Conditions: Porphyria Cutanea Tarda Hepatitis C
Keywords: Interventional, Open-label, PCT, Hepatitis C
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
In the medical literature there case reports that Harvoni improves symptoms in patients with PCT. However, this has never been systematically tested. Therefore, the purpose of this study is to assess whether Harvoni alone is an effective therapy of active PCT in patients with Chronic Hepatitis C.

Detailed description:
This is a clinical trial, which means its purpose is to study an intervention or treatment. In this study all patients with PCT will be given a standard dose of Harvoni and monitored for two years. Currently there are two standard therapies for PCT, phlebotomies (removing certain amounts of blood at specific intervals), or low dose hydroxychloroquine (an oral pill). These treatments are used for patients with PCT whether or not they also have HCV. For patients with HCV however, we do not know whether treating the HCV first will also resolve the PCT symptoms. There will be an initial visit to determine whether participants are eligible to be in the study. If a participant is found to be eligible, he/she will be asked come to the study site once every month over the course of one year, and then once every 3 months for an additional year. There will be approximately 17 visits over the course of the whole study. At these visits the study doctors will check in with the participant and some blood and urine samples will be taken. Participants will not be charged for any of the lab tests that are being done as a part of this study alone. All participants in this study will receive the Harvoni pills at no cost to them.

Arms:
arm 1: 1 tablet per day, oral, taken with or without food. 8 weeks for patients without cirrhosis, not previously treated with HCV GT1 and HCV rNA \< 6 million IU/mL; 12 weeks for patients without cirrhosis; 24 weeks for patients with compensated cirrhosis

Interventions: intervention 1: Harvoni
Intervention descriptions: intervention 1: One capsule of Harvoni/ ledipasvir, 90 mg + sofosbuvir, 400 mg administered daily for 8, 12, or 24 weeks

Protocol document:
Prot_SAP_001.pdf: 
Official Title:  Newer Direct-Acting Anti-Viral Agents as Sole Therapy of 
Porphyria Cutanea Tarda in Subjects With Chronic Hepatitis C 
NCT03118674
IRB-Approved Date:  5/5/2020


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Rare Diseases Clinical Research Network 
 
Porphyrias Consortium 
 
 
Newer Direct-Acting Anti-Viral Agents as Sole 
Therapy of Porphyria Cutanea Tarda in Subjects 
with Chronic Hepatitis C 
 
 
 
Study Chair: 
 
Herbert L. Bonkovsky MD 
Professor of Medicine, Molecular Medicine & Translational Science 
Wake Forest School of Medicine 
Medical Center Blvd 
Winston-Salem, NC 27157 
Phone:  336-713-7341 
Fax: 336 713 7322 
 
 
 
Email: hbonkovs@wakehealth.edu 
 
 
This protocol is for research purposes only, and should not be copied, 
redistributed or used for any other purpose.  The procedures in this 
protocol are intended only for use by the Porphyrias Consortium 
investigators in carefully controlled settings.  The Study Chair of this 
study should be consulted before using or attempting any procedure in 
this protocol. 


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Table of Contents 
1. Protocol Synopsis ..................................................................................................................................... 3 
1.1 Overview ............................................................................................................................................. 5 
2. Specific Aims (Hypothesis and Objectives) .............................................................................................. 6 
3. Background ............................................................................................................................................... 6 
4. Study Design and Methods ....................................................................................................................... 7 
4.1 Inclusion Criteria ................................................................................................................................. 9 
4.2 Exclusion Criteria ................................................................................................................................ 9 
4.3 Recruitment of Participants............................................................................................................... 10 
4.4 Retention Strategies ......................................................................................................................... 11 
4.5 Data Elements .................................................................................................................................. 11 
4.6 Study Procedures ............................................................................................................................. 12 
4.7 Schedule of Events ........................................................................................................................... 15 
4.8 Investigational Product ..................................................................................................................... 16 
5.0 Data and Safety Monitoring Plan .......................................................................................................... 16 
5.1 Study Oversight ................................................................................................................................ 17 
5.2 Definitions and Standards ................................................................................................................. 17 
5.3 Expected/Known Risks/Discomforts/Adverse Events Associated with Study Intervention and 
Procedures: Definition of Expected Adverse Events .............................................................................. 17 
5.4 Reporting Timeline ............................................................................................................................ 19 
5.5 RDCRN DMCC Adverse Event Monitoring  System  ....................................................................... 20 
5.6 Study Discontinuation ....................................................................................................................... 20 
5.7 Subject Discontinuation .................................................................................................................... 21 
5.8 Data Quality and Monitoring Measures ............................................................................................ 21 
5.9 Quality Control: Study Related Procedures ...................................................................................... 21 
6. Statistical Considerations ........................................................................................................................ 22 
7. Data Management ................................................................................................................................... 24 
7.1 Registration ....................................................................................................................................... 24 
7.2 Data Entry ......................................................................................................................................... 25 
8. Human Subjects ...................................................................................................................................... 25 
8.1 GCP Statement ................................................................................................................................. 25 
8.2 Benefits ............................................................................................................................................. 25 
8.3 Risks ................................................................................................................................................. 25 
8.4 Written Informed Consent ................................................................................................................. 26 
8.5 Process of Consent .......................................................................................................................... 26 
9. References .............................................................................................................................................. 28 
10. Appendices ........................................................................................................................................... 29 
I. Sample Processing Instructions .......................................................................................................... 29 
 


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1. Protocol Synopsis 
Interventional Synopsis 
Protocol Number: 
7210 
Protocol Title: 
Newer Direct-Acting Anti-Viral Agents as Sole Therapy of 
Porphyria Cutanea Tarda in Subjects with Chronic Hepatitis 
C 
Study Chair: 
Herbert L. Bonkovsky, MD 
Statistician: 
Inga Peter, PhD; Jessica Overbey, MS 
Consortium: 
Porphyrias Consortium 
Activation Date: 
04AUG2017 
Current Status: 
Enrolling 
Sample Size: 
49 
Target Enrollment Period: 
3 years 
Study Design: 
Interventional, one arm, open label non-inferiority 
Primary Study Objective: 
To assess whether Harvoni alone is an effective therapy of active 
PCT (measured as resolution of active PCT by 7 months) in 
patients with Chronic Hepatitis C (CHC).   
Secondary Study 
Objective(s): 
To assess time to resolution of active PCT after initiation of 
treatment with Harvoni; To assess time course of normalization of 
urinary porphyrin profiles; To assess cure of chronic hepatitis c 
Study Population and Main 
Eligibility/ Exclusion 
Criteria: 
Inclusion Criteria: 
1. Willing and able to give informed consent 
2. ≥18 years of age 
3. Symptoms and signs consistent with PCT and well 
documented biochemical diagnosis (urinary total 
porphyrin excretion > 500 mcg/g creatinine with HPLC 
pattern typical of PCT—predominance of 8- and 7-
carboxyl porphyrins [>50% of total]) 
4. Clinical diagnosis of PCT established by a study PI 
5. Chronic hepatitis C: HCV RNA positive and quantifiable 
in serum detected within 90 days of enrollment, and 
documented HCV genotypes 1,4, 5, or 6 for which 
Harvoni is an approved therapy. 
6. Women of child-bearing potential must be willing to avoid 
pregnancy and use an accepted and effective 
contraceptive method during treatment.   
Exclusion Criteria: 
1. Women who are pregnant or who are breast-feeding 
2. Patients who have already started treatment of PCT with 
phlebotomy or low dose hydroxychloroquine or 
chloroquine, or who have been in such treatment in the 
past 30 days 
3. Patients who have already started another treatment 
regimen for CHC, or who have taken such treatment in 
the past 30 days 
4. HIV infection with CD4 counts at baseline less than 
350/µL or with evidence of any active AIDS-defining 
illnesses 
5. Ongoing active alcohol abuse, defined as a history of 
drinking more than 25 drinks of alcohol per week during 
most weeks in the prior 4 months (History of prior, but not 
current alcohol abuse will NOT be grounds for exclusion 
because we seek to treat subjects with PCT and CHC of 
the type typically seen in clinical practice) 


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6. Any ongoing active IV drug use 
7. Patients who are taking amiodarone or who have taken 
amiodarone within 60 days prior to enrollment 
8. Patients who are taking, or within the prior 28 days have 
taken, rifampicin or St John’s wort (Hypericum 
perforatum), both of which are P-gp inducers, which may 
significantly reduce the drug levels and therapeutic 
effects of Harvoni 
9. Uncontrolled diabetes (Hgb A1c >9.5% within 60 days 
prior to enrollment) 
10. Chronic hepatitis B 
11. Autoimmune hepatic liver injury—autoimmune hepatitis, 
primary biliary cholangitis/sclerosing cholangitis or 
overlap syndrome 
12. Alcoholic hepatitis 
13. Other metabolic disorders of the liver, e.g. Alpha 1 
antitrypsin deficiency with ZZ Pi type, Wilson’s disease 
14. Prior known or suspected drug-induced liver injury within 
6 months of enrollment 
15. Known or suspected hepatocellular carcinoma 
16. On liver transplant list, or current MELD >12 
17. History of liver transplant 
18. Estimated GFR (creatinine clearance) <30 mL/min (per 
Sofosbuvir being cleared by the kidney) 
19. Serum ALT or AST >10x upper limit of normal 
20. Serum bilirubin >2 mg/dL (excluding patients with known 
or suspected Gilbert’s syndrome) 
21. Any other comorbid condition, which in the opinion of the 
investigator precludes participation 
22. Incarcerated individuals 
Treatment (if applicable) 
Agent- 
Harvoni—ledipasvir, 90 mg + sofosbuvir, 400 mg  
Dosage, schedule, route of 
administration- 
1 tablet per day, oral, taken with or without food.  8 weeks for 
patients without cirrhosis, not previously treated with HCV GT1 
and HCV RNA < 6 million IU/mL; 12 weeks for patients without 
cirrhosis; 24 weeks for patients with compensated cirrhosis.  
Safety Issues- 
The drug is well-tolerated and highly effective for cure of HCV 
Primary Outcome 
Measures: 
The primary endpoint will be resolution of active PCT, defined as 
normalization of plasma porphyrins (less than 0.9 mcg/dL) by 7 
months after start of therapy. 
Secondary Outcome 
Measures: 
Time to resolution of active PCT, defined as cessation of any new 
blisters or bullae and normalization of plasma porphyrins.  
Complete resolution of skin manifestations is expected to occur 
later than normalization of plasma porphyrins, because it takes 
time for healing of the skin fragility that predisposes of blister 
formation to occur.   
Decrease of the sum of urinary uro- and hepta-carboxyl 
porphyrins to less than 100 mcg/g creatinine, and a normal urine 
porphyrin HPLC pattern. 
Cure of CHC, defined as no detectable HCV RNA at end of 
treatment (EOT) and persisting for at least 12 weeks after EOT. 
Statistical Considerations 
(sample size and analysis 
plan): 
The primary study hypothesis is that the proportion of patients 
whose PCT resolves by 7 months will be non-inferior to the 
performance goal of 50%.   The non-inferiority margin will be set 
to 10%; a difference from the performance goal judged to be both 


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clinically acceptable and well within the margin needed to assure 
that the performance of Harvoni is at established levels of benefit 
from conventional therapies. Thus, the null hypothesis tested by 
this study is H0: π ≤ 0.40, against the alternative hypothesis H1: π 
> 0.40. 
 
