A Prospective Comparison of Low Dose Hydroxychloroquine and Phlebotomy in the Treatment of Porphyria Cutanea Tarda. IRB 02-435
Phase: PHASE2
Conditions: Porphyria Cutanea Tarda
Sponsor: The University of Texas Medical Branch, Galveston

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Page 1 
 
 
 
Rare Diseases Clinical Research Network 
 
 
 
The Porphyrias Consortium 
 
 
 
Therapeutic Studies in Porphyria Cutanea Tarda 
 
 
 
 
 
 
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 Consortium 
investigators in carefully controlled settings.  The Chair of this study should be consulted before 
using or attempting any procedure in this protocol. 
 
 
 
 
Study Chair 
Karl E. Anderson, M.D. 
University of Texas Medical Branch 
Porphyria Center 
301 University Boulevard 
Galveston, TX 77555-1109 
Phone: 409-772-4661 
Fax: 409-772-6287 
Email: kanderso@utmb.edu 
 
 

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Participating Institutions/Investigators Table  
 
 
Principal Investigator: Robert J. Desnick, PhD, MD 
Contact:  Hetanshi Naik, MS, CGC 
Institution: Icahn School of Medicine at Mount Sinai  
Address: Department of Genetics & Genomic Sciences 
One Gustave L. Levy Place, Box 1497 
New York, NY, 10029 
Phone: 212-241-7699 
Fax: 212-426-9065 
Email: robert.desnick@mssm.edu; hetanshi.naik@mssm.edu 
  
Sub-
Investigators: 
Manisha Balwani, MD; Lawrence Liu, MD 
  
 
Principal Investigator: Joseph R. Bloomer, MD 
Contact: Toni Ann Seay 
Institution: University of Alabama Birmingham 
Address: UAB Porphyria Center 
Liver Center, Division of Gastroenterology and Hepatology, Department of 
Medicine 
1720 2nd Avenue South, BDB 398 
Birmingham, Alabama 35294-0012 
Phone: 205-934-7332 
Fax: 205-975-9777 
Email: jbloomer@uab.edu 
Sub-
Investigators: 
Ashwani Singal, MD; Brendan M. McGuire, MD 
  
 
Principal Investigator: D. Montgomery Bissell, MD 
Contact: Yuvraaj Kapoor 
Institution: University of California at San Francisco 
Address: UCSF Porphyria Center 
350 Parnassus Avenue, Suite 410 
San Francisco, CA 94143-0657 
Phone: 415-502-5356 
Fax: 415-476-0659 
Email: montgomery.bissell@ucsf.edu 
Sub-
Investigator: 
Bruce Wang, MD; Jennifer Lai, MD 
  
 
Principal Investigator: John Phillips, PhD 
Contact: Sharada Dixit 
Institution: University of Utah 
Address: Porphyria Center 
Department of Internal Medicine, Division of Hematology 

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30 North 1900 E, Room # 5C402 
Salt Lake City, Utah 84132 
Phone: 801-581-6650 
Fax: 801-585-3432 
Email: john.phillips@hsc.utah.edu 
Sub-
Investigators: 
Charles Parker, MD 
 
Principal Investigator: Karl E. Anderson, MD 
Contact: Csilla Hallberg, MD 
Institution: University of Texas Medical Branch 
Address: Porphyria Center 
301 University Boulevard 
Galveston, TX 77555-1109 
Phone: 409-772-4661 
Fax: 709-772-6287 
Email: kanderso@utmb.edu 
Sub-
Investigators: 
 
  
 
Principal Investigator: Herbert Bonkovsky, MD 
Contact: Dee Faust 
Institution: Wake Forest 
Address: Department of Internal Medicine/Gastroenterology 
Wake Forest University School of Medicine 
Winston-Salem, NC 27157 
Phone: 336-713-7301 
Fax: 336-713-7322 
Email: hbonkovs@wakehealth.edu 
Sub-
Investigators: 
 
  
 
Principal Investigator: Jeffrey Krischer, PhD 
Contact: Carrie Light, Research Compliance Administrator 
Institution: Data Management and Coordinating Center (DMCC), Pediatrics 
Epidemiology Center, University of South Florida 
Address: 3650 Spectrum Blvd., Suite 100, Tampa, FL 33612 
Phone: 813-396-9248 
Fax: 813-910-5997 
Email: carrie.light@epi.usf.edu 
  
 
 
 

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Table of Contents 
Participating Institutions/Investigators Table .............................................................................. 2 
1. PROTOCOL SYNOPSIS......................................................................................................... 6 
1.A. Abstract. ......................................................................................................................... 8 
1.B Overview .......................................................................................................................... 9 
2. BACKGROUND .................................................................................................................... 10 
3. SPECIFIC AIMS ................................................................................................................... 18 
4. RESEARCH DESIGN AND METHODS ................................................................................ 19 
4.A. Treatment sites and laboratory resources ......................................................................20 
4.B. Design.. .........................................................................................................................21 
4.C. Treatment definitions. ....................................................................................................21 
4.D. Recruitment and availability ...........................................................................................22 
4.E. Enrollment and treatment assignment. ...........................................................................22 
4.F. Treatment Phase ...........................................................................................................27 
4.G. Study visits during the Treatment Phase .......................................................................29 
4.H. End of treatment ............................................................................................................30 
4.I. Follow Up Phase .............................................................................................................31 
4.J. Study duration and end of study .....................................................................................31 
4.K. Treatment outcomes and schedule of events. ................................................................31 
4.L. Safety. ............................................................................................................................32 
SCHEDULE OF EVENTS ......................................................................................................... 32 
STUDY FLOW DIAGRAM: ....................................................................................................... 34 
4.M. Efficacy. ........................................................................................................................37 
4.N. Concomitant therapy ......................................................................................................38 
4.O. Adverse experiences .....................................................................................................38 
4.P. Patient withdrawal ..........................................................................................................38 
4.Q. Treatment failure or intolerance. ....................................................................................39 
4.R. Data analysis and statistical considerations ...................................................................39 
5. PROTECTION OF HUMAN SUBJECTS ............................................................................... 41 
5.A.  RISKS TO THE SUBJECTS .........................................................................................41 
5.B.  ADEQUACY OF PROTECTION AGAINST RISKS ........................................................42 
5.C.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND 
OTHERS ...............................................................................................................................42 
5.D.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED ..............................................43 
5.E.  INCLUSION OF WOMEN .............................................................................................43 
5.F.  INCLUSION OF MINORITIES .......................................................................................43 

