive a heart transplant from a genotype 1 or 4 HCV-
positive donor, leading to post-transplantation de-novo HCV infection. 
 
2. Primary safety objective:  To determine the safety of administration of open-label Zepatier among HCV-
negative patients who receive a heart transplant from a genotype 1 or 4 HCV-positive donor and 
develop post-transplant HCV infection. 
Secondary aim: 
1. To determine 1-year graft survival rates of HCV-negative heart transplant patients who receive a heart 
transplant from a genotype 1 or 4 HCV-positive donor, including those who spontaneously clear HCV 
and those who receive open-label Zepatier upon development of de-novo HCV. 
 
2. To obtain preliminary data on the distribution of changes in circulating biomarkers of endothelial 
damage and coronary vasculopathy in HCV-negative patients transplanted with hearts from HCV-
positive donors prior to HCV treatment, after viral clearance, and after SVR. 
 
3. To evaluate rates of spontaneous clearance of HCV among HCV-negative patients who receive a heart 
transplant from a genotype 1 or 4 HCV-positive donor. 
 
4. 
To identify the viral reservoirs leading to HCV transmission in HCV-negative patients receiving a heart 
transplant from a HCV-positive donor based on endomyocardial biopsies, measures of HCV antigens in 
peripheral mononuclear blood cells, and histological examination of arterial and venous tissue 
surrounding the transplanted heart. 
 
5. 
To compare the quality-of-life of HCV-negative patients receiving a heart transplant from a HCV-
positive donor to those of similar patients remaining on the waitlist for a standard deceased donor 
heart transplant. 
 
 
 
 
 


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6 CHAPTER 3: SCREENING AND SUBJECT SELECTION 
6.1. Recruitment: identification and screening process 
The trial’s phases can be categorized as “screening phase,” (when patients are consented and will undergo 
testing and evaluation for enrollment), “waiting list phase” (when patients are enrolled and are waiting for an 
offer of transplantation) and “transplantation phase” (after a HCV-positive heart has been received and 
transplanted. 
 
We will approach patients meeting the above criteria to receive a heart transplant from an HCV-positive donor.  
We anticipate needing to approach 50 patients in order to enroll the necessary 25-35 patients. We will continue 
to follow these patients for updates on transplant status even after initial review and noted as apart of study 
data.  
 
Prior to consenting to be in the study, patients will be screened for any underlying liver diseases using serologic 
testing, and will be evaluated by a transplant hepatologist and abdominal transplant surgeon, to ensure that 
besides the underlying cardiac disease, the patient would meet criteria for listing for liver transplantation.  Once 
patients are consented and enrolled, the heart transplant team will be made aware of the patient’s enrollment, 
and he/she will then have his/her status on UNET changed to be eligible to receive a heart from an HCV-positive 
donor. 
 
We expect to screen 200 subjects, including patients being newly evaluated for a heart transplant, and those 
that are already on the waitlist.  Of these, we expect 100 to meet inclusion/exclusion criteria, of whom 35 will 
consent to be screened, and 25 will remain eligible following all screening tests. 
 
Patients who are screened will be tracked in a pre-screening log to facilitate the screening process.  The study 
team has worked with their department’s Information Technology Team and their recommendations for 
protecting potential subject health information will be put into place. 
 
Subjects who are temporarily inactive and unable to receive any heart offers until reactivated will continue to be 
followed.  If the subject is reactivated, his/her status based on the inclusion and exclusion criteria will be 
reviewed by the investigator team to ensure the patient is still eligible for the study.   
 
Only subjects who would be eligible for a liver transplant if HCV caused them to experience liver failure will be 
enrolled in this study. To be deemed eligible for a liver transplant at Penn, all patients (not only study subjects) 
must be examined by both a hepatologist and a liver transplant surgeon.  
6.2. Subject selection criteria 
6.2.1. Inclusion criteria 
• 
New York Heart Association (NYHA) Class III or IV CHF refractory to maximal medical therapy (ACE 
inhibitor, B-blocker, digoxin and diuretics, resynchronization therapy or ICD when applicable) 
and/or conventional surgery   AND/OR  Inoperable coronary artery disease with intractable 
anginal symptoms   AND/OR  Malignant ventricular arrhythmias unresponsive to medical or 
surgical therapy   
• 
40-65 years of age 
• 
Obtained agreement for participation from the transplant cardiology team 
• 
No evident contraindication to liver transplantation other than the underlying cardiac disorder 


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14 
• 
Able to travel to the University of Pennsylvania for routine post-transplant visits and study visits 
for a minimum of 6 months after transplantation 
• 
No active illicit substance abuse 
• 
Women must agree to use birth control in accordance with Mycophenolate Risk Evaluation and 
Mitigation Strategy (REMS) following transplant due to the increased risk of birth defects and/or 
miscarriage 
• 
Both men and women must agree to use at least one barrier method of birth control or remain 
abstinent following transplant due to risk of HCV transmission 
• 
Inclusion criteria for treatment (not for entry as study patient) will include any detectable HCV 
RNA by week 4 post-heart transplantation 
• 
Able to provide informed consent 
6.2.2. Exclusion criteria 
• 
Hepatocellular carcinoma 
• 
HIV positive 
• 
HCV antibody positive and/or RNA positive 
• 
Hepatitis B surface antigen, core antibody, and/or DNA positive 
• 
Any other chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD) with abnormal 
liver enzymes 
• 
Persistently elevated liver transaminases 
• 
Congenital heart disease  
• 
Fibrosis by liver biopsy or total bilirubin > 2.5 with associated evidence of synthetic dysfunction.  
• 
Pregnant or nursing (lactating) women 
• 
Known allergy or intolerance to tacrolimus that would require post-transplant administration of 
cyclosporine, rather than tacrolimus given the drug-drug interaction between cyclosporine and 
ZEPATIER 
• 
Waitlisted for a multi-organ transplant  
• 
Evidence of end organ damage due to diabetes (e.g. retinopathy, nephropathy, ulcerations) and 
/or brittle diabetes mellitus (e.g. history of diabetic ketoacidosis) and/or uncontrolled diabetes as 
evidence by a HgbA1C of 7.5-8.5.  
• 
Chronic bronchitis, chronic obstructive pulmonary disease, inability to stop smoking. 
• 
Hematologic: Significant coagulation abnormalities, bleeding diatheses. 
• 
Psychosocial: Profound neurocognitive impairment with absence of social support. 
• 
Active mental illness or psychosocial instability  
• 
Inadequate insurance or financial support for post-transplant care.  
• 
Evidence of drug, tobacco or alcohol abuse within the past six months and completion of 
recommended therapy/services or meets satisfied parameters as indicated by social work staff 
and/or consult team.  
• 
History of chronic non-compliance.  
• 
Amyloidosis (restricted to cardiac only, without evidence of extra cardiac involvement) 
• 
BMI ≥38  
• 
Active peptic ulcer disease.  
• 
Severe malnutrition.  
• 
Major chronic disabling illness (e.g. lupus, severe arthritis, neurologic diseases, previous stroke 
with profound residual). 
• 
Pulmonary infarction within the past 6 weeks  


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• 
Severe pulmonary hypertension as evidenced by a fixed pulmonary vascular resistance of greater 
than 4 Wood units on appropriate medical therapy.  
• 
Patient refusal to receive blood products or transfusions during heart transplant surgery.  
• 
Severe chronic obstructive pulmonary disease 
• 
Current clinical sepsis.  
• 
Symptomatic or severe vascular disease.  
• 
Chronic Kidney Disease Stage IV, GFR < 30  
• 
History of Mantle radiation.  
• 
Asymptomatic renal cell carcinoma <1 year from curative treatment.  
• 
Symptomatic renal cell carcinoma <5 years from curative treatment.  
• 
Prostate cancer <2 years from curative treatment.  
• 
Uterine or cervical cancer <2 years from curative treatment.  
• 
Any other cancer other than the above including malignant melanoma, < 5 years from treatment 
apart from other skin malignancies. 
• 
On mechanical circulatory support maintained on suppressive antibiotics for chronic infection. 
6.3. Donor Organ Selection Criteria 
 
General criteria (although there can be exceptions on a case-by-case basis) 
• 
Detectable HCV RNA 
• 
Genotype 1 or 4 HCV 
• 
Age <=55 years  
• 
No history of coronary artery disease 
• 
No congenital heart disease except a repaired atrial septal defect (ASD) provided the patient has 
normal right ventricular function 
• 
No history of arrhythmia (atrial fibrllation, atrial flutter or VT) except during resuscitation from fatal 
event. 
• 
No evidence of cirrhosis 
Echocardiographic criteria 
• 
Left ventricular ejection fraction (LVEF) >=50% 
• 
Normal right ventricular function  
• 
No left ventricular hypertrophy (LVH) – septal wall thickness  <1 cm 
• 
No left ventricular hypertrophy (LVH)– posterior wall thickness <1 cm 
• 
No significant valvular heart disease – more than mild tricuspid regurgitation, more than mild mitral 
regurgitation, more than trace aortic regurgitation.  No mitral or aortic stenosis.   
• 
No congenital heart disease – transposition of the great vessels, ventricular sepatal defect (VSD), 
ASD, and/or single ventricle (Fontan)  
 Right heart catheterization criteria 
• 
Right atrial pressure <=10mmHg 
• 
Pulmonary capillary wedge pressure <=18mmHg 
• 
CI >=2.1 l/min/m2 
• 
Pulmonary hypertension is allowed if the patient has normal right ventricular function and a normal 
tricuspid valve 


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16 
6.3.1. Donor Genotyping 
We will ensure that subjects only receive a heart transplant from a confirmed Genotype 1 or 4 HCV-positive 
donor by testing the HCV genotype using the standard of care assay at the Hospital of the University of 
Pennsylvania. 
 