Sample size requirements are based on an exact test of a 
binomial proportion. Assuming that the study drug has a true 
success probability of 58%, 49 patients yield 80% power to reject 
the null hypothesis at a one-sided significance level of 0.05.   
Sponsors (federal, state, 
foundation and industry 
support): 
Gilead Sciences; National Institutes of Health (NIH) 
 
1.1 Overview 
The purpose of this study is to learn whether Harvoni, a simple oral treatment for 
chronic hepatitis C infection, is effective for treatment of porphyria cutanea tarda 
(PCT). 
 
PCT is the most common form of porphyria in the USA and most other countries 
and regions of the world.  There are two major types of PCT:  acquired (type 1, 
which accounts for about 80% of cases) and inherited (type 2).  The major risk 
factors for type 1 PCT are heavy alcohol use, iron overload, hepatitis C (HCV) or 
human immunodeficiency virus (HIV) infection, and ingestions of estrogens.  
Most patients with PCT, either type 1 or type 2, have one or more of these risk 
factors.  In type 2 PCT, subjects have a partial deficiency, usually ~ 50% of 
normal, activity of the enzyme uroporphyrinogen decarboxylase (UROD), 
whereas, in type 1 PCT, the deficiency in UROD activity is limited to the liver, and 
it appears usually to be acquired and due to excess iron, alcohol, HCV, HIV, etc. 
 
The time-honored treatment of first choice for either form of PCT has been iron 
reduction, usually carried out most quickly and efficiently by therapeutic 
phlebotomy.  However, (hydroxy) chloroquine in low doses also is effective.  
There have been anecdotal reports of treatment of HCV infection with interferon 
with or without ribavirin being effective treatment.  To date, however, there have 
been no prospective case series of such treatments, nor have there been 
comparisons of results with anti-viral treatments, compared with iron reduction or 
(hydroxyl) chloroquine. 
 
With the recent development of newer and highly active and effective therapies 
for HCV infection, with fewer side-effects than were heretofore possible, we have 
felt that it now is time for a careful and formal study to assess whether these 
agents are effective treatments for PCT. 
 
This is an open-label study with a non-inferiority design, to assess whether 
Harvoni is an effective treatment of PCT. 
 


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2. Specific Aims (Hypothesis and Objectives) 
 
Aim:  To assess whether Harvoni alone is an effective and durable therapy of active 
PCT in patients with CHC due to any genotype for which Harvoni is approved for 
treatment, currently genotypes 1, 4, 5, or 6.  Genotype 1 HCV accounts for ~ 75% of 
chronic hepatitis C infections in the USA.  Genotype 4 is common in Egypt; rare in the 
USA, but it does occur.   Our goal is to be as inclusive as possible and to test effects of 
Harvoni treatment in real-world situations.  We will test whether Harvoni treatment is 
non-inferior to previously published remission times of other standard treatments of PCT 
(low dose hydroxy chloroquine or phlebotomy therapy) (Singal et al, 2012). 
 
Hypothesis: Treatment of PCT associated with CHC with Harvoni is as effective and as 
durable as published data on the current standard treatments of iron reduction by 
phlebotomies or low dose hydroxychloroquine. 
3. Background:   
CHC is a well-known risk factor for PCT.  Other risk factors include hepatic iron 
overload, often related to mutations of HFE associated with hereditary 
hemochromatosis, excess alcohol use, estrogen therapy, and HIV infection (Bonkovsky 
et al, 1998, 2013; Egger et al, 2002; Besur et al, 2014). 
 
The standard of care therapy for PCT has been iron reduction by therapeutic 
phlebotomy, which has been effective in nearly all subjects, regardless of underlying 
major risk factors (Besur et al, 2014; Bonkovsky et al, 1998, 2013).  Based upon more 
recent results, low-dose therapy with 4-aminoquinolones, (chloroquine and/or 
hydroxychloroquine), also has become a standard therapy, as has a combination of iron 
reduction and one of these agents (Stölzel et al, 2009; Singal et al, 2012; Bonkovsky 
HL, unpublished).  However, it has been found that decreases in measures of iron 
status following chloroquine therapy did not occur in subjects with HFE mutations and 
that C282Y +/+ subjects did not respond very well to chloroquine (Stölzel et al, 2003).  
In addition, the use of 4-aminoquinolones, as against phlebotomy therapy, may be 
associated with earlier recurrence of active PCT after a course of therapy than after a 
course of iron reduction and maintenance of an iron-reduced state (Stölzel et al, 2003, 
2009; & Bonkovsky, unpublished observations).  This led to the recommendation that, 
for those with HFE-linked hemochromatosis, therapeutic phlebotomy should remain the 
treatment of first choice (Stölzel et al, 2003). 
 
During the past 20 years or so, there have been anecdotal reports of PCT resolving with 
successful anti-viral therapy of CHC, although there also have been reports of such 
therapy precipitating or worsening PCT (Bonkovsky et al, 2013).  Because active 
cutaneous lesions of PCT are generally more symptomatic than CHC, which usually 
occurs with few, if any, symptoms until late in the course of advanced liver disease, and 
because typically PCT is successfully treated within about 6 to 7 months, either with iron 
reduction or one of the 4-aminoquinolones (Singal et al, 2012), the usual 
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recently, therapy of CHC has been longer (usually at least 48 weeks), less often 
successful and fraught with adverse effects, especially related to the use of interferon 
alpha, which has been the cornerstone of treatment.  However, during the past few 
years, newer and more effective oral therapies for CHC, with far fewer and less severe 
side-effects have been approved by the US FDA, the EMA, and other regulatory 
agencies.  In particular, sofosbuvir (Sovaldi) with interferon and ribavirin or with 
simeprevir (Olysio), and more recently, the combination of ledipasvir + sofosbuvir 
(Harvoni) (Gilead Sciences) have proven highly effective and to produce far fewer 
severe adverse effects than the earlier therapeutic regimens based upon interferon 
(usually in combination with ribavirin) (Syllabus of Post-Graduate Course and 
presentations at annual meeting of AASLD, Nov 7-11, 2014, Boston, MA).  Other 
combinations of all oral, direct-acting antivirals have recently been approved (e.g., 
Viekira Pak, Abbvie; Mavyret, Abbvie; Zepatier, Merck) and/or are in late-stage clinical 
trials. 
 
Because treatment for CHC is now highly successful within as short a time as 8-12 
weeks and with few adverse effects, it is reasonable to consider this treatment first in 
patients with both CHC and PCT.  However, experience is needed with a reasonable 
number of patients in order to validate this approach, and in particular to demonstrate 
that time to remission is as rapid and that remission of PCT is as durable following 
therapy with Harvoni as with phlebotomy or (hydroxy) chloroquine.  Also, PCT is a 
heterogeneous, multifactorial disease, and it is important to ascertain whether other co-
existing susceptibility factors influence response to a new treatment approach and 
durability of remission. 
 
The Office of Rare Diseases (ORD) of the National Institutes of Health (NIH) 
established a Rare Diseases Clinical Research Network (RDCRN) in collaboration with 
other NIH Institutes and has funded several rare diseases clinical research consortia 
and one Data Management and Coordinating Center (DMCC). The Porphyrias 
Consortium was created as part of the RDCRN, to study the human porphyrias.  
 
4. Study Design and Methods   
 
This will be a one arm, open-label non-inferiority study of Harvoni for treatment of 
PCT complicating chronic hepatitis C infection caused by HCV genotypes for 
which Harvoni is approved as therapy, compared to a performance goal of a 50% 
remission rate at 7 months.   This performance goal is based on recently published 
results from our Consortium (Singal et al, 2012), in which the median time to remission 
for subjects treated either with phlebotomy or hydroxychloroquine was 7 months, and on 
expert consensus that if Harvoni demonstrates a median time to remission of 7 months, 
porphyrias experts would consider using Harvoni over phlebotomy or 
hydroxychloroquine as a first line of treatment for PCT patients with Hepatitis C.  Our 
aim is to be as inclusive as possible, so that the results will be as generalizable as 
possible to regular clinical practice.  Comparison of response rates, both for 
amelioration of PCT (the primary endpoint) and for cure of HCV infection (a secondary 


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endpoint) will be by comparison to recently published results from our Consortium 
(Singal et al, 2012) and elsewhere (results of recent trials of Harvoni for treatment of 
chronic hepatitis C).  
 
Adult subjects, of either gender with well-established PCT, who also have CHC due to 
an HCV genotype 1, 4, 5, or 6, for which Harvoni is approved as therapy, will be invited 
to take part. PCT patients with CHC typically have additional susceptibility factors, such 
as alcohol use, estrogen exposure, smoking, HFE mutations, UROD mutations or HIV 
infection (Bonkovsky et al, 1998, 2013; Egger et al, 2002), and none of these will be 
reasons for exclusion.  Subjects previously treated for PCT and/or HCV infection will be 
eligible, provided they meet the current criteria for inclusion and exclusion. 
 
Assessment of Stage of Liver Disease:   
 
Cirrhosis will be considered to be present according to the following two-tiered 
approach:   
 
Stage 1—based upon historical data:   
a. Any prior liver biopsy that was interpreted by a pathologist as showing 
definite or probable cirrhosis (Ishak fibrosis score of 5 or 6; or Metavir 
fibrosis score of 4); and/or 
b. Hepatic elastography/Fibroscan value, performed within the prior three 
years, that showed liver stiffness > 12.5 kPa.  
 
Stage 2—for subjects without historical data:  
a. A liver biopsy  performed on the subject that shows definite or probable 
cirrhosis (Ishak fibrosis score of 5 or 6; or Metavir fibrosis score of 4); 
and/or 
b. Hepatic elastography/ Fibroscan, performed for screening purposes, that 
shows liver stiffness greater than 12.5 kPa; and/or 
c. Hepatic imaging study (ultrasound, CT or MRI), performed within three 
months of enrollment that showed findings typical of cirrhosis, such as 
irregular, lobulated or nodular appearance of the liver, enlargement of the 
spleen, gastro-esophageal varices, ascites, or other evidence of portal 
hypertension; and/or  
d. Physical examination that shows findings typical of cirrhosis, such as 
multiple spider angiomas, red palms, prominent venous pattern of the 
upper abdominal wall, palpable and firm or hard liver, often with increased 
prominence of the left lobe, when accompanied by a decreased platelet 
count (<140,000/µL) in peripheral blood.   
 
As is standard practice, if subjects use alcohol, they will be strongly encouraged not to 
consume alcohol in any form, at least for the duration of the study and it’s follow-up.  
They also will be asked to stop any use of estrogens; and those that smoke cigarettes 
will be advised to stop smoking.  Adherence to these recommendations will be tracked 
by patient interviews. Continuing use of estrogens and/or smoking will NOT be grounds 


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for removal of subjects from the study. Subjects may have HIV infection, as long as their 
CD4 counts at baseline are greater than or equal to 350/µL and they do not have 
evidence of any active AIDS-defining illnesses.  
 
4.1 Inclusion Criteria 
 
1. Willing and able to give informed consent 
2. ≥18 years of age 
3. Symptoms and signs consistent with PCT and well documented biochemical 
diagnosis (urinary total porphyrin excretion > 500 mcg/g creatinine with HPLC 
pattern typical of PCT—predominance of 8- and 7-carboxyl porphyrins [>50% of 
total]) 
4. Clinical diagnosis of PCT established by a study PI 
5. Chronic hepatitis C: HCV RNA positive and quantifiable in serum detected within 
90 days of enrollment, and documented HCV genotype for which Harvoni is an 
approved therapy:  genotype 1, 4, 5, or 6. 
6. Women of child-bearing potential must be willing to avoid pregnancy and use an 
accepted and effective contraceptive method during treatment.   
 