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5.G.  INCLUSION OF CHILDREN .........................................................................................44 
5.H.  DATA AND SAFETY MONITORING PLAN ...................................................................44 
5.H.1. Study Oversight ......................................................................................................45 
5.H.2. Definitions and Standards .......................................................................................45 
5.H.3. Expected/Known Risks/Discomforts/Adverse Events Associated with Study 
Intervention and Procedures: Definition of Expected Adverse Events ................................46 
5.H.4. Reporting Timeline ..................................................................................................47 
5.H.5. RDCRN Adverse Event Data Management System (AEDAMS) ..............................47 
5.H.6. Study Discontinuation .............................................................................................48 
5.H.7. Data Quality and Monitoring Measures ...................................................................48 
5.H.8. Data Management ..................................................................................................48 
5.H.9. Registration .............................................................................................................49 
5.H.10. Data Entry .............................................................................................................49 
5.H.11. Data Quality Control ..............................................................................................49 
6. REFERENCES CITED .......................................................................................................... 51 
7. APPENDICES ....................................................................................................................... 56 
A. Informed Consent Template: .............................................................................................56 
B. Patient Compliance Chart for Hydroxychloroquine Use .....................................................66 
C. Report Form for Phlebotomies ..........................................................................................67 
D.  Patient Compliance Chart for Phlebotomies ....................................................................68 
 
 
 

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1. Protocol Synopsis 
Protocol Number: 7206 
Protocol Title: Therapeutic Studies in Porphyria Cutanea Tarda 
Study Chair: Karl E. Anderson, MD 
Statistician: Kristofer Jennings, PhD 
Consortium: Porphyrias Consortium 
Participating Sites: Icahn School of Medicine at Mount Sinai , New York, NY  
University of Alabama at Birmingham, Birmingham, AL  
University of California, San Francisco, San Francisco, CA  
The University of Texas Medical Branch, Galveston, TX 
University of Utah, Salt Lake City, UT 
Wake Forest, Winston-Salem, NC 
Activation Date: 06/16/2011 
Current Status: Approved 
Sample Size: 100 participants with porphyria cutanea tarda (PCT) 
Target Enrollment 
Period: 
10 years 
Study Design: Pragmatic Interventional study 
Primary Study 
Objective: 
To determine and compare time to remission with treatment 
with low-dose hydroxychloroquine or repeated phlebotomy 
in participants with PCT.   
Secondary Study 
Objective(s): 
1.  To assess the effects of susceptibility factors on 
responses to treatment of PCT by these methods. 
2.  To determine and compare rates of recurrence of PCT 
after treatment with low-dose hydroxychloroquine or 
phlebotomy.   
Study Population and 
Main Eligibility/ 
Exclusion Criteria: 
Inclusion Criteria: 
1. Willing to give informed consent 
2. Willing to return to clinic or work with a local physician 
to have necessary labs done and samples sent to study 
site 
3. Age 18 or greater 
4. Women of child-bearing potential must be willing to 
avoid pregnancy and use an accepted and effective 
contraceptive method during treatment.   
5. Well-documented PCT: 
i. 
Clinical features – A history of blistering 
cutaneous    photosensitivity and/or skin fragility. 
ii. 
Biochemical findings – a and b are required 
a. A substantial increase in urinary porphyrins 
[>450 nmol/24 hours or g of creatinine, or 
more than 1.5-fold increase (relative to ULN 
of 300 nmol/24 hours or g of creatinine or 
>300 ug/24 hours or g of creatinine, or more 
than 1.5-fold increase (relative to ULN of 200 
ug/24 hours or g of creatinine)] and/or 
plasma porphyrins [>2.7 ug/dL, or >3-fold 
increase (relative to ULN of 0.9 ug/dL), and a 

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fluorescence peak at ~619 nm]; a porphyrin 
pattern in urine or plasma showing a 
predominance of uroporphyrin and 
heptacarboxylateporphyrin, and normal or 
only slightly elevated urine ALA and normal 
PBG.   
b. Normal or only slightly elevated erythrocyte 
porphyrins [<200 ug/dL, or less than 1.5-fold 
increase (relative to ULN of 80 ug/dL)], 
unless elevated erythrocyte protoporphyrin 
are due to a non-porphyric condition in the 
opinion of the investigator.   
 
iii. 
.   
 
Exclusion Criteria 
1. Evidence for another cause of blistering skin 
lesions, such as another type of cutaneous 
porphyria, or pseudoporphyria 
2. Pregnancy 
3. Prior treatment by phlebotomy, 
hydroxychloroquine or chloroquine within one 
month, unless all appropriate lab results from 
before treatment was started can be obtained, to 
document baseline porphyrin levels.   
4. Unwillingness to comply with the protocol 
5. Previous treatment as a participant in this 
protocol.  
Treatment  
Agent- Hydroxychloroquine vs. repeated phlebotomy 
Dosage, schedule, route 
of administration- 
Hydroxychloroquine 100 mg twice weekly for up to 24 
months by mouth vs. phlebotomy 450 mL biweekly until 
target serum ferritin reached, or up to 24 months.   
Safety Issues- 1.  Side effects of phlebotomy or hydroxychloroquine, which 
are the same as in clinical practice.    
Primary Outcome 
Measures: 
1.  Time to achievement of a normal plasma total porphyrin 
level.   
2.  Tolerability and safety of both treatments 
Secondary Outcome 
Measures: 
1.  Time to disappearance of a plasma fluorescence peak 
at neutral pH.   
2.  Time to normalization of urinary total porphyrins.   
3.  Time to normalization of the urinary total porphyrin 
pattern by HPLC 
4.  Effects of susceptibility factors such as hepatitis C, 
inherited UROD deficiency, etc. on efficacy and safety of 
the two treatment methods.   
5.  Rates of recurrence after each type of treatment and the 
effects of susceptibility factors on recurrence rates.   

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Statistical 
Considerations (sample 
size and analysis plan): 
Time to achieving biochemical endpoints will be determined 
from individual subject data.  Outcome measures such as 
time to remission will be compared using Cox proportional 
models to study the effects of susceptibility factors on the 
hazard ratio to compare the two treatments.  Additional 
modeling will assess factors affecting the frequency of 
recurrence and seasonality effects using logistic regression 
modeling and log-rank testing, respectively. 
Sponsors (federal, state, 
foundation and industry 
support): 
National Institutes of Health (NIH) 
 