To briefly outline this procedure, donor genotyping will be performed on specimens provided to the Molecular 
Pathology Laboratory by LABS and Gift-of-Life, the local organ procurement organization.  These specimens will 
be taken from potential heart donors once Gift-of-Life has been notified of the potential donor and will be 
qualified for testing by Gift-of-Life. Per standard of care, LABS will analyze specimens for the presence of HCV via 
serological testing and qualitative nucleic acid testing. If a specimen is positive for both HCV tests, it will be 
couriered to the University of Pennsylvania via a Gift-of-Life courier, only if and after the donor’s authorizing 
next-of-kin has given authorization for donation and research.  The Molecular Pathology Laboratory (MPL) at the 
Hospital of the University of Pennsylvania (HUP) will then determine the HCV genotype(s) present in the 
specimen.  Once resulted, a printed copy will be sent to Gift-of-Life and the study investigators, and will be kept 
in the locked research file by the study investigators. 
 
The assay that will be used for HCV genotyping is a laboratory-developed assay that was validated by the HUP 
MPL under the guidance of Vivianna Van Deerlin, MD, PhD. The validation process entailed testing multiple past 
clinical samples with known HCV genotypes, as well as purchased HCV genotype controls, and assessing 
concordance between the results obtained and the expected results.9 This assay (the eSensor® HCVg Direct Test, 
GenMark Diagnostics) has also been validated by multiple external laboratories with the following results: 
Covance Central Laboratory Services (482 samples, 98.6% concordance), University of Minnesota (135 samples, 
96.4% concordance), and the University of Washington (77 samples, 97.4%).10-12 In the HUP MPL, overall, the 
assay was able to genotype all purchased controls correctly (n=15, HCV genotypes 1 through 6, concordance = 
100%). It was also able to correctly genotype the vast majority of prior clinical samples (n=56 of 61, HCV 
genotypes 1 through 6, concordance = 92%). Resolution of discordant samples showed that the limitations of 
the assay, as determined by the validation, included decreased ability to genotype samples with: low viral loads, 
mixed genotype infections, or HCV genotype 4f infection. These limitations are felt to be minor as low viral load 
specimens are not expected from HCV-untreated organ donors, and mixed genotype / genotype 4f specimens 
are very rarely encountered in the United States. The validation samples were picked to better understand the 
limitations of the assay and so had a higher proportion of mixed infection samples (n=6) and rare genotype 
samples (e.g. Type 4f, n=1) than what is encountered clinically. A retrospective review by the MPL of HCV 
genotypes resulted at HUP over a 14-month period (July 2014 to October 2015) by the previous MPL HCV 
genotyping assay (Siemens VERSANT HCV Genotype 2.0) found a total of 6 mixed infections and one genotype 4f 
infection out of 1,551 samples tested (~0.4% and 0.06%, respectively).  
6.3.2. Drug Resistance Testing 
Participants with Genotype 1a and Genotype 1 with an unknown subtype will have baseline NS5A drug 
resistance assay testing checked at the start of treatment. The Hepatitis C Viral RNA Genotype 1 NS5a Drug 
Resistance test will be used to check for NS5A drug resistance. This test uses reverse transcription polymerase 
chain reaction (PCR) and DNA sequencing to detect mutations [resistance associated variants (RAVs)] in the 
NS5a inhibitors. It has not been cleared or approved by FDA but has been validated pursuant to the CLIA 
regulations. The test will be performed by a lab qualified by the Principal Investigator Team. It has an analytical 
sensitivity of >95% for viral loads ≥1800 IU/mL.13 Reported results include mutations and polymorphisms 
associated with NS5A inhibitor resistance (only if HCV genotype 1a, 1b, or 1 detected) as well as a patient 
specific interpretation:  
• 
Resistance predicted: ≥1 mutation predicting NS5A inhibitor resistance detected 


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• 
Resistance not predicted: no mutations predicting NS5A inhibitor resistance detected 
 
 


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7 CHAPTER 4: TREATMENTS 
7.1. Zepatier (grazoprevir and elbasvir) 
Zepatier tablets will be provided by Merck as part of this investigator-initiated protocol funded by Merck. Open-
label Zepatier (grazoprevir 100 mg and elbasvir 50 mg) will be administered once daily by mouth for 12 weeks. 
An exception to the 12 week course of treatment will be if patients have polymorphisms at positions M28, Q30, 
L31, and/or Y93 as determined by the Hepatitis C Viral RNA Genotype 1 NS5a Drug Resistance test. In this case, 
treatment with Zepatier will be extended to 16 weeks and renally-adjusted Ribavirin will be initiated at the 
clinician’s discretion, and continued for the remainder of therapy (until the 16 week mark).  Such a strategy will 
provide optimal treatment, without delaying therapy prior to receipt of results of NS5A drug resistant testing. 
Grazoprevir (GZR)/ elbasvir (EBR) is a fixed-dose combination tablet without ribavirin.  
 
GZR is an HCV ns3/4a inhibitor while EBR is an HCV NS5A inhibitor. Both are direct-acting antivirals, which 
together form an effective therapy for HCV virus and reduce the likelihood and effects of long-term liver-related 
HCV complications. GZR/EBR exhibits broad in vitro activity against most HCV genotypes and in vitro activity 
against many clinically relevant resistance-associated variants (RAVs).  
 
Zepatier (GZR/EBR) has been evaluated globally in multiple phase I, II, and III trials to treat HCV. Randomized, 
placebo-controlled trials have been completed and led to obtain FDA approval for Zepatier as a treatment for 
genotype 1 and 4 HCV. As of July 1, 2015, a diverse population of over 1000 HCV patients has been exposed to 
Zepatier either as a single agent or in combination with ribavirin or sofosbuvir in phase I/II/III studies.  Zepatier 
has been generally well tolerated at doses of 50-100 mg GZR and 50 mg EBR orally once daily.  It has been 
comparably effective across all subgroups it has been tested in, including non-cirrhotic and/or treatment-naïve 
subjects. 
 
Headaches, fatigue, and nausea represent the most common adverse drug reactions with Zepatier. Other drug-
related adverse events have included arthralgia, insomnia, diarrhea, dizziness, pyrexia, and asthenia. Drug-
related serious adverse events are uncommon, but include allergic reactions, possible adverse interactions with 
other medications, or elevated liver enzymes. In past Zepatier trials, the majority of the adverse events were 
reversible. These adverse events are usually grade 1 or 2 mild or moderate events.  
 
The dosage in our study (100/50 mg qd) is a commonly attainable dose in clinical practice. In the event dialysis is 
needed after transplant, Zepatier has shown to be safe for subjects with chronic kidney disease or who are on 
hemodialysis. Less than 1% of Zepatier is excreted renally. In Merck C-SURFER, a phase 1 randomized, controlled 
Zepatier trial, subjects with advanced heart disease tolerated the drug well for the required 12 weeks and had 
no need for dose adjustments.  
 
Zepatier trials have demonstrated a 94-100% success rate achieving HCV RNA levels of <15 IU/ml after 12 weeks 
of treatment (SVR-12) among genotype 1 and 4 HCV patients.  
 
As of January 2016, Zepatier was approved by the Food and Drug Administration. It has been extensively studies 
in multiple large clinical trials.  This drug regimen was chosen as first-line therapy, rather than other approved 
agents (i.e., Sofosbuvir/Ledipasvir, trade name Harvoni), as Zepatier has been shown to be safe and efficacious 
in patient with significant renal dysfunction. As a result, if a subject’s heart function has not fully recovered 
when treatment is initiated, the investigational agents can safely be administered, unlike other approved agents.  


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
19 
7.1.1. Administration of study medication 
Merck & Co will manufacture, package, and label Zepatier drug. There will be one bottle per subject containing a 
28-day supply (28 capsules) of 100/50 mg Zepatier tablets.   Daily dose will be one tablet.   
 
The Investigational Drug Services (IDS) pharmacy, directed by Kenneth Rockwell, PharmD, will only be required 
to store and distribute the study drug. Sofosbuvir and Ribavirin will be purchased and sourced locally. Both of 
these medications will be purchased and stored by the IDS pharmacy at Penn. Ribavirin will be generic and the 
manufacturer will vary depending on monthly price fluctuations.  
 