4.2 Exclusion Criteria 
 
1. Women who are pregnant or who are breast-feeding 
2. Patients who have already started treatment of PCT with phlebotomy or low dose 
hydroxychloroquine or chloroquine, or who have been in such treatment in the 
past 30 days 
3. Patients who have already started another treatment regimen for CHC, or who 
have taken such treatment in the past 30 days 
4. HIV infection with CD4 counts at baseline less than 350/µL or with evidence of 
any active AIDS-defining illnesses 
5. Ongoing active alcohol abuse, defined as a history of drinking more than 25 
drinks of alcohol per week during most weeks in the prior 4 months (History of 
prior, but not current alcohol abuse will NOT be grounds for exclusion because 
we seek to treat subjects with PCT and CHC of the type typically seen in clinical 
practice) 
6. Any ongoing active IV drug use 
7. Patients who are taking Amiodarone or who have taken Amiodarone within 60 
days prior to enrollment 
8. Patients who are taking, or within the prior 28 days have taken, rifampicin or St 
John’s wort (Hypericum perforatum), both of which are P-gp inducers, which may 
significantly reduce the drug levels and therapeutic effects of Harvoni 
9. Uncontrolled diabetes (Hgb A1c >9.5% within 60 days prior to enrollment) 
10. Chronic hepatitis B 
11. Autoimmune hepatic liver injury—autoimmune hepatitis, primary biliary 
cholangitis/sclerosing cholangitis or overlap syndrome 
12. Alcoholic hepatitis 


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13. Other metabolic disorders of the liver, e.g. Alpha 1 antitrypsin deficiency with ZZ 
Pi type, Wilson’s disease 
14. Prior known or suspected drug-induced liver injury within 6 months of enrollment 
15. Known or suspected hepatocellular carcinoma 
16. On liver transplant list, or current MELD >12 
17. History of liver transplant 
18. Estimated GFR (creatinine clearance) <30 mL/min (per Sofosbuvir being cleared 
by the kidney) 
19. Serum ALT or AST >10x upper limit of normal 
20. Serum bilirubin >2 mg/dL (excluding patients with known or suspected Gilbert’s 
syndrome) 
21. Any other comorbid condition, which in the opinion of the investigator precludes 
participation 
22. Incarcerated individuals 
 
4.3 Recruitment of Participants 
 
The methods of recruitment will be: 
 
A. Patients followed by any of the Investigators in the Porphyrias Consortium:  
Each of the Investigators is a Porphyria specialist in a Porphyria Center, and 
provides clinical care to individuals suspected of and diagnosed with porphyria, 
providing diagnostic and follow-up evaluations, consultations, and/or treatment.  
For such patients who are likely to be eligible for the study, the Investigators will 
either discuss the study with the patient during a clinical visit or will contact the 
patient by telephone, email, or mail, as appropriate per Central IRB (CIRB) 
approval.  Any efforts to contact and recruit patients and families will be with 
CIRB approval and adhere to standards for ethical conduct of research and be 
fully HIPAA compliant.   
B. Referrals from the American Porphyria Foundation (APF) to the Porphyrias 
Consortium centers:  The APF is an advocacy group that provides education 
about porphyria to patients, their families, healthcare professionals, and the 
public and supports porphyria research.  Their outreach program includes a 
website, as well as periodic newsletters and special announcements emailed 
and/or mailed to individuals who have registered with the APF with information 
about new developments in treatment, porphyria-related education 
opportunities, and research studies available through the Porphyrias 
Consortium. Information about research studies includes contact information for 
the studies if they are interested in obtaining additional information or 
participating. The focus will be on patients and physicians from the following 
specialties: gastroenterologists, hepatologists, infectious disease physicians, 
and dermatologists.    
C. Non-study Physician referrals:  Physicians providing clinical care to individuals 
suspected of or diagnosed with PCT who are not investigators in this study may 
refer patients who may be eligible for and express interest in the study to a 
Porphyrias Consortium center.  


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D. Self-referrals: Including family members of individuals diagnosed with PCT 
(proband) and other individuals who may have heard about the study from 
other subjects or prospective subjects.  In the case of family members, initial 
contact with the family member will not be made by the study team.  The 
proband will be asked to contact such family members, requesting that they 
contact the study coordinator or to register through the RDCRN-Porphyria 
Consortium if interested in obtaining additional information or participating.  
 
This study is registered on clinicaltrials.gov (NCT 03118674). 
 
In the case of patients followed by one of the Consortium Investigators, the 
physician/Investigator or study coordinator will either: (a) contact the patient by 
telephone, email or mail informing him/her of the study and requesting that he/she 
contact the study coordinator if interested in obtaining additional information or 
participating, or; (b) discuss the study in-person during a clinical visit; informed consent 
may be obtained at this time. In all other cases, prospective subjects are instructed to 
contact the study coordinator, either the Project Manager or a site-specific study 
coordinator, by telephone, email or mail if interested in obtaining additional information 
or participating. 
 
All patients will be encouraged to simultaneously enroll in the Longitudinal Study of the 
Porphyrias (PC7201), however it will not be required for inclusion into this study.  
 
4.4 Retention Strategies 
 
Only a small number of specialists have the expertise to evaluate and treat individuals 
with PCT. Clinical relationships established by the investigators with patients who enroll 
in this study will provide a context for increased communication with patients and their 
primary physicians that can facilitate retention. Furthermore, this study will provide a 
number of beneficial services to the participants and their primary physicians that will 
enhance retention. These include providing Harvoni, periodic evaluations, repeat 
laboratory testing, and information on new research developments in the field. 
Coordinators and other personnel at each site will also work to maintain close contact 
with participants, including regular clinic visits, newsletters and communication by 
phone, email and web sites. Counseling services will be provided so that patients and 
families are made aware of the results of studies and their correct interpretation. There 
will be no charge for Harvoni, the physician services, or laboratory tests done as part of 
this study. 
4.5 Data Elements 
 
The following laboratory tests and procedures will be used as the primary data 
elements: 
• Medical history 
• Physical examination 


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• Photographs of areas with PCT skin lesions   
• Spot plasma and urinary porphyrins (including HPLC), and urinary creatinine 
concentrations 
• Alcohol Consumption Questionnaire will assess alcohol use 
• Serum HCV RNA by PCR  
• Anti-HCV antibodies 
• Complete metabolic panel (CMP), which includes: 
o Liver chemistries (serum ALT, AST, total bilirubin, albumin, total protein) 
o Serum creatinine, sodium, potassium, chloride, carbon dioxide, calcium, 
BUN, glucose 
• CBC with differential 
• INR  
• Serum iron and TIBC 
• Serum ferritin  
 
These will be completed per the 4.7 Schedule of Events Flow Chart. In addition there 
will be adverse events reviewed at each visit. 
 
If liver biopsies and/or Fibroscans have been performed, as part of standard of care, 
results of these will be entered into the study data CRF’s; however, no liver biopsies or 
Fibroscans will be required for inclusion.  
 
4.6 Study Procedures 
 
Screening and Enrollment: 
 
Potential subjects will be invited to take part and to sign informed consent forms.  All 
participating centers will obtain CIRB approval.   
 
Data collected at baseline will include demographic and clinical information. The 
screening laboratory tests will be:  
 
• Serum HCV RNA by PCR (obtained within 30 days of enrollment)  
• Anti-HCV antibodies 
• CMP 
• CBC with differential 
• INR (if not done within 4 months of screening date) 
• PTT 
• Hepatitis B surface antigen 
• Hemoglobin (Hgb) A1c 
• Antibodies to HIV (if not done within 4 months of screening date). Those found 
positive will undergo HIV RNA and CD4 counts, to assure immune competence.  
Subjects with known HIV infection, with CD4 counts > 350/µL, whether receiving 
anti-HIV therapy or not, will not be excluded unless they require continuation of 
drug(s) contraindicated in subjects to receive Harvoni 


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• Spot plasma total porphyrins 
• Spot urine delta-aminolevulinic acid (ALA), porphobilinogen (PBG), total 
porphyrins (including HPLC), and creatinine concentrations   
• UROD enzyme activity and mutation analysis, if not previously done  
• Serum iron and TIBC 
• Serum Ferritin 
• HFE genetic testing for C282Y and H63D, if not previously done 
• Documentation of PCT symptoms and photographs of affected regions (hands, 
forearms, etc.) 
• Alcohol and Tobacco use questionnaires 
• Urine pregnancy for females of child-bearing potential  
 
At baseline/screening, following informed consent, a standard interview to assess 
history of past and current alcohol use. HCV genotype should be confirmed prior to the 
screening visit as standard of care. History of smoking and current smoking status will 
also be assessed by interview and results recorded in suitable case report forms 
(CRFs).  All prescription or over-the-counter drugs, including herbals, botanicals, and 
‘supplements’ currently being taken or taken within the two weeks prior to screening, will 
be recorded, to include name, daily dose, and approximate duration of therapy 
(estimated to nearest month and year).  Particular inquiry will be made regarding any 
and all estrogen use, including phyto-estrogens, as may be found in herbals and dietary 
supplements, such as black cohosh. All subjects will be evaluated by a hepatologist (the 
site PI or a Co-I) at baseline for liver disease based on the criteria detailed above for 
inclusion/exclusion.  
 
The investigator will review that the subject has the typical clinical features of PCT, 
specifically blistering cutaneous photosensitivity, milia, thickened sclerodermatous 
changes, and/or skin fragility. The diagnosis of PCT will be confirmed at screening from 
the urine and plasma total porphyrin results. The urinary total porphyrin excretion should 
be >800 mcg/g creatinine and the HPLC pattern typical of PCT, with a predominance of 
uro- and heptacarboxyl- porphyrins. The plasma porphyrin results should be >2.7 µg/dL 
with a predominance of uro- and heptacarboxyl- porphyrins, and a fluorescence 
emission peak at ~619 nm (with excitation at ~410 nm). 
 
At baseline, subjects who, within the prior 120 days, have not already had either hepatic 
elastography with Fibroscan or similar technique and/or had Fibrosure-HCV testing 
performed will undergo one of these measures.  The decision of which test to perform 
will be at the discretion of the site PI’s (similar testing will again be performed at the end 
of the study, as shown in the Schedule of Events). 
 
All subjects found to be eligible will be invited to take part in the study.  We anticipate 
that most subjects at baseline will not be undergoing treatment for PCT or CHC, but 
they may have done so in the past and have recurrence of active PCT with persistent or 
recurrent CHC.  To be eligible, subjects previously treated for CHC must have ended 
such treatment at least 30 days prior to enrollment into this study.  
 


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Treatment and Follow-up Visits:   
The therapy will be Harvoni at the usual dose (90 mg of ledipasvir and 400 mg of 
sofosbuvir) and duration for CHC therapy. One tablet taken daily for 8 weeks for 
patients without cirrhosis, not previously treated with HCV GT1 and HCV RNA < 6 
million IU/mL; 12 or 24 weeks, duration to be determined based upon clinical features 
and prior treatment experience. 8 or 12 weeks for subjects with or without cirrhosis, not 
previously treated with anti-virals for CHC, and 24 weeks for subjects with cirrhosis who 
were previously treated with anti-virals for CHC without having achieved SVR. During 
the first year study visits will be monthly, and this includes the treatment period of either 
12 or 24 weeks. To assess cure of HCV infection, repeated HCV RNA levels at 3, 6, 
and 12 months after end of Harvoni therapy will be done, as well as annually thereafter. 
Evaluation by a hepatologist at follow up visits will be as needed, determined by the 
screening lab test results and by clinical and lab findings at follow-up visits.  
 
Lab measures to be checked monthly during therapy will include CBC, CMP, plasma 
total porphyrins, urinary total porphyrins (with HPLC), and levels of HCV RNA in serum 
by quantitative PCR (Section 4.7 Schedule of Events).  
Porphyrin specific lab tests will be performed at the UTMB Porphyria Laboratory; all 
other labs will be performed at Covance Laboratories. 
 