1.A. Abstract:  Porphyria cutanea tarda (PCT) is the most common human porphyria and the 
most responsive to treatment.  There is little information on the natural history of the disease, 
the effects of treatment, how often treatment fails or how often the disease recurs after 
successful treatment.  Two very different approaches to therapy are considered effective and 
are standard of care, and additional treatments are becoming available.  Guidelines for 
choosing between the two current standard therapies are not in place, and it is not clear how 
quickly remission can be achieved with either, which makes comparisons with emerging 
treatments difficult.   
Repeated phlebotomy is the most widely used treatment, but has disadvantages that include 
discomfort, inconvenience and expense.  A low-dose regimen of the 4-aminoquinoline 
antimalarial drugs, either hydroxychloroquine or chloroquine, is more convenient and cost-
effective but is less widely used in the U.S. as first line therapy.  Before this study, comparisons 
of these treatments have been lacking.  We need to know the times needed to achieve 
remission with these treatments in order to develop better treatment recommendations and to 
provide comparative data to evaluate other treatment approaches, such as the new more rapidly 
effective drugs becoming available for treatment of hepatitis C (found in ~70% of PCT 
participants in the U.S.).   
This study was initiated as a randomized study to compare treatment for PCT with phlebotomy 
or low-dose hydroxychloroquine, with retention of non-randomized patients in a substudy to 
provide additional safety data.  Prior to this study becoming a Porphyrias Consortium (PC) 
protocol, 48 participants with well documented PCT and also characterized for the presence or 
absence of multiple known susceptibility factors were enrolled at one site and treated by 
phlebotomy or low dose hydroxychloroquine. Unexpectedly, an interim analysis found that fewer 
than half of the participants were eligible for randomization, and adherence to treatment and 
study visits was more difficult for study subjects than had been expected.  The interim analysis 
of 30 randomized and nonrandomized patients who were evaluable because their data 
documented time to remission showed that for both treatments, time to achieving the primary 
outcome of a normal plasma porphyrin concentration averaged 6-7 months.  The original 
randomized design did not meet the needs of feasibility and analysis for an inclusive, pragmatic 
study of a rare disease.  Also, because follow up was short, the interim analysis did not 
establish that the two treatments are comparable in all important clinical respects.  This revised 
protocol continues to follow standard of care procedures for these PCT treatments and includes 
longer follow up and additional treatment outcomes.  Strengths of the study are: (1) it aims to 
enroll all patients who would otherwise undergo treatment for PCT; (2) it assures that all 
participants are characterized for multiple PCT susceptibility factors, including ethanol use, 
smoking, hepatitis C, HIV infection, estrogen use, HFE mutations and autosomal dominant 

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inheritance of a partial deficiency of uroporphyrinogen decarboxylase (UROD) due to UROD 
mutations (as in familial PCT); (3) it provides specific eligibility criteria for assignment to either 
treatment; (4) it randomizes participants eligible for both treatments, to avoid bias; (5) it defines 
primary and secondary outcomes for remission and aims to continue treatment until all are 
achieved; and (6) it provides follow up to compare recurrence rates after achieving remission.  
Visits are scheduled to document primary and secondary treatment outcomes based on the 
subject’s laboratory values at each visit.   
The continuing working treatment hypothesis is that low-dose hydroxychloroquine is comparable 
to phlebotomy in time to remission.  The study is conducted under an active IND (IND 66,042).  
It is likely that this study will define treatment guidelines and improved management of PCT.  It 
also develops standards for time to specific outcomes for phlebotomy and low-dose 
hydroxychloroquine, which are not currently available and can be used for comparing future 
treatment approaches for PCT.   
 
1.B Overview 
 
Brief Summary 
The purpose of this study is to determine whether a low dose regimen of hydroxychloroquine 
achieves remission as rapidly and safely as phlebotomy in the treatment of porphyria cutanea 
tarda (PCT).   
 
Detailed Description 
Porphyria cutanea tarda (PCT) is the most common and also the most readily treated form of 
porphyria.  Repeated phlebotomy is the most widely used therapy in the U.S., but has 
disadvantages that include discomfort, inconvenience and expense.  A low-dose regimen of the 
4-aminoquinoline antimalarial drugs, either hydroxychloroquine or chloroquine, is also effective, 
and is more convenient and less expensive, but has not been widely adopted as first line 
therapy.  Prospective data comparing these treatments are lacking, as are guidelines for 
selecting the most appropriate treatment for individual patients with PCT.   
 
Study Hypothesis: Treatment of PCT by low-dose hydroxychloroquine, which has known 
advantages in terms of cost and convenience, can achieve remission as rapidly and safely as 
treatment by phlebotomy, and the durability of treatment is also comparable.   
 
Comparison(s): This study compares treatment with a low-dose regimen of hydroxychloroquine 
to treatment by repeated phlebotomy.  The primary outcome is time to achieving a normal 
plasma porphyrin concentration.  Secondary outcomes include correction of additional porphyrin 
abnormalities that are expected with complete remission, and recurrence rates during long term 
follow up.   
 
Significance: The results will guide clinical practice by providing a basis for selecting which of 
these standard treatments should be used in individuals with PCT.  It will also provide data on 
time to treatment outcomes with both therapies that can be used for evaluating future 
therapeutic approaches.  The pragmatic design of this study will lead to results that are more 
immediately applicable to clinical practice and relevant to cost-benefit considerations.   

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2. Background  
Porphyria cutanea tarda (PCT), which has also been known as symptomatic porphyria, porphyria 
cutanea tarda symptomatica, and idiosyncratic porphyria, results from decreased 
uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) activity in the liver, and is characterized by 
blistering skin lesions on sun-exposed areas.  Other features include a varying degree of 
hepatocellular damage and siderosis (1-3).  The disease has been classified into three subtypes: 
type 1 (sporadic), type 2 (familial, autosomal dominant), and type 3 (familial, rare).  In addition, 
there are occasional cases that result from environmental exposure to polyhalogenated chemicals.  
Type 2 disease is due in part to underlying heterozygous mutations in the UROD gene, which 
result in a partial UROD deficiency that represents a predisposing factor that is inherited as an 
autosomal dominant trait with low penetrance.  Most of the multiple UROD mutations that have 
been found in type 2 disease result in no enzyme activity, and the residual ~50% UROD activity is 
therefore the product of the normal allele.  The inherited ~50% deficiency of UROD affects all 
tissues and is most readily demonstrated in erythrocytes.  Because penetrance is low, relatives 
with the inherited enzyme deficiency seldom develop PCT.  Therefore, type 2 PCT often presents 
with symptoms as a sporadic condition and with a negative family history for PCT.  UROD 
mutations are not found in patients with types 1 or 3 disease, and erythrocyte UROD activity is not 
deficient.  Type 3 disease is a rare familial form in which more than one member of a family is 
affected, and either other genetic factors, such as hemochromatosis gene (HFE) mutations are 
identified or an underlying genetic mechanism is not established (1, 2).   
All three subtypes of PCT have similar clinical features and management.  As discussed 
below, the mechanism of UROD inhibition leading to a profound deficiency of hepatic enzyme 
activity is probably the same in all types of the disease.  Type 1 or “sporadic” PCT is the most 
common and accounts for about 80% of PCT patients.  Type 2 accounts for most of the remaining 
~20% of cases.  In types 1, 2 and 3, PCT becomes manifest only when the hepatic enzyme level 
is reduced substantially – i.e. to less than ~20% of normal (2).  Iron is essential in causing a 
substantial reduction in hepatic UROD activity.  The effect of iron is not mediated by direct 
inhibition of UROD, but rather by enabling the oxidation of uroporphyrinogen to uroporphyrin and a 
UROD inhibitor (see Figure 1).  Cytochrome P450 enzymes are also involved in this process.  
CYP1A2 is especially important, at least in rodents (2, 4).  The inhibitor of hepatic UROD has been 
identified as a uroporphomethene (5).  With UROD inhibition, porphyrins (derived from the highly 
carboxylated porphyrinogens that are substrates and intermediates in the 4-step decarboxylation 
catalyzed by UROD) then accumulate in large amounts in the liver, and subsequently become 
markedly increased in the plasma and urine.  The distinctive pattern of excess porphyrins in urine 
and plasma consists primarily of highly carboxylated porphyrins.  Fecal porphyrins may be normal 
or somewhat increased, and an increase in fecal isocoproporphyrins is often prominent, and is 
readily explained by deficient hepatic UROD activity. UROD is inhibited and amounts of porphyrins 
in liver, plasma and urine are markedly increased and serve as biomarkers in PCT, and these 
become normal with treatment and remission.  However, it is not known whether hepatic δ-
aminolevulinic acid (ALA) synthase (ALAS1), the rate limiting enzyme for hepatic heme 
biosynthesis, is increased in PCT, and whether this enzyme activity decreases with treatment (1, 
2). In the past ALAS1 could only have been assessed if a biopsy was done repeatedly to obtain 
samples of liver tissue After this project with initiated, it was discovered that hepatic ALAS1 can be 
assessed noninvasively by measuring ALAS1 mRNA in exosomes that are found in plasma and 
urine.  This provides a closely related new biomarker to assess disease activity and response to 
treatment in the acute hepatic porphyrias [] and possibly in PCT as well.  This study assesses PCT 