Zepatier will be picked up from the investigational drug services (IDS) pharmacy by the research staff at 28-day 
intervals. The study staff will deliver the medication to the subjects at their study visits (patients expected to be 
at home by the time that HCV therapy is initiated and patients will be given medication at their scheduled post-
transplant/study visit). Treatment with the study drug will begin within 4 weeks post-transplant.  If hepatitis C is 
not cured after a subject has received Zepatier, he or she will be treated with a second regimen that includes 
Zepatier plus Sovaldi (Sofosbuvir) and Ribavirin.  Any patient (male or female) receiving ribavirin as part of the 
first- or second-line regimen will be required to use two methods of birth control while on Ribavirin therapy, 
with continuing two forms of birth control for up to 6 months after the last dose of the study drug. 
 
If patients have baseline NS5A drug resistance assay testing that demonstrates polymorphisms at positions M28, 
Q30, L31, and/or Y93, treatment with Zepatier will be extended to 16 weeks, rather than 12 weeks, and renally-
adjusted Ribavirin at the clinician’s discretion will be initiated, and continued for the remainder of therapy (until 
the 16 week mark).  Such a strategy will provide optimal treatment, without delaying therapy prior to receipt of 
results of NS5A drug resistant testing. 
 
7.1.2. Drug logistics and accountability  
Study medication bottles must be stored at controlled temperature of 20°C  to 25°C (68°F to 77°F); excursions 
permitted between 15°C to 30°C (between 59°F to 86°F) in a locked, secure area.  Study drug must be protected 
from moisture.  The research staff or investigator will instruct the subject on the proper administration of 
Zepatier.  Zepatier tablets should be taken once daily by mouth.  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. If a subject loses the bottle of study medication, the 
research staff should contact Kenneth Rockwell, Pharmacist at the research pharmacy. A replacement bottle 
with the appropriate amount of study medication will be made available at the research pharmacy. 
7.1.3. Destruction and return  
At the conclusion of the study, remaining medication from the study patients (and left-over medication) will be 
destroyed at the clinical site, after approval is granted by the research pharmacy for the drug destruction plan. 
Destruction will be documented in the drug accountability form. 
7.1.4. Zepatier Initial Treatment Failures 
Study subjects with treatment failure, defined as virologic breakthrough (when an undetectable viral load while 
on treatment becomes detectable or a >= one log increase from nadir HCV RNA) or virologic relapse 
(undetectable viral load after completion of treatment that during the 12-week post-treatment follow-up period 
becomes detectable) will be provided open-label Zepatier + Sofosbuvir (Sovaldi) 400 mg + Ribavirin (generic), 
renally dosed based on creatinine clearance per the manufacturer guidelines. Any subjects who experience 
treatment failure will repeat the original study lab visit and visit protocol once they begin their secondary 
treatment with Zepatier, sofosbuvir, and ribavirin, similar to subjects initiating HCV treatment following heart 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
20 
transplantation.  Prior to initiating treatment with this regimen, patients will have serum NS5A resistance (RAV) 
testing. 
  
 


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21 
8 CHAPTER 5: DATA COLLECTION 
8.1. Study visits 
Study visits are scheduled to occur following subjects’ standard post-transplant follow-up visits. Since treating 
cardiologists do not always require stable post-transplant patients to attend these visits, subjects may be asked 
to come in solely for study visits. These visits will be encouraged, but not required unless the study drug is being 
dispensed that day. For all other study visits, a missed visit by a stable subject who has had necessary labs drawn 
will not be considered a protocol violation.  
8.1.1. Informed consent 
During the screening phase, potentially eligible, interested subjects will be invited to attend an informational 
session. The following procedures will be performed during the screening process: 
• 
Sign and date the ICF and HIPAA authorization 
• 
Review of inclusion/exclusion criteria 
• 
Schedule for screening visit 
 
After completing the informational session and signing the informed consent, the subject will be scheduled for a 
screening visit within 56 days if the subject meets inclusion/exclusion criteria thus far.  The study staff 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.  
8.1.2. Screening 
The following procedures and activities will be performed during the screening process, after the informed 
consent is signed: 
• 
Review medical history 
• 
Vital signs 
• 
Physical exam 
• 
Review current medications 
• 
Labs/phlebotomy: hepatic function panel, HCV RNA, HBV DNA, and HIV antibody 
o HBV Core Antibody will be checked in patients during screening, if not checked previously. 
• 
Serum chg. pregnancy test (for women of childbearing potential) 
• 
Completion of health status questionnaire (RAND-36) 
• 
Provide instructions on recording of new medications and dose changes 
8.1.3. Post-Heart Transplant 
8.1.3.1. Post-Heart Transplant Visits 
Patients, after receiving a heart transplant are followed very closely by both the surgical and nephrology team.  
As apart of standard of care visits, the following procedures activities will be performed: 
• 
Phlebotomy 
• 
Vital signs 
• 
Physical exam 
 
The study staff will follow procedures and activities closely along with transplant team and this information (vital 
signs, physical exam, and phlebotomy results) will be collected as apart of data collection. In addition to these 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
22 
standard of care procedures and activities, the study team will also perform specific research related activities at 
specific time points.  
8.1.3.2. Post-Heart Transplant Research Phlebotomy 
Research laboratory blood draws will take place along with standard of care blood draws outlined in Section 
8.2.1. The study staff will call the research subject to coordinate research blood draws appropriately. In addition, 
study staff will assess for adverse events/side effects and obtain current medication data.  
 
As outlined in Section 8.2.1, patients with a positive HBV Core Antibody, HBV-DNA levels will be checked every 6 
weeks while on Zepatier and LFTs will be closely monitored. HBV therapy may be considered the transplant 
team as medically appropriate. 
 
Additional laboratory testing will be done if the PIs feel it is necessary for patient safety. 
8.1.3.3. Visit 1: Post-Heart Transplant (day 3 ± 1) 
The study staff will meet the subject in their HUP hospital room, three days after their heart transplant.  
 
Initiating treatment with Zepatier 
Treatment with the study drug will begin when the patient has a detectable and quantifiable HCV RNA post-
transplantation. All subjects will be provided with a 28-day supply of the study drug and instructed to begin 
treatment once HCV RNA is confirmed, which may occur any time between weeks 1-4. When the subject begins 
treatment for HCV with Zepatier, the staff will notify the subject’s primary cardiologist and primary care 
physician. 
 
As with any scientific protocol, safety will be considered before treating the patients. The treating physician will 
evaluate the patient’s overall condition and make a judgment on whether initiating treatment is safe. 
 
The following research procedures and activities will be performed: 
• 
Assess for Adverse Events 
• 
Obtain medication data 
• 
Research Phlebotomy, including the NS5A drug resistance assay testing (See Section 8.2.1 for complete 
list) 
• 
Dispense study drugs 
 
Blood samples for immunologic t-cell assays will be processed and banked or shipped.  
8.1.3.3.1. Management of patients with NS5A resistance variants 
Once HCV infection is confirmed, patients will have their HCV genotype reconfirmed. Patients with Genotype 1a 
and Genotype 1 with an unknown subtype will have baseline NS5A drug resistance assay testing. This will be 
checked at start of treatment. If patients have polymorphisms at positions M28, Q30, L31, and/or Y93, 
treatment with Zepatier will be extended to 16 weeks, rather than 12 weeks, and renally-adjusted Ribavirin at 
the clinician’s discretion will be initiated, and continued for the remainder of therapy (until the 16 week mark).  
Such a strategy will provide optimal treatment, without delaying therapy prior to receipt of results of NS5A drug 
resistant testing.  Under such a scenario, all of the study procedures referenced above and below will be 
extended by 4 weeks. Any patient (male or female) receiving ribavirin as part of the first- or second-line regimen 
will be required to use two methods of birth control while on Ribavirin therapy, with continuing two forms of 
birth control for up to 6 months after the last dose of the study drug. 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
23 
8.1.3.3.2. Management of patients with positive HBV Core Antibody 
For patients with a positive HBV Core Antibody, HBV-DNA levels will be checked every 6 weeks while on Zepatier 
and LFTs will be closely monitored. HBV therapy may be considered the transplant team as medically 
appropriate. 
8.1.3.4. Visit 2: Post-Heart Transplant (day 10 ± 2 day) 
Visit #2 should occur two weeks (10 ± 2 days) after the subject’s heart transplant and coincide with the subject’s 
regularly scheduled post-transplant follow-up visit. The staff will call the subject 1-2 days before the visit.  
During this phone call, the research staff will remind the subject where to go for the study visit,  to take their 
routine and study medications as they usually would prior to the visits.  
 
The subject will arrive at the study site outpatient clinic. The following procedures and activities will be 
performed: 
• 
Assess for Adverse Events 
• 
Obtain medication data 
• 
Research Phlebotomy (See Section 8.2.1 for complete list) 
• 
Pill count and drug diary assessed for adherence 
• 
Schedule appointments for follow-up visits 
8.1.3.5. Visit 3: Post-Heart Transplant (day 21 ± 3 days) 
Visit #3 should occur three weeks (21 ± 3  days) after the patient’s heart transplant and coincide with the 
subject’s regularly scheduled post-transplant follow-up visit. The staff will call the subject 1-2 days before the 
visit.  During this phone call, the research staff will remind the subject where to go for the study visit,  to take 
their routine and study medications as they usually would prior to the visits. 
 