Subjects who have their treatment discontinued for any reason will continue to be 
followed until the end of the study, including longer-term follow up visits, unless they 
withdraw consent. If a subject becomes pregnant during the study Harvoni will be 
discontinued. The outcome of the pregnancy will not be followed as part of this study. 
Pregnancy during the study should be reported as an SAE. 
 
Longer-Term Follow-up: 
12 months after beginning treatment, subjects will be asked to return every four months 
for one year, with repeat of interval history and physical examination (especially to 
reassess the status of cutaneous lesions of PCT) and the above studies. 
 
Every effort will be made to have all subjects return annually thereafter as part of the 
Longitudinal Study of the Porphyrias, for at least 5 years, to assess whether there has 
been relapse either of active PCT or HCV infection.  This will be done by assessing 
history of skin symptoms and measuring plasma and urine porphyrins.  All subjects will 
be strongly encouraged to return to a study center if they think they are experiencing 
recurrence of active PCT.  If there has been relapse, subjects will be treated further as 
part of routine standard of care, and their clinical and biochemical features will continue 
to be recorded. 
 


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4.7 Schedule of Events  
  
Screening 
(-30 to -1 
Days) 
Day 
0 
Day 
30 
Day 
60 
Day 
90 
Day 
120 
Day 
150 
Day 
180 
Day 
210 
Day 
240 
Day 
270 
Day 
300 
Day 
330 
Day 
360 
Day 
480 
Day 
600 
Day 
720 
(Window +/- 7 days) 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M16 
M20 
M24 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval Medical History 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Skin Assessment (including pictures) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol & Tobacco use questionnaires 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event/SAE Review 
 
 
Each visit 
Urine Pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-HCV antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B Surface Antigen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1/HIV-2 Antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Ferritin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum iron and TIBC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Metabolic Panel$ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythrocyte UROD enzyme activity* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UROD mutation analysis* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HFE genetic testing* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology with Differential#  
X 
X 
X 
X 
X 
[X]* 
[X]* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCV RNA 
X 
X 
 
 
 
[X]* 
[X]* 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
Plasma Total Porphyrins 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spot Urine ALA, PBG, Total Porphyrins 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fibroscan (if available at institution)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Dispense Study Drug€ 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
# Hematology (complete blood count): white blood cell count (WBC), red blood cell count (RBC), hemoglobin, hematocrit, platelet count  
 
 
 
$Comprehensive metabolic panel: sodium, potassium, chloride, carbon dioxide, calcium, BUN, creatinine, glucose, and liver panel, including total protein, albumin, total bilirubin (TBR), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (AP) 
 
 
 
*If not previously done 
**INR (if not done within 4 months of screening)  
 
 
 
€Drug is only to be dispensed at months 2-6 if additional therapy is warranted 
 
 
 
 
[X]* Samples at these time points will be obtained only in subjects with cirrhosis who 24 weeks of Harvoni therapy is indicated; [X] Samples at these time points will be obtained 3, 6, and 
12 months after the end of Harvoni treatment, and annually till end of study or EOT 
 
 
 


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4.8 Investigational Product 
All study drug will be stored and dispensed from individual centers’ research 
pharmacies according to their standard operating procedures. Drug will only be 
dispensed after authorized by a site Investigator and to a member of the study team. All 
study drug will be provided to each site by Gilead Sciences, Inc. through communication 
with Wake Forest University School of Medicine. 
 
Obtaining Study Drug: Once a potential participant is identified, the site will contact the 
project manager at Wake Forest University School of Medicine to have study drug sent 
to the research pharmacy at the site to be dispensed to the study team and the patient.  
 
Dispensing, Dosage, and Accountability: All participants will receive treatment for either 
8, 12, or 24 weeks depending upon the usual clinical criteria and recommendations that 
inform clinical treatment of HCV with Harvoni: We anticipate that, for most subjects, the 
duration of indicated treatment will be 12 weeks.  For patients with cirrhosis, previously 
treated for HCV infection without response or with response followed by relapse, the 
duration of treatment will be 24 weeks. Study drug will be dispensed with 4 week 
supplies (28 tablets).  It is recommended that 1 week of additional drug is provided, in 
case of the need for follow-up appointments to be rescheduled. New supplies of drug 
will not be provided to subjects until the previous supply has been accounted for by the 
site coordinator or investigational pharmacy and reconciled. Medication will only be 
provided at in person study visits, no medication will be mailed to subjects. 
 
The dosage is one tablet of the combination of ledipasvir (90 mg) + sofosbuvir (400 mg) 
taken daily with or without food. Tablets should not be broken or chewed.  No dose 
adjustments are recommended based upon considerations of age, mild or moderate 
renal impairment, or mild, moderate, or severe hepatic impairment. 
 
At each study visit the participant will bring all study drug with him or her. The site 
coordinator will count and reconcile all study medication at each visit. At each visit the 
subject will return all previous study drug and empty bottles and receive a new 4 week 
supply. At the final treatment visit (8, 12, or 24 weeks, as may be appropriate), a new 
supply will not be issued. 
 
Study Drug Destruction: Medication returned by subjects can be destroyed onsite per 
institutional SOP. 
5.0 Data and Safety Monitoring Plan 
The study protocol will be reviewed and approved by the National Institutes of Health 
(NIH) and the Data Safety Monitoring Board (DSMB) before submission to CIRB for 
approval.  Participant enrollment may only begin with CIRB approved consent forms.  
 
This is an interventional study that meets the federal definition of moderate risk. 
 


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5.1 Study Oversight 
The Study Chair has primary oversight responsibility of this clinical trial. The NIH 
appointed Data (Observational) Safety Monitoring Board (D/OSMB) has oversight 
responsibility of the Data Safety Monitoring Plan (DSMP) for this clinical trial. The 
D/OSMB will review accrual, patterns and frequencies of all adverse events, and 
protocol compliance every 6 months. The D/OSMB makes recommendations to the NIH 
regarding the continuation status of the protocol. 
 
Each site’s Principal Investigator and his/her research team (co-Investigators, research 
nurses, clinical trial coordinators, and data managers) are responsible for identifying 
adverse events. Aggregate reports- detailed by severity, attribution (expected or 
unexpected), and relationship to the study drug/study procedures – will be available 
from the DMCC for DSMB review.  Adverse events will be reviewed at each study visit 
by the research team.   A separate report detailing protocol compliance will also be 
available from the DMCC for DSMB  review. The research team will then evaluate 
whether the protocol or informed consent document requires revision based on the 
reports. 
 
5.2 Definitions and Standards 
 
The Rare Diseases Clinical Research Network defines an adverse event as:  “…an 
unfavorable and unintended sign, symptom or disease associated with a participant’s 
participation in a Rare Diseases Clinical Research Network study.” 
 
Serious adverse events include those events that “result in death; are life-threatening; 
require inpatient hospitalization or prolongation of existing hospitalization; create 
persistent or significant disability/incapacity, or a congenital anomaly/birth defects.”  
 
An unexpected adverse event is defined as any adverse experience, the specificity or 
severity of which is not consistent with the risks or information described in the protocol.  
 
Expected adverse events are those that are identified in the research protocol as having 
been previously associated with or having the potential to arise as a consequence of 
participation in the study. 
 
All reported adverse events will be classified using the current version of the Common 
Terminology Criteria for Adverse Events (CTCAE) developed and maintained by CTEP 
at the National Cancer Institute. 
 
5.3 Expected/Known Risks/Discomforts/Adverse Events Associated with 
Study Intervention and Procedures: Definition of Expected Adverse Events 
 
Drug Information for Harvoni 
 


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It was determined by the Food and Drug Administration that this study does not require 
an Investigational New Drug application. 
 
Human Toxicity/ Adverse Events (adapted from package insert dated March 2015) 
The safety assessment of HARVONI was based on pooled data from three Phase 3 
clinical trials of subjects with genotype 1 chronic hepatitis C (CHC) with compensated 
liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who 
received HARVONI for 8, 12 and 24 weeks, respectively.  
 
The proportion of subjects who permanently discontinued treatment due to adverse 
events was 0%, <1%, and 1% for subjects receiving HARVONI for 8, 12, and 24 weeks, 
respectively. 
 
The most common adverse reactions (≥10%) were fatigue and headache in subjects 
treated with 8, 12 or 24 weeks of HARVONI. 
 
Table 2 lists adverse reactions (adverse events assessed as causally related by the 
investigator, all grades) observed in ≥5% of subjects receiving 8, 12, or 24 weeks 
treatment with HARVONI in clinical trials. The majority of adverse reactions presented in 
Table 2 occurred at severity of grade 1. The side-by-side tabulation is to simplify 
presentation; direct comparison across trials should not be made due to differing trial 
designs. 
 
Table 2 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 
12, or 24 Weeks of Treatment with HARVONI 
HARVONI 8 weeks HARVONI 12 weeks 
HARVONI 24 weeks 
N=215 
N=539 
N=326 
Fatigue 
16% 
13% 
18% 
Headache 11% 
14% 
17% 
Nausea 
6% 
7% 
9% 
Diarrhea 
4% 
3% 
7% 
Insomnia 3% 
5% 
6% 
 
 
Laboratory Abnormalities: 
Bilirubin Elevations: Bilirubin elevations of greater than 1.5×ULN were observed in 3%, 
<1% and 2% of subjects treated with HARVONI for 8, 12, and 24 weeks, respectively. 
 
Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3×ULN 
were observed in <1%, 2%, and 3% of subjects treated with HARVONI for 8, 12, and 24 
weeks, respectively. 
 
Creatine Kinase: creatine kinase was not assessed in Phase 3 trials of HARVONI. 
Isolated, asymptomatic creatine kinase elevations (Grade 3 or 4) have been previously 
reported in subjects treated with sofosbuvir in combination with ribavirin or 
peginterferon/ribavirin in other clinical trials. 


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Study Procedures:  
Venipuncture:  The vein in which the needle has been inserted to draw blood may 
become sore and red.  A temporary “black and blue mark” may develop, and rarely 
fainting may occur. 
 
Safety Endpoints 
 
Grade 3 or 4 toxicities: According to the scale of the World Health Organization. For 
liver tests, total serum bilirubin greater than 2.5 mg/dL or, if elevated at baseline, more 
than at 3-fold increase above the baseline level; serum ALT or AST or AP greater than 
3 x ULN, or if elevated at baseline, > 3 x baseline level; INR > 2.0. 
 
Worsening PCT symptoms: PCT is a rare disease and no standard disease severity 
scale exists. A standardized detailed skin assessment including pictures will be done at 
each time point in this study. If a subject experience significantly worsening symptoms 
in the opinion of the investigator that persist for 60 days, HCV therapy will be 
discontinued under the study and standard of care PCT treatment will be initiated. This 
length of time may be shortened depending on the severity of the subject’s PCT 
symptoms. Any patient who experiences worsening PCT symptoms must be discussed 
by the site PI with the Study Chair prior to discontinuing Harvoni.  
 
5.4 Reporting Timeline 
 
• Within 24 hours (of learning of the event), investigators will report any reportable 
Serious Adverse Event (SAE) that: 
o 
Is considered life-threatening/disabling or results in death of subject 
-OR- 
o 
Is Unexpected/Unanticipated  
• Investigators will report all other reportable SAEs within 5 working days (of learning 
of the event). 
• All other (suspected) reportable AEs will be reported to the RDCRN within 20 
working days of the notification of the event or of the site becoming aware of the 
event. 
 