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patients biochemically using 
previously known biomarkers, 
and also clinically before and 
after application of either of the 
two standard treatments for 
PCT, and provides a unique 
opportunity to assess the 
potential of exosomal ALAS1 
mRNA as an additional  and 
closely related biomarker in 
PCT.   
Multiple susceptibility 
factors can contribute to 
inhibition of hepatic UROD in all 
subtypes of the human disease.  
These factors include alcohol, 
hepatitis C, estrogen, HIV, 
smoking and mutations of the 
HFE gene (6-14).  Some factors, 
including HFE mutations, alcohol 
and hepatitis C, can decrease 
hepatic production of the iron 
regulatory hormone hepcidin and 
thereby upregulate iron 
absorption and contribute to an 
increase in hepatic iron content 
(15, 16).  More than one of these 
factors, and often 3-4 or more, 
are usually present in the 
individual patient (13, 14).  Thus, PCT is a multifactorial condition, and is also heterogeneous, in 
that combinations of susceptibility factors differ from one patient to another.  Hepatitis C is found in 
up to 80% of PCT cases in some geographic areas.  The disease is quite infrequent in some 
regions, such as Scandinavia where the prevalence in hepatitis C is relatively low.  Heavy ethanol 
use has been recognized as a contributing cause for many years, and smoking has been 
considered more recently (13, 14).  Ethanol, other components of alcoholic beverages, and 
smoking may contribute to oxidative stress through induction of cytochrome P450 enzymes in the 
liver.  PCT is generally more common in males, possibly due to greater prevalence of some of 
these susceptibility factors.  Some protection may be afforded by menstrual blood loss and 
consequent less iron retention in women.  When PCT occurs in women it is often attributable in 
part to estrogen-containing oral contraceptives or postmenopausal estrogen replacement (1, 13).  
Other recently studied factors include functional hepatic biotransformation enzymes (CYP1A2 and 
GSTM1) and vitamin C deficiency (17, 18).   
As reviewed elsewhere (1, 19), some degree of liver damage is present in virtually all 
patients with untreated PCT, including those without liver-damaging susceptibility factors such as 
hepatitis C, excess alcohol use or marked iron overload.  How marked UROD deficiency might 
lead to hepatocellular damage is not known, but the massive hepatic porphyrin accumulation that 
is known to occur in this disease may contribute.  Liver dysfunction can improve with treatment of 
PCT at least in some patients.   
-Aminolevulinic acid 
Glycine + Succinyl CoA 
Uroporphyrinogen 
ALAS1 
Uroporphyrin 
CYP1A2 
Fe 
Specific inhibitor 
Coproporphyrinogen 
Fe2+ 
UROD 
Heme 
Figure 1.  Postulated generation of a UROD inhibitor from 
uroporphyrinogen in liver in the presence of iron and cytochrome 
P450 enzymes.   

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Liver biopsy is of value in the management of PCT.  The marked excess in porphyrins 
found in hepatocytes in PCT patients biopsied before treatment is a specific histological finding.  
But other histopathological features, including excess iron, are quite nonspecific.  Because few of 
the susceptibility factors for PCT are readily evident by liver histopathology, liver biopsy does not 
contribute greatly to classifying PCT patients.  However, liver biopsy may lead to recognition of 
unsuspected liver conditions, such as nonalcoholic steatohepatitis (NASH), determine the degree 
of advancement of any associated liver disease and the degree of iron overload with or without 
HFE mutations.  A higher prevalence of diabetes and NASH has been reported in some PCT case 
series (20, 21) 
Although PCT is the most common porphyria and occurs worldwide, its prevalence is less 
well characterized than that of other porphyrias (1, 2).  Physicians other than porphyria specialists 
consider the disease to be rare and are not familiar with issues related to diagnosis and treatment.  
Commonly cited prevalence estimates for the United States and the Czech Republic/Slovakia are 
about 1 in 25,000 and 1 in 5,000, respectively (2, 12, 22, 23).  Translation of these estimates to 
the population of the United States of ~300 million indicate that the prevalence of PCT in this 
country is less than 200,000 cases, as shown in the table below.   
 
Country 
Estimated 
prevalence 
Number of cases in
a population of 300 
million 
Reference 
 
United States 
1 in 25,000 
12,000 
(22) 
 