The subject will arrive at the study site outpatient clinic. The following procedures and activities will be 
performed: 
• 
Assess for Adverse Events 
• 
Obtain medication data 
• 
Research Phlebotomy (See Section 8.2.1 for complete list) 
• 
Pill count and drug diary assessed for adherence 
• 
Schedule appointments for follow-up visits 
8.1.3.6. Visit 4 Post-Heart Transplant (day 28 ± 3 days) 
Visit #4 should occur 4 weeks (28 ± 2 days) after the subject’s heart transplant and coincide with the subject’s 
regularly scheduled post-transplant follow-up visit. The staff will call the subject 1-2 days before the visit.  
During this phone call, the research staff will remind the subject where to go for the study visit,  to take their 
routine and study medications as they usually would prior to the visits. 
 
The subject will arrive at the study site outpatient clinic. The following procedures and activities will be 
performed: 
• 
Assess for Adverse Events 
• 
Obtain medication data 
• 
Research Phlebotomy (See Section 8.2.1 for complete list) 
• 
Health Status Questionnaire (RAND-36) (to assess changes in health status from pre- to post-transplant) 
• 
Pill count and drug diary assessed for adherence 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
24 
• 
Replenish study drug 
• 
Schedule appointments for the follow-up visits 
 
HCV Non-Transmission 
It is possible that a subject may not develop chronic HCV infection, either due to non-transmission or 
spontaneous clearance of HCV by week 4 (defined as an initial positive HCV RNA and subsequent undetectable 
HCV RNA without treatment).  If a subject has an undetectable HCV RNA based on the week 4 HCV RNA, a repeat 
HCV RNA will be checked at week 8 to ensure non-infection with HCV, rather than a false-negative HCV RNA.  If 
the week 8 HCV RNA confirms lack of infection (undetectable week 8 HCV RNA), then no further treatment will 
be needed. Subjects will be assessed at a study visit and HCV RNA levels re-checked at week 16 and 28 post-
heart transplantation. Should any subject spontaneously clear HCV without treatment, another subject will 
replace them in order to meet our planned treatment sample size. 
8.1.3.7. Visits 5-7: Post-Heart Transplant (day 42±7, day 56±7, day 70±7) 
Visit #5 should occur 6 weeks (42±7 days) after the subject’s heart transplant and will coincide with the subject’s 
regularly scheduled post-transplant follow-up visit.  Visit #6 should occur 8 weeks (56±7 days) after the subject’s 
heart transplant and will immediately follow the subject’s regularly scheduled post-transplant follow-up visit. 
Visit #7 should occur 10 weeks (70±7 days) after the subject’s heart transplant and will immediately follow the 
subject’s regularly scheduled post-transplant follow-up visit. 
 
For both visits, the staff will call the subject 1-2 days before the visit to remind subject of visit. During this phone 
call, the research staff will remind the subject where to go for the study visit,  to take their routine and study 
medications as they usually would prior to the visits. 
 
The following procedures and activities will be performed: 
• 
Assess for Adverse Events 
• 
Obtain medication data 
• 
Research Phlebotomy (See Section 8.2.1 for complete list) 
• 
Replenish study drug 
• 
Pill count and drug diary assessed for adherence 
• 
Schedule appointments for follow-up visits 
 
The staff will replenish the subject’s 28-day supply of the Zepatier study drug sometime during visits #5 & 6, 
depending on when the subject began treatment.  
8.1.3.8. Visits 8 & 9: Post-Heart Transplant (day 87 + 7, day 115 + 14) 
Visit #8 should occur 12 weeks (87 + 7 days) after the subject’s heart transplant and will coincide with the 
subject’s regularly scheduled post-transplant follow-up visit.  Visit #9 should occur 16 weeks (115 + 14 days) 
after the subject’s heart transplant and will immediately follow the subject’s regularly scheduled post-transplant 
follow-up visit.  
 
Midway between these study visits, subjects will be phoned in order to ensure drug adherence, if necessary 
 
For both visits, the staff will call the subject 1-2 days before the visit to remind subject of visit. During this phone 
call, the research staff will remind the subject where to go for the study visit,  to take their routine and study 
medications as they usually would prior to the visits. 
 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
25 
The following procedures and activities will be performed: 
• 
Assess for Adverse Events 
• 
Obtain medication data 
• 
Research Phlebotomy (See Section 8.2.1 for complete list) 
o Note: Timing for HCV RNA viral load, post treatment, should, as best possible, follow the 
important data collection points post treatment. These are as follows: 
 
Post-treatment: This should occur after the subject has completed treatment of the 
study drug. 
 
SVR 4: This should occur ~4 weeks after the subject has completed treatment. 
 
SVR 8: This should occur ~ 8 weeks after the subject has completed treatment. 
 
SVR 12: This should occur ~12 weeks after the subject has completed treatment. 
 
SVR 24: This should occur ~24 weeks after the subject has completed treatment. 
• 
Health Status Questionnaire (RAND-36) (to assess changes in health status from pre- to post-transplant) 
• 
Pill count and drug diary assessed for adherence 
• 
Replenish study drug 
o Note: The staff will replenish the subject’s supply of the Zepatier study drug between visits 7 & 
8, if necessary.  This is based on management of patients NS5A resistance variants, in any were 
are present .  The staff will also remind the subject how to take the medication, for those 
subjects still on study medication. 
8.1.3.9. Visit 10 Post-Heart Transplant (day 171 ±7 days) 
Visit #10 should occur 24 weeks (171 ±7 days) after the subject’s heart transplant and will coincide with the 
subject’s regularly scheduled post-transplant follow-up visit.   
 
For this visit, the staff will call the subject 1-2 days before the visit.  During this phone call, the research staff will 
remind the subject where to go for the study visit,  to take their routine and study medications as they usually 
would prior to the visits. 
 
The following procedures and activities must be performed: 
• 
Assess for Adverse Events 
• 
Research Phlebotomy (See Section 8.2.1 for complete list) 
o Note: Timing for HCV RNA viral load, post treatment, should, as best possible, follow the 
important data collection points post treatment. These are as follows: 
 
Post-treatment: This should occur after the subject has completed treatment of the 
study drug. 
 
SVR 4: This should occur ~4 weeks after the subject has completed treatment. 
 
SVR 8: This should occur ~ 8 weeks after the subject has completed treatment. 
 
SVR 12: This should occur ~12 weeks after the subject has completed treatment. 
 
SVR 24: This should occur ~24 weeks after the subject has completed treatment. 
• 
Health Status Questionnaire (RAND-36) (to assess changes in health status from pre- to post-transplant) 
8.1.3.10. Visit 11 Post-Heart Transplant (day 365 ±14) 
Visit #10 should occur 52 weeks (365 ±14 days) after the subject’s heart transplant and will coincide with the 
subject’s regularly scheduled post-transplant follow-up visit.   
 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
26 
For this visit, the staff will call the subject 1-2 days before the visit.  During this phone call, the research staff will 
remind the subject where to go for the study visit,  to take their routine and study medications as they usually 
would prior to the visits. 
 
The following procedures and activities must be performed: 
• 
Assess for Adverse Events 
• 
Research Phlebotomy (See Section 8.2.1 for complete list) 
• 
Health Status Questionnaire (RAND-36) (to assess changes in health status from pre- to post-transplant) 
 
The Research Staff should fill out the Study Closeout Form. This form must be signed by the principal 
investigator. 
8.1.3.11. Additional Visits  
Additional visits will only be necessary in the case of treatment failures. If treatment failure occurs, subjects will 
be treated with Zepatier and two other hepatitis C medications, Sofosbuvir (Sovaldi), and Ribavirin for an 
additional 12 weeks. All study and lab visits will be repeated during this secondary treatment period.  NS5A 
resistance (RAV) testing will be checked again (a second time) prior to initiating second-line therapy. 
8.1.4. Future research 
Subjects will also be approached to provide optional blood sample for testing of viral kinetics (HCV RNA), donor 
and recipient IL-28B polymorphisms, and alloimmune responses (T- and B-cell function).  Samples will be stored 
in a locked freezer, using encrypted patient IDs.  
 
De-identified samples from subjects may be sent to other investigators for their research. These samples may 
include information such as sex, age, health history, or ethnicity. These samples will not be sold. Some future 
studies may need health information (such as smoking history or present health status) that may require 
contacting the subject to obtain. 
8.2. Study schedule of procedures 
8.2.1. Visits, lab testing, and other clinical testing   
See next page for table. 
 