Any SAE or Special Situations Reports (SSR) will also be reported to the Gilead Drug 
Safety and Public Health department within 15 days of learning of the event. Redacted 
SAE/SSR reports are preferred by email at the following contact information: 
 
Gilead Sciences, Inc. 
Drug Safety and Public Health 
333 Lakeside Dr. 
Foster City, CA 94404 
Fax: 650 522 5477 
Phone:  650 522 5114 


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Email: Safety FC@gilead.com 
 
 
Local institutional reporting requirements to CIRB, any GCRC oversight committee and 
the FDA, if appropriate, remain the responsibility of the treating physician and the Study 
Chair. 
 
5.5 RDCRN DMCC Adverse Event Monitoring Process  
 
The DMCC will make adverse event reports available for review. Upon entry of a 
serious adverse event (SAE) into the DMCC database, the Study Chair, site PIs, the 
RDCRN D/OSMB medical review officer, and any additional agencies (if applicable- 
industry sponsor) will be notified immediately by email.  
 
Serious adverse events: The NIH appointed Medical Review Officer (MRO) reviews the 
site investigator’s report and determines causality (definitely not related, probably not 
related, possibly related, probably related, definitely related) of the adverse event. The 
MRO may request further information if necessary and possibly request changes to the 
protocol or consent form as a consequence of the adverse event. Any follow up reports 
or requested additional participant data will be entered into the DMCC Adverse Event 
Monitoring System by the reporting site and reviewed by the MRO. Completed AE 
reviews by the MRO will be sent to Study Chair, site PIs, and the appointed NIH 
officers.  
 
If warranted, the MRO may request an ad hoc call with the DSMB to review the adverse 
event. All reported AE’s will be reviewed during the regularly scheduled DSMB call. 
The DMCC Adverse Event Monitoring Process maintains audit trails and stores data 
(and data updated) and communication related to any adverse event in the study. 
 
Non-serious expected adverse events: Except those listed above as immediately 
reportable, non-serious adverse events that are reported to or observed by the 
investigator or a member of his research team will be submitted to the system in a 
timely fashion (within 20 working days). The events will be presented in tabular form 
and given to the MRO and RDCRN D/OSMB on an annual basis. Local site 
investigators are also required to fulfill all reporting requirements of their local 
institutions. 
 
The DMCC will post aggregate reports of all adverse events (serious/not serious and 
expected, unexpected) for the DSMB, site investigators and CIRB. 
 
 
5.6 Study Discontinuation  
 
The NIH, RDCRN DSMB, and CIRB have the authority to stop or suspend this trial at 
any time. This study may be suspended or closed if: 


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• The study objectives have been met 
• The Study Chair / Study Investigators believe it is not safe for the study to 
continue 
• The RDCRN DSMB suspends or closes the trial 
• The NIH suspends or closes the trial 
• The FDA suspends or closes the trial 
• Gilead Sciences elects to suspend or close the trial 
 
5.7 Subject Discontinuation 
 
An intent to treat approach will be used. All data acquired prior to termination for the 
reasons outlined below will be included in the primary analysis. Every effort will be 
made to conduct a final study visit with the participants and participants will be followed 
clinically until, if applicable, all adverse events resolve.  
 
• Withdrawal of consent by the participant 
• Withdrawal by the investigator if early stopping rules have been met: If there are 
Grade 4 toxicities, such as severe bradycardia with syncope, Harvoni will be 
stopped. Subject’s PCT symptoms worsen significantly (as specified in section 
5.3) 
• Withdrawal by the investigator for other reasons 
• Intercurrent illness or event that precludes further visits to the study site or ability 
to evaluate disease (e.g. mental status change, large pleural effusion).  
 
5.8 Data Quality and Monitoring Measures 
 
As much as possible data quality is assessed at the data entry point using intelligent on-
line data entry via visual basic designed screen forms. Data element constraints; 
whether independent range and/or format limitations or ‘relative’ referential integrity 
limitations can be enforced by all methods employed for data input. QA reports assess 
data quality post-data entry. As we note, data quality begins with the design of the data 
collection forms and procedures and incorporates reasonable checks to minimize 
transcription and omission errors.  Of the more important quality assurance measures 
are the internal validity checks for reasonableness and consistency.  
 
• Data Monitoring: The RDCRN DMCC identifies missing or unclear data and 
generates a data query to the consortium administrator contact.  
• Data Delinquency Tracking: The Data Management and Coordinating Center will 
monitor data delinquency on an ongoing basis.   
 
5.9 Quality Control: Study Related Procedures 
 


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The standard laboratory measures will be performed at each Covance Central 
Laboratory.  Porphyrin measurements will be performed in the CLIA certified laboratory 
of Dr. Karl Anderson, University of Texas Medical Branch, Galveston, TX (see Appendix 
I for processing instructions).  
 
The investigational pharmacy at each site will be responsible for drug accountability 
while the investigators/coordinators will be responsible for compliance of the subjects. 
The Investigational Drug Service at Wake Forest University will serve as the 
coordinating pharmacy for this study.   
6. Statistical Considerations 
 
Primary endpoint: The primary endpoint is resolution of active PCT, defined as 
normalization of plasma porphyrins (less than 0.9 mcg/dL) by 7 months after the start of 
therapy. The primary hypothesis will be assessed by computing the exact (i.e., based 
on the binomial distribution) lower one-sided 95% confidence bound for the proportion 
of patients whose PCT resolves by 7 months. If this lower confidence bound exceeds 
0.40 (the performance goal of 0.50 minus the non-inferiority margin of 0.10) then 
Harvoni will be declared non-inferior to the performance goal.  Seven months has been 
chosen based upon recent results comparing iron reduction and hydroxychloroquine as 
therapy for PCT (Singal et al, 2012) and on the consensus of the investigators of the 
Porphyrias Consortium that a median time to resolution of 7 months would cause them 
to consider using Harvoni over phlebotomy or hydroxychloroquine as a first line of 
treatment for PCT patients with Hepatitis C. 
 
Patients missing primary endpoint data are a potential problem in all clinical trials, with 
the potential for biased inference increasing with the amount of missing outcome data.    
We will report reasons for missing data, and examine the effect that any missing data 
might have on results via sensitivity analysis of augmented data sets (for example, best-
case or worst-case scenarios).  Patients missing the trial’s primary endpoint will be 
included in the analysis by modern imputation methods for missing data. 
 
If data are missing due to severity of illness, the patient will be counted as a treatment 
failure (i.e. resolution not achieved).  Patients with missing primary outcome data not 
due to severity of illness will have their 7 month resolution status imputed via multiple 
imputation assuming that the data are missing at random (i.e. the missing nature of the 
variable is independent of the value of the variable given the observed data).  The 
specific imputation model to be used will be determined prior to examination of any 
outcome data, but will include any measured plasma porphyrins from baseline to 6 
months.  Imputed data will be rounded to 0 (failure/resolution not achieved) or 1 
(success/resolution achieved). 
 
After the imputations are completed, all of the data (complete and imputed) will be 
combined and the analysis performed for each imputed-and-completed dataset.  
Rubin’s method of multiple (i.e., repeated) imputation will be used to estimate treatment 


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effect.  We propose to use 15 datasets (an odd number to allow use of one of the 
datasets to represent the median analytic result).  
 
Secondary Endpoints:  
Time to resolution of active PCT, defined as normalization of plasma porphyrins (less 
than 0.9 mcg/dL): The median time to resolution by this definition will be computed 
using Kaplan-Meier estimation and compared descriptively to the median time to 
resolution reported by standard therapies. 
 
Time to resolution of active PCT, defined as cessation of any new blisters or bullae: 
Complete resolution of skin manifestations is expected to occur later than normalization 
of plasma porphyrins, because it takes time for healing of the skin fragility that 
predisposes of blister formation to occur.  The median time to resolution by this 
definition will be computed using Kaplan-Meier estimation and compared descriptively 
to the median time to resolution reported by standard therapies. 
 
Complete Biochemical remission of PCT: Complete biochemical remission of PCT will 
be measured as a decrease of the sum of urinary uro- and hepta-carboxyl porphyrins to 
less than 100 mcg/g creatinine, and a normal urine porphyrin HPLC pattern, defined as 
the total of highly carboxylated porphyrins (uro- and heptacarboxyl-porphyrins) being 
less than that of coproporphyrins, and absence of a fluorescence peak by fluorescence 
scanning.  The proportion of patients who achieve complete biochemical remission by 
the end of study period will be computed and the median time to resolution by this 
definition will be computed using Kaplan-Meier estimation. Because of underlying liver 
disease and/or possible continuing alcohol use, total urinary porphyrins may remain 
elevated, due to increased coproporphyrins.  We will explore whether and to what 
extent total urinary porphyrins may remain elevated, due to increased coproporphyrins 
descriptively in these subjects. 
 
Cure of CHC: Cure of CHC will be defined as no detectable HCV RNA at end of 
treatment (EOT) and persisting for at least 12 weeks after EOT, now taken as usual 
definition of sustained virological response (SVR).  The proportion of patients who 
achieve CHC cure will be reported.  
 
Sample Size: The primary study hypothesis is that the proportion of patients whose 
PCT resolves by 7 months will be non-inferior to the performance goal of 50%.   This 
performance goal is based on previously published data that reported a median time to 
resolution between 6-7 months for PCT patients undergoing treatment with iron 
reduction by therapeutic phlebotomies or hydroxychloroquine (Singal et al, 2012).  The 
non-inferiority margin will be set to 10%; a difference from the performance goal judged 
to be both clinically acceptable and well within the margin needed to assure that the 
performance of Harvoni is at established levels of benefit from conventional therapies. 
Thus, the null hypothesis tested by this study is H0: π ≤ 0.40, against the alternative 
hypothesis H1: π > 0.40. 
 


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Sample size requirements are based on an exact test of a binomial proportion. 
Assuming that the study drug has a true success probability of 58%, 49 subjects yield 
80% power to reject the null hypothesis at a one-sided significance level of 0.05.    
 
The null hypothesis would be rejected at the final analysis if 26 or more successes out 
of 49 subjects were observed (an observed success rate of 53.1%).  The power of the 
test assuming a true success rate of 58% for Harvoni is 80.2%. Operating 
characteristics for the decision rule corresponding to the final analysis are given below 
(Table 3). 
 
Table 3: Operating characteristics for the decision rule (Final analysis) 
True Harvoni 
success rate (π) 
Prob (26 or more 
successes|π, N=49) 
0.40 
0.0434 
0.45 
0.1609 
0.50 
0.3877 
0.55 
0.6627 
0.60 
0.8718 
0.65 
0.9695 
7. Data Management 
 
As much as possible, data quality is assessed at the data entry point using intelligent 
on-line forms via the DMCC. Data element constraints; whether independent range 
and/or format limitations or ‘relative’ referential integrity limitations can be enforced by 
all methods employed for data input. QA reports assess data quality post-data entry. As 
we note, data quality begins with the design of the data collection forms and procedures 
and incorporates reasonable checks to minimize transcription and omission errors.  Of 
the more important quality assurance measures are the internal validity checks for 
reasonableness and consistency.  In addition to those described above, we propose to 
build these checks into the initial tables and cross tabulations that should reveal any 
remaining data quality issues.  The NIH Program Staff, the DMCC, and Porphyrias 
Consortium staff are responsible for assuring and monitoring data quality. 
 
All study data will be collected via systems created in collaboration with the RDCRN 
Data Management and Coordinating Center and will comply with all applicable 
guidelines regarding patient confidentiality and data integrity. 
 
7.1 Registration 
Registration of participants on this protocol will employ an interactive data system in 
which the clinical site will attest to the participant’s eligibility as per protocol criteria and 
obtain appropriate informed consent. CIRB approval for the protocol must be on file at 
the DMCC before accrual can occur from the clinical site. 
 