Czechoslovakia 
1 in 5,000 
60,000 
(23) 
The yearly incidence of PCT in the United Kingdom was estimated at 2 to 5 per million (2).  If this 
estimate is applicable to the U.S., which has a population of ~300 million, the incidence would be 
up to 1,500 cases per year.  If treated, the disease is likely to be of shorter duration than one year.  
Therefore, all estimates of which we are aware indicate that the prevalence of PCT is less than 
200,000 in the U.S.  PCT was reported as prevalent in the Bantus of South Africa in association 
with iron overload (24), but other risk factors such as hepatitis C may have played a role and were 
not studied.   
Treatment.  PCT is the most readily treated human porphyria.  Phlebotomy and a low-
dose regimen of one of the 4-aminoquinoline antimalarials, chloroquine or hydroxychloroquine, 
are specific forms of treatment in PCT that are virtually always effective in all PCT subtypes.  
Either treatment leads to reductions and usually normalization of porphyrin levels, new blisters 
cease and scarring then resolves more gradually.  However, studies comparing these 
treatments and guidelines for choosing treatment are lacking.  This study addresses the current 
major issues regarding treatment of PCT in clinical practice.   
These treatments are highly specific for PCT.  Other porphyrias, particularly variegate 
porphyria (VP), as well as hereditary coproporphyria, and even mild cases of congenital 
erythropoietic porphyria and hepatoerythropoietic porphyria can produce the same cutaneous 
lesions, but are unresponsive to phlebotomy or 4-aminoquinolines.  Therefore, it is important to 
establish a diagnosis of PCT and exclude other porphyrias such as VP before specific treatment 
is initiated.  As a practical matter, specific treatment can be started after excluding VP by a 
screening plasma porphyrin determination (including analysis of the fluorescence spectrum at 
neutral pH) while urine and fecal studies are still pending (25, 26).  As noted below, chloroquine 
and hydroxychloroquine may initially increase porphyrin levels before remission occurs.  These 
drugs are effective in children, in whom phlebotomies may be more difficult (27-29).  Other 
antimalarials, including 8-aminoquinolines, have no effect on the disease.   

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Patients should cease exposure to alcohol, estrogens, iron supplements, or other 
exogenous agents that are judged to have contributed to the disease.  Estrogen replacement 
(preferably transdermal) can be resumed in postmenopausal women after successful treatment 
of PCT (30).  Drugs such as barbiturates, phenytoin, and sulfonamides, which are harmful to 
patients with acute porphyrias, are seldom reported to precipitate PCT, but they may contribute 
and should be avoided as a precaution (1).  Although some patients improve dramatically after 
the cessation of alcohol (31), the results are generally unpredictable or slow (32).  Therefore, it 
is generally advisable to begin phlebotomy or low-dose chloroquine or hydroxychloroquine as 
well.  PCT may improve when coexisting hepatitis C infection is treated with interferon (33, 34).  
However, because until recently treatment of hepatitis C had been lengthy and often not 
effective, it is preferable to treat PCT initially by phlebotomy or low-dose hydroxychloroquine 
and assess the need for treatment of hepatitis C later. This may change given the newer direct-
acting antiviral treatments for hepatitis C, however studies need to be done to assess this.  
Each of these standard treatments are described in some detail below, and advantages 
and disadvantages of each are listed.   
Treatment by phlebotomy.  Phlebotomy was introduced for treatment of PCT by Ippen in 
1961, is still most widely used as standard therapy and can induce remissions in almost all 
patients (31).  This approach was prompted in part because patients with PCT commonly have 
mild or moderately increased levels of hemoglobin (probably due to chronic pulmonary disease 
resulting from smoking).  The original aim was to normalize the hemoglobin level, stimulate 
erythropoiesis and perhaps channel excess porphyrins to hemoglobin synthesis in the bone 
marrow (35).  It is now appreciated that the major biochemical pathology in PCT is confined to 
the liver, and the intermediates that accumulate there and then in plasma are primarily oxidized 
porphyrins that are not available as reduced porphyrinogens to re-enter the heme biosynthetic 
pathway.  Therefore, the rationale for this treatment has changed.  The current rationale is to 
reduce total body iron stores and liver iron content in order to interrupt oxidative formation of a 
UROD inhibitor.  To gradually reduce excess hepatic iron, about 450 mL of blood can be 
removed at intervals of ~2 weeks.  In one series, an average of 5.4 phlebotomies was required 
to induce a remission (36).  The most valuable guides to the efficacy of phlebotomy therapy are 
plasma (or serum) levels of ferritin and porphyrins (37, 38).  Phlebotomies should be stopped 
when the serum ferritin reaches the lower limit of normal, and the plasma porphyrin level will 
then fall to normal, usually within several weeks (19).  At this point, skin lesions and friability are 
usually improved but not fully resolved, and will continue to gradually improve.  Hemoglobin or 
hematocrit levels should be repeated during the course of the phlebotomies to prevent 
development of significant anemia.  The tolerated level of hemoglobin depends upon the initial 
level and the age and clinical condition of the patient.  In most patients the blood hemoglobin 
should not fall below 10-11 g/dl, and probably should be maintained at a higher level in elderly 
patients and those with significant concurrent medical conditions.   
Pretreatment plasma porphyrin levels in PCT are generally 10-25 mcg/dL (normal <0.9 
mcg/dL).  New skin lesions are unlikely after the plasma porphyrin concentration becomes 
normal.  Friability, hypertrichosis, milia and areas of atrophy, scarring and hyper- or 
hypopigmentation improve over periods of weeks or months after this.  Even scarring and the 
more extensive scarring and contraction (pseudoscleroderma) that sometimes occur in PCT can 
disappear (31), but showed little or no improvement in one series (39).  Liver function 
abnormalities can also improve (40).  Siderosis, needle-like inclusions, and red fluorescence in 
liver can be expected to improve or disappear, although other histological abnormalities may not 
(41, 42).  After a remission is obtained, continued phlebotomies are usually not needed even if 
ferritin levels later increase to typical normal levels.  However, it is advisable to follow porphyrin 

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V3 Date: 25FEB2020 
Page 14 
levels and reinstitute treatment if porphyrin levels begin to rise.  Relapses are reported to 
respond to another course of phlebotomies.   
The time to remission with phlebotomy is not well established in the literature to serve as 
a standard to compare with other treatments, since many studies did not follow ferritin and 
plasma or urine porphyrin levels during treatment.  Reports that phlebotomies for as long as one 
year are necessary for remission (43, 44) are not consistent with experience at most centers.  
Our experience and the interim analysis for this study indicate that with good adherence to 
scheduled phlebotomies the target ferritin can be reached in 3-4 months in most cases, and 
remission can be achieved in 6-7 months (19, 45).   
Most patients with PCT have some degree of hepatic siderosis, but not marked iron 
overload (36).  Therefore, only about 6-8 phlebotomies are needed to induce a remission in most 
cases.  However, if the initial ferritin is markedly increased it can be predicted that more than the 
usual number of phlebotomies will be needed.  As discussed above, many such individuals have 
hereditary hemochromatosis and are homozygous for the C282Y mutation of the HFE gene 
(especially among individuals of northern European origin) or are C282Y/H63D compound 
heterozygotes.  Therefore it is important to measure serum ferritin, iron, and transferrin 
saturation, and to screen for the C282Y and H63D mutations in the HFE gene prior to starting 
phlebotomies.  Infusions of deferoxamine, an iron chelator, or orally administered iron chelators, 
may be an alternative approach when phlebotomy is contraindicated, but are much less efficient 
for iron reduction (46, 47).   
Advantages of phlebotomy can be summarized as follows:  
1. Successful use for more than 50 years 
2. Rationale is strong for treatment of an iron-related disease 
3. Frequent visits facilitate monitoring of progress during treatment 
4. Target laboratory value (ferritin) for completing therapy is well established 
Disadvantages of phlebotomy include: 
1. Expense 
2. Discomfort, inconvenience and time requirements 
3. Visits to clinic or blood bank required 
4. Sometimes poorly tolerated (syncope, symptoms of iron deficiency, venous access 
problems, etc.)  
Chloroquine and hydroxychloroquine.  A low-dose regimen of these 4-aminoquinoline 
drugs is considered to be effective and a suitable alternative treatment when phlebotomy is 
contraindicated or difficult, and when there is not marked iron overload (48), as assessed by 
serum ferritin, liver biopsy or HFE mutations (particularly homozygosity for C282Y).  This is the 
preferred therapy at some centers, especially for patients without marked iron overload (48, 49).  
These closely related drugs are interchangeable for this purpose, although hydroxychloroquine is 
considered to be safer in terms of retinal toxicity (50).   
It was noted initially that the larger dosages of chloroquine or hydroxychloroquine used 
for other diseases such as rheumatoid arthritis may, when administered in patients who also 
have PCT, induce fever, malaise, nausea and marked increases in urinary uroporphyrin and 
heptacarboxylate porphyrin, plasma porphyrins, serum transaminases, other liver function tests 
and ferritin levels.  In addition, cutaneous manifestations of PCT can be acutely increased.  