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27 
 
 
Visit Schedule 
Research Visit Activities 
Research Labs 
Standard of Care 
Week(s) post-KT 
Day(s) post-
KT 
Visit 
Study Visits 
Lab-Only 
Informed Consent 
Assess Adverse Events 
Current Medications 
RAND-36 
Health Status 
Questionnaire
HBV DNA HIV AB & LFTs 
HBV Core Antibody 
Urine Preg Test 
Urine Protien/Cre Ratio 
HCV RNA 
Viral Kinetics (optional) 
NS5A Resistance 
Genotyping 
Vitals & 
Physical Exam 
Surveillance biopsy 
CMP* 
CBC 
Tacrolimus 
Screening 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
 
 
 
✓ 
 
 
 
 
1 (Begin 
treatment) 
3 ± 1 day 
V1 
✓ 
 
 
✓ 
✓ 
 
 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
1 
7 ± 1 day 
 
 
✓ 
 
 
✓ 
 
 
 
 
 
✓ 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
2 
10 ± 1 day 
V2 
✓ 
 
 
✓ 
✓ 
 
 
 
 
 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
2 
14 ± 1 day 
 
 
✓ 
 
 
✓ 
 
 
 
 
 
✓ 
✓ 
 
 
 
\ 
✓ 
✓ 
✓ 
3 
21 ± 3 day 
V3 
✓ 
 
 
✓ 
✓ 
 
 
 
 
 
✓ 
✓ 
 
 
✓ 
 
✓ 
✓ 
✓ 
4 
28 ± 3 day 
V4 
✓ 
 
 
✓ 
✓ 
✓ 
 
 
 
✓ 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
6 
42 ± 7 day 
V5 
✓ 
 
 
✓ 
✓ 
 
 
✓ 
 
 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
8 
56 ± 7 day 
V6 
✓ 
 
 
✓ 
✓ 
 
 
 
 
 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
10 
70 ± 7 day 
V7 
✓ 
 
 
✓ 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
12 
84 ± 7 day 
V8 
✓ 
 
 
✓ 
✓ 
 
 
✓ 
 
✓ 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
13 
 (End treatment)† 
91 ± 7 day 
 
 
✓ 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
16 (SVR 4)† 
112 ±14 day 
V9 
✓† 
 
 
✓ 
✓ 
✓ 
 
 
 
 
✓ 
✓ 
 
 
✓† 
✓ 
✓ 
✓ 
✓ 
20 (SVR 8) 
140 ±7 day 
 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
24 (SVR 12) 
168 ±14 day 
V10 
✓ 
 
 
✓ 
 
✓ 
 
 
 
✓ 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
28† 
196 ±7 day 
 
 
✓ 
 
 
 
 
 
 
 
 
 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
32 
224 ±7 day 
 
 
✓ 
 
 
 
 
 
 
 
 
 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
36  (SVR 24) 
252 ±7 day 
 
 
✓ 
 
 
 
 
 
 
 
✓ 
✓ 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
40 
280 ±14 day 
 
 
✓ 
 
 
 
 
 
 
 
 
 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
52 
365 ±14 day 
V11 
✓ 
 
 
✓ 
 
✓ 
 
 
 
✓ 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
* CMP=comprehensive metabolic panel which includes basic metabolic panel and liver function tests        Viral Kinetics testing can be done anytime there is a standard of care blood draw 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
28 
†If patients require the 16 weeks of therapy, the last 4 weeks would be the same as weeks 9-12 of therapy        Only if HBV Core Antibodies are positive. 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
29 
8.2.2. Blood sampling volumes 
Maximum Post-Transplant Blood Draw Totals 
Week 
Post-
KT 
CBC CMP Tacrolimus 
HBV 
Core 
Antibody 
HCV 
RNA 
Viral 
Kinetics 
(optional) 
NS5A 
Resistance 
Blood Draw Total 
1 
4 
4.5 
4 
4 
6 
6 
2 
28.5 
1 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
2 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
2 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
3 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
4 
4 
4.5 
4 
0 
6 
6 
0 
18.5 
6 
4 
4.5 
4 
4 
6 
6 
0 
24.5 
8 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
10 
4 
4.5 
4 
0 
0 
6 
0 
18.5 
12 
4 
4.5 
4 
4 
6 
6 
0 
28.5 
16 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
20 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
24 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
28 
4 
4.5 
4 
0 
0 
6 
0 
18.5 
36 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
40 
4 
4.5 
4 
0 
0 
6 
0 
18.5 
52 
4 
4.5 
4 
0 
6 
6 
0 
24.5 
Total 
68 
76.5 
68 
0 
84 
102 
2 
400.5 
 There may be additional blood draws due to optional Viral Kinetics lab testing increasing the total sample 
volume. 
8.3. Subject retention and drug adherence 
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 staff 
will call before each study visit to remind the subject to attend.  We will also obtain contact information of a 
family member or friend so that we can contact him/her if the subject does not answer his/her regular phone 
number. 
An adequate record of receipt, distribution, and return of all study drugs must be kept. Subject adherence 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 staff and physician will explain the importance of adherence with the study protocol at each 
subject contact. If a subject fails to comply with a study visit, the staff will contact him or her by telephone. If 
this fails, the staff will send two certified express letters one week apart, to request follow-up. 
We have considered how to minimize non-adherence 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 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 


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30 
will allow for analysis by intention-to-treat. If a study subject withdraws consent, he/she will no longer be 
followed. 
 


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31 
9 CHAPTER 6: ASSESSMENT OF EFFICACY AND OUTCOME MEASURES 
9.1. Assessments of Efficacy 
The primary aims of the study are to determine sustained virologic response rates (SVR) of open-label Zepatier 
administered to HCV-negative patients with heart failure who receive a heart transplant from a genotype 1 or 4 
HCV-positive donor, leading to post-transplant de-novo HCV infection.   
9.1.1. Sustained Virologic Response (SVR) 
SVR will be based on the standard definition of SVR-12, defined as an undetectable HCV RNA in a subject’s 
serum 12 weeks after completing treatment for HCV (12 weeks after the subject takes the last dose of Zepatier). 
9.2. Secondary Outcome Measures 
• 
To determine safety of administering Zepatier to heart transplant recipients who were previously HCV-
negative, but developed de-novo HCV after receiving a heart transplant from an HCV-positive donor 
• 
To determine 1-year graft survival rates of HCV-negative heart transplant patients who receive a heart 
transplant from a genotype 1 or 4 HCV-positive donor, including those who spontaneously clear HCV 
and those who receive open-label Zepatier upon development of de-novo HCV. 
• 
To evaluate rates of spontaneous clearance of HCV among HCV-negative patients who receive a heart 
transplant from a genotype 1 or 4 HCV-positive donor. 
9.2.1. Safety 
Subject safety and adverse events will be based in CTCAE Version 4 criteria, listed in Section 13, and will include 
adverse events and serious adverse events, related both to receipt of a heart transplant from an HCV-positive 
donor among HCV-negative subjects with heart failure, and adverse events related to administration of Zepatier. 
9.2.2. Graft Survival 
Graft survival will be based on standardize United Network for Organ Sharing (UNOS) criteria, with a graft failure 
defined as subject death, or re-transplantation  within the first year post-transplantation. 
9.2.3. Spontaneous Clearance or Non-Transmission of HCV 
Spontaneous clearance or non-transmission of HCV will be based on an undetectable HCV RNA level at post-
transplant weeks 1-4 in the absence of treatment among HCV-negative subjects who receive a heart transplant 
from a confirmed genotype 1 or 4 HCV-positive donor. Any subject who experiences spontaneous clearance of 
HCV or non-transmission of HCV will still be tested for HCV RNA at weeks 8, 16, and 28, to ensure that their 
levels are still undetectable.  


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10 CHAPTER 7: STATISTICAL CONSIDERATIONS 
10.1. Study Design 
This open-label trial involves one primary and several secondary objectives.  Post-transplant HCV status will be 
monitored, and patients will be treated with 12-16 weeks of Zepatier therapy, after which time, treatment will 
be complete, barring instances of treatment failure, which would require an additional 12 weeks of therapy.*   
10.2. Disposition of Subjects and Baseline Comparisons 
Summaries of all subjects screened, recruited, and enrolled will be provided, according to the CONSORT 
guidelines. The treatment groups will be evaluated at baseline with respect to demographics and baseline 
measurements related to efficacy and safety without formal statistical testing. 
10.3. Analyses of Outcome Measures 
The primary analysis will evaluate SVR-12 rates of HCV-negative heart transplant recipients who receive a heart 
from an HCV-positive donor and subsequently develop de-novo HCV.  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.  
10.4. 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. Subjects who withdraw consent 
will no longer be followed in this protocol.  Patients will receive care from the patients’ clinicians. 
 
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. 
10.5. Protocol Violations 
Serious protocol deviations such as discontinuation of experimental treatment unrelated to adverse events (AEs) 
will be carefully recorded and regularly reviewed by co-Principal Investigators. Remedial changes in procedure 
will be recommended where feasible to reduce the incidence of such deviations. 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. A missed study visit will not be considered a 
protocol violation unless the study drug was scheduled to be dispensed at the visit, the subject did not have 
necessary labs done, or the subject has not been stable.  
10.6. 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 at days 14, 30, 60, 90, 118, 
and 184, and will be reported at each DSMB meeting.  SAEs will be evaluated by the DSMB..  
 
 


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11 CHAPTER 8: QUALITY CONTROL AND DATA HANDLING 
 
11.1. Personnel Training 
Prior to enrolling the first subject in the study protocol, the Principal Investigators will ensure that the 
Investigator 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 staff who will perform the outcome assessments 
will be trained in all procedures, including completion of the REDCap database. 
 