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The DMCC will use a system of coded identifiers to protect participant confidentiality 
and safety.  Each participant enrolled will be assigned a local identifier by the enrollment 
site.  This number can be a combination of the site identifier (location code) and a serial 
accession number.  Only the registering site will have access to the linkage between 
this number and the personal identifier of the subject.  At time of enrollment, each 
subject is registered through the DMCC provided web-based registration system. A 
unique participant ID will be generated at the time of enrollment, which will allow for a 
common ID to link a participant to multiple studies.  Thus each participant will have two 
codes: the local one that can be used by the registering site to obtain personal 
identifiers and a second participant ID.   For all data transfers to the DMCC both 
numbers will be required to uniquely identify the subject.  In this fashion, it is possible to 
protect against data keying errors, digit transposition or other mistakes when identifying 
a participant for data entry since the numbers should match to properly identify the 
participant.   
 
7.2 Data Entry 
Study data will be entered into an electronic data capture (EDC) system supported by 
the DMCC. The EDC system is hosted in a secure, cloud-based environment managed 
by the DMCC, and complies with all applicable guidelines to ensure patient 
confidentiality, data integrity, and reliability. All data management best practices 
including quality controls and data validation procedures will be applied to ensure the 
validity and accuracy of the clinical database.   
8. Human Subjects 
8.1 GCP Statement 
 
This clinical trial will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki, and that are consistent with Good Clinical 
Practice and all applicable regulatory requirements. 
 
8.2 Benefits  
 
Benefits of taking part include especially the opportunity for eligible subjects to receive 
Harvoni at no cost to them or their insurance carriers and to receive frequent and 
careful follow-up during and after this course of therapy.  This is expected to lead to 
cure of HCV infection in the great majority of subjects.  It may also lead to resolution of 
PCT. 
 
The potential benefits of this protocol are felt by the investigators to outweigh the risks. 
 
8.3 Risks  
 
The potential risks of this study are: 
 


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1) Side effects of Harvoni: the most frequent side effects have been fatigue and 
headache, which have been of low severity. 
 
2) Blood Draw: Needle insertion can cause pain and bruising at the site of insertion. 
Rarely fainting caused by a vasovagal response to the phlebotomy procedure 
may occur. Because the skin is penetrated by the needle, there is a low risk for 
infection at the venipuncture site. The amount of blood needed for each study 
visit (8mL tubes) is within approved safety limits. For any participant who has a 
medical condition that restricts their capacity to provide adequate sample 
volume, the number of tubes of blood obtained will be modified on an individual 
basis. 
 
3) Loss of confidentiality: The risk of loss of confidentiality is low because as there 
are many safe guards in place. Conceivably, data including clinical and 
diagnostic information could be accidentally divulged. If such an event occurred, 
subjects might be at risk for discrimination by life or health insurance companies, 
by employers, and by adoption agencies. The Genetic Information Non-
Discrimination Act (GINA) is a federal law that protects Americans from being 
treated unfairly because of differences in their DNA that may affect their health. 
This law prohibits genetic discrimination in the workplace and by health insurers. 
However, it provides no such protection for life insurance and disability 
insurance. 
 
8.4 Written Informed Consent 
 
Written informed consent will be obtained from each participant before any study-
specific procedures or assessments are done and after the aims, methods, anticipated 
benefits, and potential hazards are explained.  The participant’s willingness to 
participate in the study will be documented in writing in a consent form, which will be 
signed by the participant with the date of that signature indicated.  The investigator will 
keep the original consent forms and signed copies will be given to the participants.  It 
will also be explained to the participants that they are free to refuse entry into the study 
and free to withdraw from the study at any time without prejudice to future treatment.  
Written and/or oral information about the study in a language understandable by the 
participant will be given to all participants. 
 
8.5 Process of Consent  
 
At each of the Porphyrias Consortium sites the principal investigator and/or study 
coordinator will identify subjects with PCT and HCV who are eligible for this study. The 
PI and/or coordinator will then approach the subject, either via a phone call or at a clinic 
visit, to fully describe the intent of the study and what the potential risks and benefits of 
participation in this study will be. The subject will have an opportunity to review the 
consent form and ask any questions of the study team, as well as discuss the study with 


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their primary care physician or others of their choosing, prior to signing the consent 
form. 
 
8.6 Certificate of Confidentiality  
 
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, 
documents, or biospecimens that may identify the participant in any federal, state, or 
local civil, criminal, administrative, legislative, or other action, suit, or proceeding, or be 
used as evidence, for example, if there is a court subpoena, unless the participant has 
consented for this use. Information, documents, or biospecimens protected by this 
Certificate cannot be disclosed to anyone else who is not connected with the research 
except, if there is a federal, state, or local law that requires disclosure (such as to report 
child abuse or communicable diseases but not for federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings, see below); if the participant consents 
to the disclosure, including for their medical treatment; or if it is used for other scientific 
research, as allowed by federal regulations protecting research participants.  
 
The Certificate cannot be used to refuse a request for information from personnel of the 
United States federal or state government agency sponsoring the project that is needed 
for auditing or program evaluation by the U.S. Department of Health and Human 
Services and/or the National Institutes of Health, which is funding this project.  The 
Certificate of Confidentiality does not prevent a participant from voluntarily releasing 
information about themselves or their involvement in this research. If a participant wants 
research information released to an insurer, medical care provider, or any other person 
not connected with the research, the participant must provide consent to allow the 
researchers to release it. 
 
Even with the Certificate of Confidentiality, the investigators continue to have ethical 
obligations to report child abuse or neglect and to prevent an individual from carrying 
out any threats to do serious harm to themselves or others.  If keeping information 
private would immediately put the study participant or someone else in danger, the 
investigators would release information to protect the participant or another person.  
The Certificate of Confidentiality will also not be used to prevent disclosure as required 
by federal, state, or local law, such as reports of child abuse and neglect, or harm to self 
or others. 
 


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9. References 
 
1. Ahmad W, Ijaz B, Jawed FT.  A comparison of four fibrosis indexes in chronic 
hepatitis C viral infection.  Development of a new fibrosis-cirrhosis index (FCI).  
BMC Gastroent 2011; 11:  44-54. 
2. Balwani M, Doheny D, Bishop DF, et al.  Loss-of-function ferrochelatase and 
gain–of –function erythroid 5-aminolevulinate synthase mutations causing 
erythropoietic protoporphyria and X-linked protoporphyria in North American 
patients reveal novel mutation and a high prevalence of X-linked protoporphyria.  
Molec Medicine 2013; 19: 26-35.  [PMID:23364466] 
3. Besur S, Hou W, Schmeltzer P, Bonkovsky HL.  Clinically important features of 
porphyrin and heme metabolism and the porphyrias.  Metabolites 2014; 4: 977-
1006.  [PMID 25372274]  
4. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, et al.  Porphyria cutanea tarda, 
hepatitis C, and HFE gene mutations in North America.  Hepatology 1998; 27: 
1661-1669.  [PMID: 9620340] 
5. Bonkovsky HL, Hou W, Li T, Guo J-T, Narang T, Thapar M.  Porphyrin and heme 
metabolism and the porphyrias.  In Wolkoff A, Lu S, and Omary B (Eds).  
Comprehensive Physiology, 2013; 3:365-401. [The American Physiological 
Society, Bethesda, MD, Wiley and Co] [PMID 23720291] 
6. Bonkovsky HL, Maddukuri V, Yazici C, et al.  Acute porphyrias in the USA:  
features of 108 subjects from porphyria consortium.  American Jl of Medicine, 
2014; 127: 1233-1241. [PMID: 25016127]. 
7. Egger NG, Goeger DE, Payne DA, et al.  Porphyria cutanea tarda: multiplicity of 
risk factors including HFE mutations, hepatitis C, and inherited uropophyrinogen 
decarboxylase deficiency.  Dig Dis Sci 2002; 47: 419-426. [PMID 17187403] 
8. Fallatah HI.  Noninvasive biomarkers of liver fibrosis:  an overview.  Adv Hepatol 
2014; http://dx.doi.org. 10.1155/2014/357287. 
9. Gilead Sciences, Approved package insert for Harvoni, revised 3/2015. 
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-
disease/harvoni/harvoni_pi.pdf. 
10. Singal A, Kormos-Hallberg C, Lee C, et al.  Low-dose hydroxychloroquine is as 
effective as phlebotomy in treatment of patients with porphyria cutanea tarda.  
Clin Gastroenterol Hepatol 2012; 10: 1402-1409. [PMID 22985607] 
11. Stölzel U, Köstler E, Schuppan D, et al.  Hemochromatosis (HFE) gene 
mutations in porphyria cutanea tarda.  Arch Dermatol 2003; 139: 309-313.  
[PMID 12622622] 
 
 


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10. Appendices 
 
I. Sample Processing Instructions 
 
For Urine Porphyrin testing: 
• Put 10 ml urine into a urine collection container with no preservatives. Label with 
the patient’s name, date of birth, and date sample was taken, wrap immediately 
in aluminum foil, or place in amber bag, to protect from light, and freeze at -800C. 
If a -800C freezer is not available a -200C freezer is acceptable. 
 
For Plasma Porphyrin testing: 
• 5 ml blood drawn in sodium heparin (green-top) tube. Centrifuge and separate as 
follows: 
• Transfer 1 ml plasma into two plastic (Eppendorf) tubes each. Label with the 
patient’s name, date of birth, and date sample was taken, wrap immediately in 
aluminum foil, or place in amber bag, to protect from light, and freeze at -800C. If 
a -800C freezer is not available a -200C freezer is acceptable. 
 
 
Samples should be shipped overnight on dry ice after each visit to the following: 
Porphyria Lab  
University of Texas Medical Branch 
700 Harborside Drive, Ewing Hall 3.102 
Galveston TX 77555-1109 
**Write on shipping label “INSIDE DELIVERY ONLY” 
 
Check with the Porphyria Laboratory before shipping to assure that samples are 
not delivered on holidays or weekends.   
 