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V3 Date: 25FEB2020 
Page 15 
These are manifestations of acute hepatic damage and the release of large amounts of stored 
porphyrins from the liver.  Indeed, chloroquine administration can unmask previously 
unrecognized PCT (51, 52).  But it was also noted that these adverse effects of 4-aminoquinoline 
compounds, which are unique to PCT, are transient and followed by complete remission of the 
disease (53).  Chloroquine-induced remission was observed even with continued estrogen 
treatment for prostate cancer (54).  Later, it was found that a low-dose regimen of either 
chloroquine (e.g., 125 mg by mouth twice weekly) or hydroxychloroquine (e.g. 100 mg by mouth 
twice weekly) was preferred compared to standard doses, because porphyrins are mobilized 
from liver more gradually with little or no increase in plasma porphyrins or hepatocellular 
damage.  Treatment may be continued until plasma or urinary porphyrins are normalized (55-58), 
but the endpoint of treatment is not well established.  Some patients have required later 
treatment with larger doses, and there is at least some risk of retinopathy (58).  In a retrospective 
study of 62 German patients, low-dose chloroquine was effective in all but the 3 patients who 
were homozygous for the C282Y mutation of the HFE gene (48), which suggests that the degree 
of excess hepatic iron may influence this treatment response.   
The mechanism of the effects of these antimalarial drugs in PCT is not established. Liver 
tissue obtained before and after standard doses of chloroquine showed that acute increases in 
urinary porphyrins occurred when liver porphyrin concentrations were decreasing, suggesting 
that mobilization of porphyrins from liver rather than increased porphyrin synthesis accounted for 
the transient increase in urinary porphyrins (54).  These agents ameliorate hexachlorobenzene-
induced porphyria in rats, which like human PCT is associated with decreased hepatic UROD 
and a similar pattern of accumulated porphyrins (59-62).  Chloroquine concentrates in liver, and 
particularly in lysosomes and other acidic intracellular organelles, and may form complexes with 
many different types of porphyrins that are then more readily mobilized from the liver (62, 63).  
However, studies by Scholnick and coworkers (63), which are frequently cited to support this 
mechanism, were in a rat model in which the dicarboxylate porphyrin protoporphyrin 
accumulates due to inhibition of ferrochelatase, the final enzyme of the heme biosynthetic 
pathway.  By contrast, in PCT primarily uroporphyrin (octacarboxylate porphyrin) and 
heptacarboxylate porphyrin accumulate due to inhibition of UROD.  Studies in animals loaded 
with hematoporphyrin (also a dicarboxylate porphyrin) did not show an effect of chloroquine to 
mobilize the administered hematoporphyrin from tissues, and therefore did not support the notion 
that chloroquine can mobilize a variety of porphyrins from liver and other tissues (64).  
Interestingly, urinary excretion of heptacarboxylate porphyrin increased in rats treated with 
hematoporphyrin and chloroquine (65).  Moreover, the lack of efficacy of chloroquine in other 
porphyrias with deficiencies of heme pathway enzymes other than UROD, such as variegate 
porphyria and congenital erythropoietic protoporphyria (66) indicates that its mechanism of action 
in PCT is highly specific and not related to nonspecific binding of a variety of different porphyrins.  
Other mechanisms, such as mobilization of hepatic iron (55, 66) or inhibition of uroporphyrin 
synthesis (67, 68) have been suggested.  Although it is reported that chloroquine does not 
reduce hepatic siderosis, at least acutely (54), iron excretion may increase in some patients (55, 
58) and serum iron markers may improve (48).  Low dose chloroquine may decrease 
hemosiderin deposition in liver, but otherwise has little effect on liver histology (69).  If the 
response to 4-aminoquinolines relates to the degree of excess hepatic iron, as suggested by a 
report that C282Y homozygotes are treatment-resistant (48), the mechanism of response may 
indeed involve hepatic iron.  However, it seems most likely that because 4-aminoquinolines are 
taken up by lysosomes they may in the presence of large amounts of porphyrins, disrupt these 
intracellular organelles, leading to porphyrin release and transient hepatocellular damage, 
especially with higher doses.  But at present this and other mechanisms remain unproven even 
though the clinical usefulness of these antimalarials is accepted at least as an alternate therapy.   