The co-PIs 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 IB. 
11.2. Data Quality  
The co-PIs and research staff will perform continuous monitoring of data quality and completion of CRFs. All 
consent forms and screening logs will be subject to audit by the University of Pennsylvania.  Summary statistics 
from the screening logs will be sent to Merck quarterly or as requested. Finally, Merck staff reviews the 
reporting, documentation and follow-up of SAEs to assure that these events were handled according to required 
study procedures.  All data on AEs and SAEs will be made available to the DSMB, as per the timeline outlined in 
the DSMB Charter. 
11.3. Audit and Inspection 
Inspections may be carried out by regulatory health authority representatives [i.e., FDA] as well as the IRB. 
11.4. 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. 
 
 
 


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12 CHAPTER 9: PARTICIPANT SAFETY AND CONFIDENTIALITY 
 
12.1. Informed Consent 
Informed 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 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 after the subject consents voluntarily and 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 sign and date the form.  The 
subject 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 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. 
 
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. 
12.2. Institutional Review Board Process  
Study staff will obtain IRB approval before any study procedures are initiated. 
 
12.3. Insurance 
The heart transplant itself will be paid for by subjects’ insurance carriers, and does not require any additional 
pre-authorization because of the potential to receive a heart from a hepatitis C-positive donor.  The costs of all 
visits and tests described above will be billed to the insurance carrier, except for the blood draw for research 
purposes (which includes the hepatitis C genotype test, which is based on a laboratory-developed test using 
materials purchased from the commercial entity that developed this test, and will be paid for by the research 
team), and the study drug, which will be paid for by Merck. Subjects are still responsible for any deductibles or 
applicable co-pays for routine office visits, blood work and procedures. We do not expect subjects to have 
health insurance coverage/payment issues due to becoming infected with hepatitis C, per se, and the study is 
designed so subjects do not require additional study visits post-transplant, provided there are no adverse 
events. 
 


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35 
12.4. Laboratory Values 
The following clinical laboratory tests will be measured and repeated at time points specified in schedule of 
procedures (section 8.2.1) and as clinically indicated. 
12.4.1. Chemistry 
• 
Hepatic function panel including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, 
total and direct bilirubin, and albumin.   
• 
Basic metabolic panel including BUN and creatinine. 
12.4.2. Serum virologic testing 
• 
HCV RNA (with Genotyping per protocol) 
• 
Hepatitis B surface antigen  
• 
HIV antibody testing.    
• 
HBV Core Antibody (as needed) 
12.4.3. Pregnancy Testing 
Blood and urine pregnancy tests will be performed (as appropriate) per the schedule of procedures (section 5.2). 
12.4.4. Hepatitis C Viral Kinetics  
Each time standard of care laboratories are drawn, subjects may have one additional purple -top tube drawn 
(4cc of blood). This blood test is optional. The research coordinator will process the tube and store it in a -80◦ 
freezer in the Perelman Center for Advanced Medicine 7th Floor Gastroenterology Research Office. Each month, 
these tubes will be shipped to Abbott Pharmaceuticals so they can test for HCV antibodies, HCV core antigen, 
and HCV RNA. These additional tests will be included in the informed consent process for all subjects. Abbott will 
perform these tests free of charge to University of Pennsylvania once both are able to reach a Material Transfer 
Agreement (MTA). 
12.4.5. IL28B Genotype Testing 
At the time of the subject’s heart transplant, both donor and recipient will have one tube of blood drawn to be 
used for IL28B Genotype Testing. Donors’ families will have already agreed to this test when they consent to 
research testing. Recipients must sign an additional consent form before this test is performed.  
12.5. Zepatier Related Laboratory Abnormalities and Drug Interactions 
Laboratory Abnormalities 
The following laboratory abnormalities were observed in studies done with Zepatier: 
 
Late elevations in aminotransferase levels greater than 5 times the upper limit of normal generally occurred in around 1-
3% of patients in previous Zepatier clinical trials; these increases were rarely associated with hyperbilirubinemia. These 
abnormalities were reversible and had no major clinical consequences.  
 
Effects of Zepatier on antiretrovirals: 
• 
Atazanavir/ritonavir 300/100mg co-administered with MK-5172 200mg daily somewhat increased atazanavir 
exposure (AUC increased 43%, Cmax increased 12%, C24 increased 23%). Co-administration of these 
medications is not recommended.  


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
36 
• 
Darunivir/ritonavir 600/100 mg co-administered with MK-5172 200 mg was not significantly altered by either 
MK-5172 or MK-8742. However, due to DRV/r effects on Zepatier exposure, co-administration is not 
recommended.  
• 
Efavirenz was not significantly impacted when co-administered with Zepatier, though it may negatively impact 
Zepatier exposure. 
• 
Lopinavir/ritonavir exposures were not significantly impacted when co-administered with Zepatier. However, 
due to LPV/r effects on Zepatier exposure, co-administration is not recommended.  
 
Effect of Antiretrovirals on Zepatier: 
• 
Atazanavir/ritonavir 300/100mg co-administered with MK-5172 200mg significantly increased exposure 
of MK-5172 (AUC increased 10.58-fold, Cmax increased 6.24-fold, and C24 increased 11.6-fold). These 
findings were similar when ATV/r was combined with 50mg MK-8742. MK-8742 AUC geometric mean 
ratio (GMR) was 4.76, probably due to ATV/r CYP3A4/Pgp inhibition and possible inhibition of OATP-
mediated disposition of MK-8742. Co-administration of these medications is not recommended.  
• 
Exposures of MK-5172 were significantly increased when MK-5172 200 mg was co-administered with 
darunavir/ritonavir 600/100 mg daily. MK-5172 AUC increased 7.5-fold, Cmax increased 5.27-fold, and 
C24 increased 8-fold. MK-8742 exposures were also significantly increased when combined with DRV/r 
600/100 mg daily. MK-8742 AUC GMR following co-administration was 1.66. This increase is likely 
caused by CYP3A4/Pgp inhibition by DRV/r and possibly inhibition of OATP-mediated disposition of MK-
8742. For these reasons, co-administration of Zepatier and DVR/r is not recommended.  
• 
Efavirenz 600mg co-administration with MK-5172 200 mg decreased MK-5172 AUC by 84%, most likely 
due to CYP3A4 induction. The same dose EFV combined with MK-5172 50 mg also decreased MK-8742 
AUC 54% for the same reasons. Co-administration of these medications may cause sub-therapeutic MK-
5172 exposure. 
• 
Lopinavir/ritonavir 400/100 mg co-administered with MK-5172 200 mg significantly increased MK-5172 
exposure. MK-5172 AUC increased 12.86-fold, Cmax increase 7.31-fold, and C24 increased 21.7-fold. 
When the same dose of LPV/r was administered with MK-8742 50 mg, MK-8742 AUC GMR was 
increased to 3.71. LPV/r likely impacts MK-8742 exposures due to CYP3A4/Pgp inhibition and possible 
inhibition of OATP-mediated disposition. Co-administration of these medications is not recommended.  
 
Effect of Zepatier on Other Drugs: 
• 
Rosuvastatin 10 mg co-administered with Zepatier 200/50 mg increased rosuvastatin exposure. 
Rosuvastatin AUC and Cmax were increased 59% and 325% respectively when exposed to MK-5172 
alone and 126% and 449% when exposed to the combined Zepatier pill. The most likely cause of the 
increase is pre-systemic inhibition of rosuvastatin efflux in the liver and/or gut due to BCRP inhibition. 
Clinicians may want to avoid co-administration of Zepatier and rosuvastatin.  
• 
Midazolam 2 mg/mL combined with multi-dose MK-5172 200 mg daily decreased midazolam AUC to 
34%. MK-5172 is likely a weak CYP3A4 inhibitor.  
• 
Multiple oral doses of rifampin did not significantly affect MK-5172 AUC, but reduced C24h by 85%. This 
decrease was presumably due to the combined effect of OATP inhibition and CYP3A4/Pgp induction by 
chronic rifampin administration. Clinicians should avoid co-administration of these medications until 
further data becomes available. 
 
Effect of Other Drugs on Zepatier: 
• 
Rosuvastatin 10 mg co-administered with Zepatier 200/50 mg did not significantly alter MK-5172/8742 
exposure. However, due to Zepatier effects on rosuvastatin exposure, clinicians may wish to avoid co-
administration. 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
37 
• 
Ketoconazole (CYP3A4 and P-gp inhibitor) approximately tripled MK-5172 AUC. In healthy male subjects 
taking 400 mg multi-dose ketoconazole, MK-8742 AUC increased by 31%.   
• 
Combining MK-5172 200 mg and a single dose of 600 mg IV rifampin caused a 12.6-fold increase in MK-
5172 AUC, compared to an 8.35-fold increase with a single dose of oral rifampin 600 mg. This is likely 
due to P-gp and OATP inhibition by rifampin. Clinicians should avoid co-administration of these 
medications until further data becomes available.  
12.6. 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 may or may 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. 
12.7. Safety and Adverse Events 
12.7.1. Definitions 
Adverse event (AE):  Any untoward medical occurrence associated with the protocol procedures, whether or 
not considered product or process related. Any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Inter-current 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 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
38 
there is evidence to suggest a causal relationship between the drug/investigational product and the adverse 
event.  
 