ICF_000.pdf: 
Official Title:Newer Direct-Acting Anti-Viral Agents as Sole Therapy of 
Porphyria Cutanea Tarda in Subjects With Chronic Hepatitis C 
IRB Approved Date: 12/16/21
NCT03118674


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The University of Texas Medical Branch at Galveston 
Research Consent Form
Protocol Title
Newer Direct-Acting Anti-Viral Agents as Sole Therapy of Porphyria 
Cutanea Tarda in Subjects with Chronic Hepatitis C
IRB Number:
17-0081
Sponsors:
Icahn School of Medicine at Mt. Sinai
Wake Forest School of Medicine
Gilead Sciences
National Institute of Diabetes and Digestive and Kidney
Diseases/NIH/DHHS
Principal Investigator: Karl E. Anderson, MD
Address:
 
Phone:
 (during business hours)
(after business hours)
Fax:
Why am I being asked to take part in this research study?
You are being asked to take part in this study because you have been diagnosed with both 
Porphyria Cutanea Tarda (PCT) and Chronic Hepatitis C caused by an infection of the Hepatitis 
C virus (HCV).
STUDY SUMMARY:
The purpose of this study is to learn whether Harvoni, a simple oral treatment for the HCV 
infection, is effective as treatment for PCT. The duration of the study is two years. If you choose 
to participate, you will be asked to come to University of Texas Medical Branch (UTMB) every 
month for the first year of the study, and every 4 months during the second year of the study. At 
each visit, blood and urine samples will be collected for testing. Based on these results, Dr. Karl 
Anderson, the principal investigator of this study, will determine how long you will need to take 
Harvoni for (8. 12, or 24 weeks).
Risks or discomforts from this research could include pain upon needle insertion during the 
blood draw, fatigue or headaches from taking Harvoni, or your PCT symptoms not improving.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00043341
Meeting Date Approved 12/16/2021          
Version Valid Until: 12/12/2022


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There may not be direct benefits for you, however, possible benefits include successful treatment 
with Harvoni for your Hepatitis C, and/or resolution of your PCT symptoms.
Taking part in this research study is voluntary. You do not have to participate and you can stop at 
any time. Please take your time to read this entire form and ask questions before deciding if you 
want to take party in this research study.
What is the purpose of this research study?
The purpose of this study is to learn whether Harvoni, a simple oral treatment for chronic 
hepatitis C virus (HCV) infection, is effective as treatment for Porphyria Cutanea Tarda (PCT). 
Harvoni is approved by the FDA for treatment of hepatitis C, and is a combination of 90 mg of 
ledipasvir and 400 mg of sofosbuvir, which are two direct-acting antiviral agents. Harvoni is 
considered investigational in this study, meaning it is not approved for marketing by the FDA for 
use in treating PCT.
PCT is the most common form of porphyria in the USA and most other countries. It is due to an 
acquired deficiency of the enzyme uroporphyrinogen decarboxylase (UROD) in the liver.
Susceptibility factors for PCT include heavy alcohol use, iron overload, HCV infection, human 
immunodeficiency virus (HIV) infection and estrogens. Genetic factors may include UROD 
mutations, which are found in about 20% of PCT patients and partially reduce UROD from birth, 
and HFE mutations, which predispose to iron overload. Most patients with PCT have at least 
several of these acquired and inherited susceptibility factors.
The current standard treatments for PCT is phlebotomy, which reduces the amount of iron in the 
body by removing a specific amount of blood at regular intervals (usually a pint every 2 weeks). 
A second standard treatment is a medication called hydroxychloroquine, which is given in small 
doses to remove porphyrins from the liver.
There have been reports of patients with PCT having their PCT symptoms resolve with HCV 
infection treatments. But treatment of HCV infection has been difficult and not always 
successful, so PCT has generally been treated first. With the recent development of better 
therapies for HCV infection such as Harvoni, with fewer side-effects and better success rates, it 
is important to look into whether these HCV therapies can also help resolve PCT symptoms.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00043341
Meeting Date Approved 12/16/2021          
Version Valid Until: 12/12/2022


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This is a study to determine whether Harvoni (the study drug) is as effective a treatment for PCT 
as the current standard of care treatments, phlebotomy or hydroxychloroquine. You may qualify 
to take part in this research study because you have been diagnosed with PCT and HCV.
Funds for conducting this research are provided by Icahn School of Medicine at Mt. Sinai, Wake 
Forest School of Medicine, National Institute of Diabetes and Kidney Diseases/NIH/DHHS, and 
Gilead Sciences. Gilead is the manufacturer of the study drug and is providing Harvoni for the 
study at no cost.
How many people will take part in this study?
Your participation in this research study is expected to last for two years.
The number of people expected to take part in this research study at UTMB is about 20. The total 
number of people expected to take part in this research study at this and other sites is 49.
What procedures are involved as part of this research study?
If you agree to participate in this research study, the following information describes what may 
be involved. All clinically relevant results of this research will be communicated with you, in 
particular your response to treatment with Harvoni.
Baseline visit:
This first study visit will take place at our study center. To participate in this study, we will ask 
you to sign this consent form. This visit can take up to 2 hours to complete. You will be seen by 
a liver specialist at this visit.
We will ask you questions about your medical and family history, and give you a physical 
examination. We will ask you about any medicines that you are taking or that you have taken in 
the past. We will check your medical records for information that will help us determine if you 
are eligible for the study, such as laboratory tests and previous or ongoing treatment. We will 
take your blood pressure, temperature, pulse, height, weight and other body measurements. You 
will have to complete questionnaires about your PCT symptoms and we will also take pictures of 
your skin blisters and scars. If these pictures are of your face your eyes will be blacked out so 
you are not easily recognized.
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Institutional Review Board 
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A collection of samples will be obtained, including blood (about 2-4 tablespoons) and urine 
(about 1/4 cup) for testing. These lab tests are standard tests to diagnose HCV and PCT and 
monitor them during treatment. DNA analysis will look for a mutations (or change) in the UROD 
gene and the HFE (hemochromatosis) gene, unless already done and documented. UROD 
mutations are found in only about 20% of PCT patients, and HFE mutations are more common. 
You will also be tested for HIV antibodies if not already done within 4 months of screening.
A test to estimate liver fibrosis (scarring) or stiffness will be performed This may be a blood test 
called Fibrosure, or a scan such as Fibroscan that uses a non-invasive probe that estimates 
stiffness using sound waves. Delivering sound waves to the liver does not entail any significant 
risk.
Testing on these samples may include measurement of certain products, such as porphyrins, 
found in the blood and urine of people with porphyria, and DNA analysis to find the mutations 
(or changes) in genes known to play a role in PCT (the UROD and HFE genes).
PCT can be associated with some liver abnormalities which can resemble those due to other liver 
conditions. Therefore, tests will be done to rule out other liver diseases, including other types of 
hepatitis (such as hepatitis B) and diabetes, unless these were done before. A liver ultrasound and 
a liver biopsy are not required as part of this study, but may be recommended as part of your 
standard medical care and will not be covered by the study.
You will also be tested for other conditions that would not allow you to participate in this study, 
such as diseases affecting the kidneys or bone marrow. If you are female, a urine pregnancy test 
will also be performed during this visit.
As part of your treatment for PCT, you have been advised to avoid things that make PCT worse, 
such as drinking alcohol, smoking, and other recreational substances. You should also avoid 
sunlight exposure (direct sunlight, tanning beds, etc.) until your condition has been successfully 
treated.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00043341
Meeting Date Approved 12/16/2021          
Version Valid Until: 12/12/2022


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Treatment and Follow-Up Visits:
The study drug will need to be taken daily for 8, or in most cases 12 or 24 weeks; your study 
doctor or the liver specialist will determine whether you should take it for 8, 12 or 24 weeks. For 
the first year you are in the study, including when you take the study medication, you will need 
to return to the study center every month for monitoring and some of the same procedures done 
during the baseline visit will be repeated.
If you stop before you complete Harvoni therapy or if you are still experiencing PCT symptoms 
or your porphyrin levels have not returned to normal after you complete Harvoni therapy, then 
standard PCT treatment would be offered. This care will be billed to you or your insurance in the 
ordinary manner and you will be responsible for all treatment costs not covered by your 
insurance, including deductibles, co-payments and coinsurance. We would ask you to still 
participate in follow-up visits for this study if this happens.
After one year you will be asked to return every four months for another one year. This is to 
determine if PCT and its symptoms return. You will be seen by a liver specialist at some of these 
follow up visits. If you did not complete the study within the proposed two-year time period due 
to unforeseen circumstances, such as the COVID-19 pandemic, we may extend the study in 
order to complete the last visit (month 24) and collect important data needed to conclude the 
study.
After two years you will be asked to participate in the Longitudinal Study of the Porphyrias and 
to continue coming to the study center once a year for check-ups. This is to see if PCT returns 
after treatment with Harvoni, but without phlebotomy or hydroxychloroquine.
You will be given a unique code number which will be used to label all samples (blood and 
urine) and information from you. The information collected from you, including health and 
family history information, will be entered into a computer. This information will be linked to 
you, meaning that we will be able to find out whom the samples (blood and urine) and 
information came from. This may be important if the researchers need additional information or 
samples to help the research. Additionally, the information collected for this study will be stored 
by the NIH at the Data Management and Coordinating Center (DMCC) at the Cincinnati 
Children’s Hospital Medical Center in Cincinnati, OH and also sent to a Federal data repository. 
The DMCC uses several layers of protection for the clinical data stored there. It meets all of the 
local and federal security requirements for research datacenters. Your information is stored using 
only your code number. No personal identifiers like your name, address or medical record 
number will be sent to the DMCC.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00043341
Meeting Date Approved 12/16/2021          
Version Valid Until: 12/12/2022


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The following table shows what will happen at each visit. The Baseline Visit is to determine 
whether or not you are eligible to participate in the study, inform you about all the study 
procedures and then give you the opportunity to sign this consent form. The study drug may be 
started then, or at a later visit, after eligibility and consenting are complete.
Follow-Up Visits (Months After Start of Study Medication)
Procedure 
s
Bas 
e- 
line 
Visi 
t*
Start 
of 
Study 
Medi
-
catio 
n
1
2
3
4
5
6
7
8
9
10
11
12
16
20
24
Consent
X
Medical 
history
X
Follow-up 
history
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
exam
X
X
X
X
X
X
X
X
PCT
symptom 
questionnai 
re & skin 
pictures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood & 
urine 
collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fibroscan 
or 
Fibrosure
X
X
X
Provide 
study 
medication
X
X
X
X
†
X
†
X
†
*Up to one month before you begin study medication.
†If additional medication is indicated for treatment for 24 weeks rather than 12 weeks.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00043341
Meeting Date Approved 12/16/2021          
Version Valid Until: 12/12/2022


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If you decide to take part in this research study you will be responsible for the following things:

Reliably taking the study medication on a daily basis and reporting if and when study
medication has not been taken

Coming to your scheduled study visits on time

Providing us with a urine and blood samples at each visit

Providing accurate details about your medical history as well as medications you are
taking.

Reporting any illnesses or medical problems that occur during the time you are taking the
study medication

Completing questionnaires during the study visits

It is advised that you stop drinking alcohol and smoking while taking part in this study. If
you do not stop you will not be removed from the study but you must report how much
you drink and smoke to the study team

If you are female you must be taking an acceptable method of contraception to avoid
pregnancy. For a list of these methods ask the study team. If you become pregnant while
taking Harvoni the study drug will be stopped. We will not collect information on your
pregnancy.