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 16 
Most reports of efficacy of the 4-aminoquinolines in PCT are single cases or small series 
of patients.  To our knowledge, only one randomized study comparing hydroxychloroquine and 
phlebotomy for treatment of PCT has been reported (44).  In that study 61 patients in Milan, Italy 
were randomized to phlebotomy or hydroxychloroquine 200 mg twice weekly and studied for one 
year, and better results were reported with hydroxychloroquine at the end of the study.  However, 
this study has several features that make generalization of the results difficult.  For example, only 
8 of 31 patients (26%) treated by phlebotomy were improved after one year, which is 
considerably less than expected for this treatment, and serum ferritin levels were not reported.  
In our experience, phlebotomy is typically effective within ~6 months with good compliance and if 
the target ferritin level is attained.  Moreover, these investigators used a higher dose of 
hydroxychloroquine than is now customary for low-dose 4-aminoquinoline treatment in PCT.  
This study illustrates the need for further comparative studies with more frequent observations 
and the expectation that complete remissions are likely in ~6 months.   
Advantages of 4-aminoquinolines for treatment of PCT include:  
1. Efficacy supported by reports for more than 40 years 
2. Inexpensive 
3. Convenient (oral dosing) 
4. No visits required for administration of treatment 
5. Twice-weekly dosing helps ensure compliance 
Disadvantages of 4-aminoquinoline compounds:  
• 
Off-label indication 
• 
No adequate comparison studies to other therapies 
• 
Dosage form not available; tablets not scored for division 
• 
Difficult or inconvenient to monitor course of treatment 
• 
Target laboratory values not established 
• 
Duration of treatment not established 
• 
Standard doses cause adverse effects in PCT 
• 
Low-dose regimen may cause some increases in liver function tests 
• 
Adverse effects on retina unlikely, but still of concern 
• 
Rationale not established and mechanism not known 
This study will test the hypothesis that time to remission with treatment of PCT with low-
dose hydroxychloroquine is comparable to that with repeated phlebotomy.  Although this is not a 
mechanistic study, the study provides an opportunity for observations in some participants that 
may enhance our understanding of how 4-aminoquinolines act in PCT.  Such efforts to better 
understand the underlying mechanism are important because they are likely to enhance 
acceptance of this form of therapy.  For example, patterns of porphyrins in urine will be 
compared during both types of therapy to determine if there is preferential excretion of 
heptacarboxylate porphyrin, as we observed in chloroquine-treated rats (64).  Serum iron, iron-
binding capacity and percent transferrin saturation will be measured at each visit to determine if 
these serum iron markers are affected by low-dose hydroxychloroquine.  We will also compare 
on an optional research basis urinary excretion of iron in participants on each type of therapy, 
since there is some evidence that chloroquine can mobilize iron from the liver in PCT (48, 55, 
59).  Hepatitis C plays an important role in many participants with PCT, and it is of interest to 
know whether or not 4-aminoquinolines might affect this viral infection during treatment of PCT.  
Therefore, we will measure hepatitis C viral load (serum HCV RNA levels) on an optional basis in 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 17 
participants with both PCT and HCV during treatment with hydroxychloroquine or phlebotomy. A 
change in HCV RNA titer may indicate that treatment alters the production and/or release of this 
virus.  Examination of pilot results in these groups of participants will determine if further 
observations in additional participants are warranted.   
Study initiation.  This study was started at UTMB in 2006 with grant support from the 
FDA Office of Orphan Product Development.  It was initially conceived as a randomized 
noninferiority study, with retention of nonrandomized participants to be treated and followed in a 
substudy, to provide additional safety data.  A planned interim analysis of 48 patients enrolled at 
UTMB was carried out and published in 2012 (45); 4 additional patients were enrolled after the 
interim analysis, for a total of 52 enrolled at that site.  The study then became a Porphyrias 
Consortium (PC) study with the same design.  Additional subjects have been enrolled, mostly at 
UTMB.  However, the interim analysis and discussions with the DMCC and the DSMB have 
pointed to a need to amend the study, as in this protocol version.   
Results of the interim analysis.  We analyzed results from 48 consecutive patients with well-
documented PCT who were also well characterized for susceptibility factors and were 
prospectively treated by phlebotomy (450 mL, every 2 weeks until they had serum ferritin levels 
of 20 ng/mL) or low-dose hydroxychloroquine (100 mg orally, twice weekly, until at least 1 
month after they had normal plasma levels of porphyrin) (45).  Unexpectedly (1) fewer than half 
of the patients could be randomized, such that more patients were assigned to phlebotomy than 
hydroxychloroquine, (2) many treatment and study visits were missed, especially with 
phlebotomy, and this delayed remission, and (3) due mostly to missed study visits near the time 
of remission, time to achieve a normal plasma porphyrin concentration (the primary outcome) 
was evaluable in only 30 of 48 subjects (17 treated with phlebotomy and 13 with 
hydroxychloroquine, see Figure 2).  Medium times to the primary endpoint were comparable – 
between 6 and 7 months for both treatments, when either all of the 30 evaluable patients or only 
the 17 randomized evaluable patients were analyzed.  Noninferiority was not established, and 
numbers were insufficient to assess effects of individual susceptibility factors on treatment 
response.  Compliance was better with hydroxychloroquine than phlebotomy.  It was noted that 
when plasma porphyrin levels became normal, other measurements, such as urine porphyrin 
levels and porphyrin patterns, were often still abnormal, suggesting that a normal plasma 
porphyrin level may not be a sign of full remission.  Therefore, continuing treatment with 
Figure 2.  Enrollment, assignment to treatment with or without randomization of 48 study patients with 
PCT in the interim analysis, and inclusion of the 30 patients who achieved a normal plasma porphyrin 
concentration in the analysis comparing time to remission with phlebotomy and low-dose 
hydroxychloroquine. 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 18 
hydroxychloroquine until these additional outcome measures become normal may be beneficial.  
There were no significant side effects with either treatment.  Follow up was insufficient to 
compare recurrence rates with these treatments.  
Based on these interim findings we concluded that (1) the study should continue with changes 
to better assess response and durability with these two standard treatments.  (2) Time to 
achieving treatment endpoints in addition to normal plasma porphyrin levels should be 
assessed. (3) All available PCT patients who require treatment should be enrolled, if possible, 
and assigned treatment based on medical indications, preference, or randomization (for patients 
suitable for either treatment).  (4) A noninferiority design is not appropriate, because most 
subjects are not randomized, and outcomes should be compared using descriptive methods.  
(5) Power analyses to assess effects of clinical features and susceptibility factors should 
emphasize those of greatest clinical interest.  We consider that age and sex are the clinical 
features of greatest interest, and alcohol use, hepatitis C and UROD mutations are susceptibility 
factors of greatest interest.  (6) Longer follow up is needed to assess durability of treatment, and 
whether this relates to susceptibility factors.  (7) The single primary outcome was evaluable in 
~2/3 of patients in the interim analysis.  Inclusion of additional outcomes is likely to provide 
evaluable outcomes for a greater proportion of patients.  (8) This study also will provide serial 
data and samples on a cohort of PCT participants in whom treatment responses and complete 
remission are rigorously documented, which will be valuable for future cross sectional and 
longitudinal research on the pathogenesis and natural history of this disease.   
 
3. Specific aims 
The primary working hypothesis for this study is that time to remission with low-dose 
hydroxychloroquine is comparable to phlebotomy for treatment of PCT.  Because of the very 
different features of the treatments, the study will be unblinded, but the major outcomes in terms 
of efficacy will be measurements that are objective.  The study follows standard of care 
procedures for treating PCT, but assures that all participants have well-documented PCT, are 
characterized for multiple susceptibility factors, are assigned to treatment based on consistent 
criteria, and documents remission and recurrence of the disease, which are aspects often not 
accomplished in clinical practice.   
The specific aims for testing the hypothesis are: 
1. Enroll up to 100 participants, including those enrolled to date, in a prospective, unblinded 
study comparing treatment by phlebotomy with treatment by low-dose hydroxychloroquine.  
Specified eligibility criteria will be used for treatment assignment and participants eligible for 
both treatments will be randomized, to avoid bias.  Tolerability and safety of both treatments 
will be assessed by interviews and questionnaires.   
2. Times to defined primary and secondary treatment outcomes will be compared and subjects 
will be followed for up to 5 years to assess durability of treatment.  
3. Characterize all participants for the presence or absence of known susceptibility factors for 
PCT, including ethanol use, smoking, hepatitis C, HIV infection, estrogen use, HFE 
mutations and an inherited partial deficiency of UROD (as in familial, type 2 PCT), the latter 
as assessed by measuring erythrocyte UROD activity and DNA studies for UROD 
mutations.  Some of these factors (e.g. heavy ethanol use, HFE mutations) will influence 
treatment assignment, and all will be used to determine if individual susceptibility traits 
influence treatment response and durability.  