Unanticipated Adverse Device Effect (ADE):  is any serious adverse effect on health or safety, or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or application, or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
12.7.2. Classifying Adverse Events 
Severity 
 
The intensity of the AE is classified according to the CTCAEv4.0.14  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/ADE known to be associated with the intervention or condition under study. 
Unexpected:  an AE/ADE 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. 
 
Relatedness 
1) Definite: the AE/ADE is clearly related to the research procedures 
2) Probably: the AE/ADE is likely related to the research procedures 
3) Possible: the AE/ADE may be related to the research procedures 
4) Unlikely: the AE/ADE is doubtfully related to the research procedures 
5) Unrelated: the AE/ADE is clearly not related to the research procedures 
 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
39 
For each identified AE/ADE, an entry on the AE/ADE form will be completed. Reporting procedures should be 
started immediately upon learning of a SAE/ADE. 
12.7.3.  Interpretation of Definitions 
AE Reporting Period 
The study period during which AEs must be reported is normally defined as the time of consent to the end of the 
study treatment follow-up. However, for this study, the AE reporting period will be divided based on the three 
phases of the study. 
 
a. Screening phase: When all screening tests have been done, we will assess for any AEs related to the 
screening tests at the time of communication with the subject about whether he/she is official eligible or 
ineligible for the study.  
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. 
 
b. Waitlist phase:   We will only capture AEs that are pertinent to the study. Specifically the following will be 
captured:  
1. Patient death,  
2. Patient develops a condition that would exclude them from the study,  
3. Patient is de-listed (taken off the heart transplant waitlist),  
4. Patient is made inactive on the transplant waitlist,  
5. Patient is transplanted with a non-HCV heart.   
In order to ascertain these events, we will review the patient’s medical record once a month, and will 
contact the patient (by phone, e-mail, or in-person) every 6-8 weeks. 
 
c. Post-transplant phase: All AEs will be assessed at every clinic visit when the subject is seen by a member 
of the study team.   
 
d. Post-study: At the last scheduled visit, the investigator will 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.   
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.  The investigator should notify the IRB 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 IRB will 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. 
 
General Physical Examination Findings (screening, post-transplant, and post-study phases) 
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. 
 
 
Abnormal Laboratory Values (post-transplant, and post-study phases) 
A clinical laboratory abnormality should be documented as an AE if any one of the following conditions is met: 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
40 
• 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 (post-transplant and post-study phase) 
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, with the exception of hospitalization at the 
time of a heart offer and/or heart transplant.  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. 
12.7.4. Reporting Procedures for Unanticipated Problems, Adverse Events, and Adverse Device Effects 
Principal investigators should notify and 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/ADE 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: 
 
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 
Related to the research procedures (An event is “related to the research procedures” if in the opinion of the 
principal investigator, the event was more likely than not to be caused by the research procedures.) 
AND 
Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
 
Additionally, all adverse events/adverse device effects shall be documented by the PI team, assessed, and 
shared with. All Serious Adverse Events will be forwarded to Merck Worldwide Product Safety. 
 
 
What Event is Reported 
By Whom is Event 
Reported 
To Whom is Event 
Reported 
When is Event Reported 


Transplanting HCV Hearts into HCV Negative Heart Recipients            Protocol V.2.5 02/06/2018 
41 
 
12.7.4.1. Reporting Process 
UPs posing risks to subjects or others as noted above will be reported to local IRB using a Medwatch or CIOMS 
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) will be 
completed. 
Fatal unexpected, suspected serious 
adverse event 
 
(SAE/ADE – death that is unexpected 
and poss/prob/def related to the 
research) 
Investigator 
Local IRB 
Within 24 hours of initial 
receipt of information 
Life-threatening unexpected, 
suspected serious adverse reactions 
 
(SAE/ADE- life-threatening, 
unexpected, poss/prob/def related to 
the research) 
 
Investigator 
Local IRB 
Within 3 calendar days of 
initial receipt of 
information  
 
Non-fatal, non-life-threatening 
unexpected, suspected serious 
adverse reactions 
 
(SAE/ADE – unexpected, poss/prob/def 
related, non-life-threatening 
hospitalization, prolonged 
hospitalization, 
disability/incapacity/birth defects, 
important medical event)  
Investigator 
Local IRB 
Unanticipated Problem that is not an 
SAE 
 
(AE/ADE 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/ADE 
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 
Investigator 
Local IRB 
Within 10 calendar days of 
initial receipt of 
information 


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42 
 
All Serious Adverse Events, regardless of causal relationship to the investigational product, will be forwarded to 
Merck Worldwide Product Safety via fax (215-993-1220) within 2 working days of the investigator becoming 
aware of the event and no later than 3 calendar days. 
 
The Principal Investigator is expected to provide as much of the following information: 
• 
Protocol name and number 
• 
Subject identifiers (no PHI will be shared with the IRB, unless requested) 
• 
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 
o Clinical assessment of participant conducted at time of SAE/AE 
o Results of any laboratory and/or diagnostic procedures, and treatment 
o Follow-up plan 
o Outcome 
o Autopsy findings (if appropriate) 
The Principal Investigator will provide details about the AE/ADE as they become available. If additional 
information cannot be obtained for whatever reason, this will be documented. The Principal Investigator should 
inform the IRB when no other information is expected. The Principal Investigator should provide the IRB with a 
logical, complete, and accurate narrative description of the SAE based upon the above information. 
 
The Principal Investigator should promptly determine an assessment of causality 
 
The IRB determines if any corrective actions should be initiated as a result of any known specific or collective 
SAE/AE(s) and inform the principal investigator of the corrective action (e.g., revision of informed consent form, 
protocol, CRF). 
 
The Principal Investigator/designee should keep originals or photocopies of all relevant documentation, 
including facsimile confirmations, and file them in the participant's file.  
 
The Principal Investigator should ensure that all routine AE(s) are reported as part of the periodic or annual 
reporting requirements to the IRB of record. 
 
The Principal Investigator should file copies of all correspondence with the IRB in the appropriate section of the 
Regulatory Master File or site study file. 
 
 
Other Reportable Events: 
The following events are also reportable to the IRB: 


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• 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. 
• 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. 
 
Unanticipated Problem Involving Risks to Subjects or Others (UPRSO): 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 
 
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. 
12.8. 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:  


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• 
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 subject may decline to participate further. The 
subject will not suffer any disadvantage as a result. 
• 
Subject becomes pregnant while undergoing treatment with Zepatier—therapy will be stopped as 
there are no human safety data of Zepatier during pregnancy.  There are no adequate and well-
controlled studies with Zepatier in pregnant women. No effects on embryo-fetal development were 
observed in rats or rabbits at grazoprevir or elbasvir exposures higher than exposures in humans at 
the recommended clinical dose. Because animal reproduction studies are not always predictive of 
human response, Zepatier should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus.  Because the transmission rates of HCV from mother to fetus are very small, 
and HCV can be treated after pregnancy and delivery, therapy will not be continued during pregnancy. 
Patients will continue with the regularly scheduled study visits, but will not be eligible to receive 
continued Zepatier therapy. 
• 
Subject develops a condition that it is life threatening or any other significant risk as judged by the 
Investigators. Patients will not receive study drug, but will continue with study visits as scheduled. 
• 
Zepatier is no longer produced by the company, or if a decision is made to stop the study patients will 
not receive study drug, but will continue with study visits as scheduled. 
 
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 
adherence 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). 
12.9. 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. 
 


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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. 
 
12.10. Potential Risks  
12.10.1. 
Risks of Study Procedures  
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 1-4 weeks during the 40-week post-transplant 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. 
 
Because we may store subjects’ blood samples, there may be confidentiality risks associated with the storage 
and analysis of those samples or the information resulting from the analysis of those samples. Samples may be 
used for genetic testing. 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 risk of undergoing screening includes potential identification of new health problems that subjects were 
unaware of. If we discover new health problems, we will answer subjects’ questions and try to arrange 
appropriate treatment if any is needed. If new health problems are discovered, it is possible that subjects would 
not be able to enter this study. It is also possible that subjects would no longer be eligible for heart 
transplantation based on the results. 
 
The risks of heart transplant surgery include blood loss, infections, and deep vein thrombosis. There are also 
risks related to immunosuppression and standard anti-infective therapy. 
 
The risks of any transplant include primary graft non-function, delayed graft function, acute rejection, and 
death. Re-admissions within 30 days after a heart transplant are expected in approximately 40% of patients. 
 
There may also be a small risk of developing Focal and Segmental Glomerulosclerosis (FSGS) after receiving a 
heart from a HCV positive donor.  However, this condition can also develop in patients who do not have HCV. 
After transplant, we will monitor all patients for FSGS and similar conditions. 
12.10.2. 
Risk of Genotyping Failure 
There is a risk of failure of the Genotyping LDT in that no result is obtained. However, the risk to the recipient 
participant, in this event, is that they would not receive the transplant. Hence, the related risk is losing the 
opportunity to use the organ.  Failure of the LDT could be due to an instrument or cartridge failure or issues with 
the sample (e.g., the sample contains a very low level of virus).  To minimize the study impact of a failed 
cartridge, the HUP Molecular Pathology Laboratory will run the study samples in duplicate due to there not 
being enough time to repeat the test (as would be done with a sample in clinical care).  The duplicate sample 


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46 
testing will serve to provide additional confirmation of the result because the RNA extraction will be performed 
twice. Thus, confirmation testing will be performed on every sample in the study with a single result generated. 
 