You should not take rifampicin or St. John’s wort while on Harvoni
It is possible your PCT symptoms might worsen if you participate in this study. If this happens, 
the study doctor will decide with you at what point you should stop HCV treatment and begin 
standard of care PCT treatment. Some of the information from your standard of care PCT 
treatments may still be entered into the study database.
What extra tests and procedures will I have if I take part in this study?
The following will be performed for research purposes and probably would not be given to you if 
you were being treated outside the study:

Alcohol and Tobacco Questionnaires

Porphyria Cutanea Tarda (PCT) questionnaire

Photographs taken as part of your skin assessment

Visits as frequently as monthly
The research study will pay for all of the above-mentioned tests and procedures.
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What are the possible risks for choosing to participate in this research study?
The study involves potential risks and discomforts. These risks will not be very different from 
standard treatment with Harvoni. Because of your participation in this study, you are at risk for 
the following side effects. You should discuss these with the researchers and your regular health 
care provider.
1. Risks of Study Procedures and Intervention
a) Blood draw: When the needle is inserted it can hurt. There is a small chance of fainting 
and/or bruising. Since the skin is broken, an infection at the puncture site can occur, 
although this is very rare. Occasionally some people become dizzy, lightheaded or feel 
faint. The amount of blood requested is within approved safety limits and will be modified 
for individuals who have a medical condition that limits their ability to provide the 
requested volume of blood.
b) Side effects of Harvoni: the most frequent side effects have been fatigue, headaches, 
nausea, diarrhea, and insomnia. Any significant new findings that the investigators learn 
about during the course of the study which could increase your risk of participating or 
developing negative reactions will be told to you.
2. Your symptoms may not improve.
There is a chance that your PCT symptoms will not improve with Harvoni, or improve 
more slowly than with standard treatment. The purpose of the study is to find out if 
Harvoni is an effective and equally rapid treatment for PCT when associated with hepatitis 
C, but this is not yet known. Although this is unlikely, your PCT symptoms may instead 
worsen while taking Harvoni. This includes blisters on sun exposed areas, fragile skin, 
increased hair growth, as well as darkening and thickening of the skin. Potential 
complications of having blisters include scarring and a small risk of blistered areas 
becoming infected. You will be instructed on how to care for any blisters.
3. Risk of loss of Confidentiality
The potential for loss of private information always exists; however, there are procedures 
in place to minimize this risk. The PI and his delegates will do their best to keep your 
information confidential; however, there is a possibility that your data, including clinical 
and diagnostic information will be accidentally divulged to the wrong source; if that 
happens you might be discriminated against in obtaining life insurance, employment or
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ability to adopt children. There is a Federal law called the Genetic Information 
Nondiscrimination Act (GINA). In general, this law makes it illegal for health insurance 
companies, group health plans, and most employers of over 15 people to discriminate 
against you based on your genetic information. However, it does not protect you against 
discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance.
4. Risks to the Fetus
If you are part of this study while pregnant or breast-feeding an infant, it is possible that 
you may expose the unborn child or infant to risks. For that reason, pregnant and breast- 
feeding females cannot participate in the study. If you can become pregnant, a urine 
pregnancy test will be done, and it must be negative before you participate in this study. If 
you take part in this study and you are sexually active, you and any person that you have 
sex with must use medically-acceptable birth control (contraceptives) during the study.
Medically-acceptable birth control (contraceptives) includes: (1) surgical sterilization 
(such as hysterectomy or “tubes tied”), (2) approved hormonal contraceptives (such as 
birth control pills, patch or ring; Depo-Provera, Implanon), (3) barrier methods (such as 
condom or diaphragm) used with a spermicide (a substance that kills sperm), or (4) a 
intrauterine device (IUD). You need to let us know which of these options you are using 
and also inform us if you change to another option during the study. Some hormonal 
contraceptives may not be advisable for someone with porphyria cutanea tarda, so you 
also should discuss these options with the study physician. If you do become pregnant 
during this study, you must tell the researchers immediately.
5. Psychological Stress
There may be risks because of the HIV and hepatitis tests, which could cause mental and 
social harm. A positive test could have a bad influence on your being able to get insurance 
or be employed, and could make family relationships difficult. You will be referred for 
appropriate counseling and medical care for any such condition that is discovered.
6. Other risks. There may be additional and unforeseeable risks from participating in this 
study.
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What are the potential benefits for participating in this research study?
If you agree to take part in this study, there may not be direct benefits to you. We hope the 
information learned from this study will benefit others with PCT in the future. However, possible 
benefits may include:

Possible successful treatment with Harvoni for your Hepatitis C

Possible resolution of your PCT symptoms
Will I be reimbursed for participating in this research study?
You will be reimbursed for travel, time and inconvenience. Every time you complete a study 
visit, you will be reimbursed $75, plus round-trip mileage at $0.57.5 per mile up to $200, for 
each study visit. Even if you do not complete the entire study, you will still be reimbursed for 
each individual study visit that you complete. You will be issued a UTMB Clincard, which is a 
debit card that your funds are loaded onto following the completion of each study visit. You can 
decide not to be reimbursed if you wish. We will validate your parking ticket for each study 
visit.
You will not be reimbursed if your visit is not scheduled in advance, or if your visit is part of 
necessary medical treatment or hospital admission at UTMB. If the visit is for more than one 
porphyria research study, you will only be reimbursed for one study. If you travel together 
within the same vehicle for a study visit with one or more family members who are also 
participating in this or another porphyria study, only one participant will be reimbursed for the 
mileage.
When a study visit is completed, funds will be approved and loaded onto your Clincard. The 
funds will be available within 72 hours and can be used at your discretion. You will be issued 
one card for the duration of your participation. If your card is lost or stolen, you can contact 
customer service at 
. We will collect some information about you, including 
name, address, telephone number, date of birth, email address, if applicable, and your social 
security number (if a US citizen) in order to issue the Clincard. All information is stored in a 
secure fashion and will be kept confidential.
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Is there an alternative treatment procedure?
Yes. You do not have to participate in this research to receive care for your medical problem. 
Instead of being in this study, you have the following options:

Standard of care treatment for PCT and hepatitis C will still be available to you in the 
usual manner. If you do not participate in the study, this will not affect your medical care 
at UTMB.
If you stop being in the research study, already collected information may not be removed from 
the research study database and will continue to be used to complete the research analysis. You 
may be asked whether the investigator can collect information from your routine medical care. If 
you agree, this data will be handled the same as research data.
You may also withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the 
address on the first page of this consent. Even if you withdraw your permission, the Principal 
Investigator for the research study may still use the information that was already collected if that 
information is necessary to complete the research study. Your health information may still be 
used or shared after you withdraw your authorization if you have an adverse event (a bad effect) 
from participating in the research study.
If I agree to take part in this research study, can I be removed from the study without my 
consent?
Yes. The researchers may decide to take you off this study if:

Your medical problem remains unchanged or becomes worse.

The researchers believe that participation in the research is no longer safe for you.

The researchers believe that other treatment may be more helpful.

The sponsor or the FDA stops the research for the safety of the participants.

The sponsor cancels the research.

You are unable to keep appointments or to follow the researcher’s instructions. 
Specimens or data stored as part of the research study can be destroyed without your 
consent.
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Will my insurance provider or I be charged for the costs of any part of this research study? 
No. Neither you, nor your insurance provider, will be charged for anything done only for this 
research study. The study drug and testing performed during this study will be provided at no 
cost to you.
What will happen if I am harmed as a result of taking part in this study?
It is important that you report any illness or injury to the research team listed at the top of this 
form immediately. Compensation for an injury resulting from your participation in this research 
is not available from the University of Texas Medical Branch at Galveston. You or your 
insurance company or health care plan, will be billed and you will be responsible for any 
charges. You will be responsible for paying any costs related to illnesses and medical events not 
associated with being in the study. There are no plans to provide other forms of compensation. 
However, you are not waiving any of your legal rights by participating in this study.
How will my information be protected?
All results obtained in this study will be kept confidential and only available to the research 
study team. Your individual information will not be reported, only the results of all participants 
as a group. Clinically important information will be included in your hospital medical records.
The clinical information collected for this study will be stored at the Data Management and 
Coordinating Center (DMCC) at the Cincinnati Children’s Hospital Medical Center in 
Cincinnati, OH and also sent to a Federal data repository. It meets all of the local and federal 
security requirements for research datacenters. Any photographs taken of you will be for 
research only and will be stored with other research information collected in a secure database 
that will not identify you by name. Also, your eyes will be blacked out on the photographs to 
help further in protecting your confidentiality and privacy. Your information is stored using only 
a coded number. No personal identifiers like your name, address or medical record number will 
be sent to the DMCC.
Certificate of Confidentiality:
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, or
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biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research participants.
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the U.S. Department of Health and Human Services and/or the National 
Institutes of Health which is funding this project. You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. If you want your research information released to an insurer, 
medical care provider, or any other person not connected with the research, you must provide 
consent to allow the researchers to release it.
Even with the Certificate of Confidentiality, the investigators continue to have ethical obligations 
to report child abuse or neglect and to prevent you from carrying out any threats to do serious 
harm to yourself or others. If keeping information private would immediately put you or 
someone else in danger, the investigators would release information to protect you or another 
person. The Certificate of Confidentiality will not be used to prevent disclosure as required by 
federal, state, or local law, such as reports of child abuse and neglect, or harm to self or others.
How will my privacy be protected?
We have rules to protect information about you. Federal and state laws and the federal medical 
Privacy Rule also protect your privacy. By signing this form you provide your permission, called 
your “authorization,” for the use and disclosure of information protected by the Privacy Rule.
The research team working on the study will collect information about you. This includes things 
learned from the procedures described in this consent form. They may also collect other 
information including your name, address, date of birth, and information from your medical
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records. This could include information about HIV and genetic testing, or treatment for drug or 
alcohol abuse or mental health problems.
The research team will know your identity and that you are in the research study.  Other people 
at UTMB, particularly your regular doctors who are not involved in the research, may also see or 
give out your information. We make this information available to your regular doctors and your 
medical records for your safety. If you think this study might affect your clinical care, please 
inform your study doctor.
As part of the study, the Principal Investigator, study team and others at UTMB may disclose 
your protected health information, including the results of the research study tests and 
procedures, to the following people or organizations: (It is possible that there may be changes to 
the list during this research study; you may request an up-to-date list at any time by contacting 
the Principal Investigator.)
-
Other collaborating research center(s) and their associated research/clinical staff who 
are working with the investigators on this project including members of the Rare 
Diseases Clinical Research Network and members of the Porphyrias Consortium.
-
Research data coordinating office and/or their representative(s) who will be 
responsible for collecting results and findings from all the centers: Data Management 
and Coordinating Center (DMCC) at the Cincinnati Children’s Hospital Medical 
Center..
-
The sponsoring government agency and/or their representative who need to confirm 
the accuracy of the results submitted to the government or the use of government 
funds: National Institutes of Health (NIH).
-
A Data Safety Monitoring Board or other committee that will monitor the study on an 
ongoing basis for safety.
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The United States Food and Drug Administration.
-
The United States Department of Health and Human Services and the Office of 
Human Research Protection.
Data or specimens collected in this research study might be de-identified and used for future 
research or distributed to another investigator for future research without your consent.
We cannot do this study without your authorization to use and give out your information. You 
do not have to give us this authorization. If you do not, then you may not join this study.
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We will use and disclose your information only as described in this form; however, people 
outside UTMB who receive your information may not be covered by this promise or by the 
federal Privacy Rule. We try to make sure that everyone who needs to see your information 
keeps it confidential – but we cannot guarantee that your information will not be re-disclosed.
The use and disclosure of your information has no time limit. You may revoke (cancel) your 
permission to use and disclose your information at any time by notifying the Principal 
Investigator of this study by phone or in writing. If you contact the Principal Investigator by 
phone, you must follow-up with a written request that includes the study number and your 
contact information. The Principal Investigator’s name, address, phone and information are on 
page one of this consent form.
If you do cancel your authorization to use and disclose your information, your part in this study 
will end and no further information about you will be collected. Your revocation (cancellation) 
would not affect information already collected in the study, or information we disclosed before 
you wrote to the Principal Investigator to cancel your authorization.
Finally, please specifically authorize the use of your private health information relating to 
substance abuse, psychiatric information, or HIV/AIDS, if applicable, for the above-described 
purposes.
Initial 
Whom can I contact with questions about this research study?
If you have any questions, concerns or complaints before, during or after the research study, or if 
you need to report a research related injury or bad side effect, you should immediately contact 
Dr. Karl Anderson at 
 or, if after normal office hours, at 
.
The Institutional Review Board (IRB) is a group of people who review the research to protect your
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rights. If you have a question about your rights as a research participant, or you would like to 
discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by 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.
CONSENT TO PARTICIPATE:
The purpose of this research study, procedures to be followed, risks and benefits have been 
explained to you. You have been given the opportunity to ask questions, and your questions have
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been answered to your satisfaction. You have been told whom to contact if you have additional 
questions. By signing this form, you are confirming that you have read this consent form and 
voluntarily agree to participate as a subject in this study.
Signature of Subject
Date
Using language that is understandable and appropriate, I have discussed this project and the items 
listed above with the subject
Signature of Person Obtaining Consent
Date and Time Consent 
Obtained
Printed Name of Person Obtaining Consent
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