There is also a risk of the Genotyping LDT giving an incorrect genotype. The risk to the recipient participant, in 
this event, is that they receive the transplant, but are possibly unable to be adequately treated for HCV 
positivity. Failure of the LDT to give an accurate genotype could be due to a mixed infection (e.g. genotype 1 and 
2) or HCV genotype 4f infection in the donor sample.   
12.10.3. 
Risk of NS5a Drug Resistance Test Failure 
The potential risks of the NS5a resistance testing are false negative and false positive test results. The risk of a 
false negative test result would be if the test does not report any one of the four pertinent polymorphisms, even 
though they are present (the presence of which would be rare). In this case, the patient would receive only 12 
weeks of Zepatier (rather than 16 weeks of Zepatier + renal-dosed Ribavirin), and potentially fail first-line 
therapy, requiring second-line therapy.   
 
A false positive result is less likely to happen than a false negative result. The risk of a false positive test result 
would be if the test reports a polymorphism when the subject does not have one. Hence, the subject would be 
exposed to Zepatier for 4 weeks longer than needed as well as Ribavirin, and potentially experiencing the 
products’ side effects.  
12.10.4. 
Risk of Study Drugs 
Zepatier 
In subjects receiving Zepatier for 12 weeks, the most commonly reported adverse reactions of all intensity 
(greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea. In subjects 
receiving Zepatier with ribavirin for 16 weeks, the most commonly reported adverse reactions of moderate or 
severe intensity (greater than or equal to 5%) were anemia and headache. 15-17The greatest risk is failure to 
achieve SVR12 after treatment with Zepatier, leading to chronic HCV. 
 
There is a risk of fetal harm and birth defects should any woman taking Zepatier become pregnant while on the 
drug.15-17 Due to the age of the participants, this is a small risk, as all will be over 40 and unlikely to become 
pregnant. However, to mitigate this risk, all pre-menopausal women with a uterus will be screened for 
pregnancy before enrollment and instructed to use a highly effective form of birth control (e.g. abstinence, 
intrauterine device, etc.). Highly effective forms of birth control will be defined by the Mycophenolate Risk 
Evaluation and Mitigation Strategy (REMS), a standard protocol used for post-transplant patients at Penn being 
treated with Mycophenolate.  
 
Sovaldi (Sofosbuvir) 
The most common adverse events (incidence greater than or equal to 20%, all grades) observed with Sovaldi in 
combination with ribavirin were fatigue and headache. The most common adverse events observed with Sovaldi 
in combination with peginterferon alfa and ribavirin were fatigue, headache, nausea, insomnia and anemia.18  
  
Ribavirin 
The hemolytic anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led 
to fatal and nonfatal myocardial infarctions. Significant teratogenic and embryocidal effects have been 
demonstrated in all animal species exposed to ribavirin. Therefore, ribavirin therapy is contraindicated in 
women who are pregnant and in the male partners of women who are pregnant.19  


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12.10.5. 
Risks of Developing HCV 
The risks of chronic HCV include severe acute inflammation of the liver that could lead to liver failure requiring a 
liver transplant. HCV may also cause a severe type of acute infection called fibrosing cholestatic HCV, that can 
cause severe liver injury, jaundice (yellowing of the eyes and skin), and progressive liver dysfunction. 
 
There is a small risk of transmission of HCV from the study subject to intimate partners during sexual activity. 
This risk is very low and should be reduced even further due to requirements for subjects to use barrier 
protection during sexual activity. 
12.11. 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. Subjects will experience clinical benefits as their heart function and quality of life 
should vastly improve following transplant. The study involves the risks of phlebotomy, development of chronic 
HCV, and loss of confidentiality, but there is a potential for future benefit for both subjects in the study and for 
future subjects, the risk/benefit ratio is favorable. 
12.12. 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. 
12.13. Ethical Considerations 
The main ethical considerations in this trial are non-maleficence, respect for persons, and autonomy. Our 
selection criteria are designed to select subjects who are at substantial risk of death and health complications 
because of heart failure. Transplantation with a HCV-positive heart and then treatment for HCV also involve 
risks, but it is plausible that survival and quality of life will still improve after transplantation compared to the 
alternative of remaining on the list.  Our informed consent procedures are designed to enable individuals to 
make decisions that are consistent with their values. We will enumerate the many possible risks and plausible 
benefits. The processes of informed consent in this study will be conducted so that patients can ask questions, 
confer with their primary cardiologists and develop a full understanding of the trial procedures and risks, all of 
which is consistent with respect for persons. Lastly, subjects in the trial will retain the ability to consider organ 
offers and decide whether to accept an organ based on their own judgment about the value of that particular 
organ and after getting advice from their transplant team.   


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13 CHAPTER 11: GOOD CLINICAL PRACTICE 
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, University of Pennsylvania requirements, and applicable institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to the FDA and a properly constituted IRB in agreement 
with local legal prescriptions for formal approval of the study conduct.  The principal investigators will not 
commence the study until the IRB has issued written approval to the PIs.  
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent form 
will be submitted with the protocol for review and approval by the IRB for the study.  The formal consent of a 
subject, using the IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent. 
 
 
 
 
 


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14 CHAPTER 12: REFERENCES 
1. 
Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment 
with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C 
virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, 
open-label phase 2 trial. Lancet. 2015;385(9973):1087-1097. 
2. 
Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with 
grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 
infection in previously untreated patients with cirrhosis and patients with previous null response with or 
without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015;385(9973):1075-
1086. 
3. 
Forns X, Gordon SC, Zuckerman E, et al. Grazoprevir and elbasvir plus ribavirin for chronic HCV 
genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. 
Journal of hepatology. 2015;63(3):564-572. 
4. 
Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive 
Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A 
Randomized Trial. Annals of internal medicine. 2015;163(1):1-13. 
5. 
Reese PP, Abt PL, Blumberg EA, Goldberg DS. Transplanting Hepatitis C-Positive Kidneys. The New 
England journal of medicine. 2015;373(4):303-305. 
6. 
O'Leary JG, Neri MA, Trotter JF, Davis GL, Klintmalm GB. Utilization of hepatitis C antibody-positive 
livers: genotype dominance is virally determined. Transpl Int. 2012;25(8):825-829. 
7. 
Reddy KR FS, et al. Ledipasvir/Sofosbuvir with Ribavirin for the Treatment of HCV in Patients with Post 
Transplant Recurrence: Preliminary Results of a Prospective, Multicenter Study. Hepatology. 
2014;60:200A. 
8. 
Roth D ND, Bruchfeld A, et al. C-Surfer: Grazoprevir Plus Elbasvir In Treatment-Naïve and Treatment-
Experienced Patients with Hepatitis C Virus Genotype 1 Infection and Chronic Kidney Disease. EASL 
2015; 2015; Vienna, Austria. 
9. 
Van Deerlin, V. (December 2015). Hepatitis C Virus Genotyping (GenMark Assay) Validation Summary. 
10. 
Pawlak R RJ, Maranan G, Michel-Treil V, Schutzbank T. A Comparative Evaluation of the Siemens 
VERSANT HCV Genotype 2.0 (LiPA) and GenMark eSensor HCV Direct Genotyping Tests. CVS 2013 
Covance; 2013. 
11. 
Dahl A HD, Ogorek T, Hansen G. Comparison of the GenMark Direct Genotype Assay with the LiPA 
Genotype Assay Using a Diverse Spectrum of HCV Clinical Samples Encountered in a High Risk Inner City 
HCV Population. CVS 2013 Hennepin; 2013. 
12. 
Woodberry M SK, Castor J, Cook L, Jerome K. Genotyping of Hepatitis C Virus by the Genmark DX 
Esensor HCVG Direct Test. CVS 2013 UW-Seattle 2013. 
13. 
Quest Diagnostics, Inc. (December 2014). Test summary guide. Hepatitis C Viral RNA Genotype 1 NS5a 
Drug Resistance.  
www.questdiagnostics.com/testcenter/testguide.action?dc=TS_HCV_NS5A_Genotype&tabview=true 
Accessed March 14, 2016. 
14. 
U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. 
(June 2010). Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
15. 
Merck Sharp & Dohme Corporation (January 2016). ZEPATIER™ tablets. Highlights of Prescribing 
Information. 2016. 
16. 
Merck Sharp & Dohme Corporation (July 2015). Elbasvir (MK-8742). Investigator’s Brochure (8th Ed.). 
2015. 
17. 
Merck Sharp & Dohme Corporation (July 2015). Grazoprevir (MK-5172). Investigator’s Brochure (10th 
Ed.). 2015. 


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50 
18. 
Gilead Sciences, Inc. (August 2015). Sovaldi® (sofosbuvir) tablets. Highlights of Prescribing Information. 
2015. 
19. 
Sandoz, Inc. (May 2015) Ribavirin capsule. Highlights of Prescribing Information. 2015. 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dc637c8f-9669-4bc5-8787-1fd5abaa588e.