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V3 Date: 25FEB2020 
Page 19 
Use of hydroxychloroquine for treatment of PCT is an off label indication.  The results of this 
study will contribute to future efforts to modify product labeling for hydroxychloroquine to include 
a specific dosing regimen for treatment of PCT.   
4. Research design and methods 
This study was initially conceived as a randomized noninferiority study, with inclusion of 
nonrandomized participants to be treated and followed in a substudy.  But as described above, 
an interim analysis found that more than half the participants were either not medically eligible 
for both treatments or preferred to choose their treatment, and therefore were not eligible for 
randomization (45).  The results found no major demographic or clinical differences between 
randomized and nonrandomized participants, and treatment responses were also similar.  For 
reasons noted above, the study will continue with inclusion of all treatment-eligible participants 
as a more pragmatic study relevant to clinical practice, with assignment to treatment based on 
uniform criteria and randomization only of participants eligible for both treatments, to avoid 
unnecessary bias.  A descriptive approach to data analysis will be employed, with clinically 
relevant comparisons of the two treatments.  A larger number of subjects will allow assessment 
of effects of susceptibility factors on treatment response and durability.   
Study visits are scheduled at 2-4 week intervals to document achieving a target ferritin 
concentration in subjects treated by phlebotomy, and for both treatments achieving a normal 
plasma porphyrin concentration.  Visits may be less frequent than 2-4 weeks early in the course 
of treatment if, for example, during a course of phlebotomies the serum ferritin is still well above 
the target concentration, or if after phlebotomies are complete or during hydroxychloroquine 
treatment the plasma porphyrin concentrations are still quite high and not yet approaching 
normal.   
Once a normal plasma porphyrin concentration is achieved visits will then be scheduled 
at 4-8 week intervals to document achieving the additional treatment outcomes and complete 
remission of PCT.  Less frequent visits may be scheduled if these outcomes are not yet 
approaching normal, although the time course of improvements in these outcome parameters 
can be difficult to predict.  The expected order of achieving these outcomes with each treatment 
is as follows:   
1. Phlebotomy only: Target ferritin (<20 ng/mL) – expected ~2 weeks after the last 
phlebotomy.  (This requirement can also be met by a ferritin of 25 ng/mL on the 
same day as the last phlebotomy.) 
2. Normal plasma porphyrin concentration 
3. Absence of a fluorescence peak in plasma at neutral pH 
4. Normal urine total porphyrins 
5. Normal pattern of urine porphyrins by HPLC 
How quickly each of these targets and outcomes will be achieved will vary greatly 
among patients.  Therefore, levels need to be followed closely to anticipate when visits are 
needed to document treatment outcomes.  If less frequent visits than recommended are 
contemplated, site investigators should review laboratory results within 3 days of receiving the 
reports and determine when the next visit and the next set of tests should be done in order to 
document all primary and secondary outcomes.   
To be considered an evaluable outcome, time to achieving each of the study outcomes 
listed above (e.g. time to achieving a normal plasma porphyrin level) will be documented by an 
abnormal finding (e.g. a high plasma porphyrin level) followed by normalization of that finding 

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V3 Date: 25FEB2020 
Page 20 
(e.g. achieving a normal plasma porphyrin level) within a specified time interval, which is 
referred to as the documentation window for achieving that outcome.  That 
interval/documentation window will be 4 weeks for achieving a normal plasma porphyrin 
concentration, and 8 weeks for achieving the later biochemical outcomes.  Therefore, a single 
missed visit that is not within one of these windows should not lead to a missed verification of a 
treatment outcome.   
The following study practices are recommended to document the major study outcomes:  
1. A phlebotomy patient should return every 2 weeks after the ferritin falls to 60 ng/mL, 
in order to either 1) document a ferritin of 25 ng/mL on the day of the last 
phlebotomy, or if serum ferritin was not measured on the day of the last phlebotomy, 
2) to document a ferritin level of <20 ng/mL ~2 weeks after the last phlebotomy.   
2. Once the plasma porphyrin level drops to less than ~4 mcg/dL, this test should be 
repeated biweekly to ensure that, even if a visit is missed, normalization is captured 
within the 4-week documentation window, which will properly document time to this 
primary treatment outcome.   
3. After the plasma porphyrin concentration is normal (<0.9 mcg/dL), visits should be 
scheduled at 4 week intervals until the other outcomes are achieved.  If visits are 
missed intermittently, this will still allow capturing a change from abnormal to normal 
within an 8-week documentation window.   
Participant adherence to the treatment regimen and study visits is tracked as a study 
objective, as this was found to significantly influence time to remission in the interim analysis.  
As in the interim analysis (45), noncompliance will be recorded in days.  For example, missing a 
biweekly phlebotomy will be recorded as 14 days of noncompliance.  Missing treatment for 
medical reasons (e.g. hematocrit too low for phlebotomy) will be recorded as medically-related 
delays rather than as noncompliance, and so described in the CRFs.   
Noncompliance from missing a dose of hydroxychloroquine will be recorded as the time 
in days between the day of the missed dose and the next dose of study drug.  With the twice 
weekly regimen for hydroxychloroquine, a half tablet is taken at an interval of 3 or 4 days.  It is 
permissible to take a twice weekly dose up to one day late, and this should be recorded, and will 
not be regarded as a day of noncompliance.  If a dose is not taken for longer than one day after 
a missed dose, that dose should be omitted and recorded as noncompliance.  The next dose 
should be taken 3 days later or as scheduled, with an interval no greater than 3 days.   
Follow up visits after all treatment outcomes are achieved are to detect biochemical or 
clinical evidence of recurrence.  Additional visits may be scheduled for events such as side 
effects or early recurrence of PCT.   
4.A. Treatment sites and laboratory resources.  Treatment sites are the six centers in the 
Porphyrias Consortium.  Other sites with suitable resources and expertise may also be 
approved.   
Samples can be sent to the Porphyria Laboratory at UTMB for all biochemical 
determinations needed to document the diagnosis of PCT and study outcomes.  This laboratory 
is part of the CLIA- and CAP-approved clinical laboratories for the UTMB Hospital.  Samples are 
sent to this laboratory for diagnostic testing on a daily basis from many physicians and medical 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 21 
centers in the U.S.  The laboratory uses published methods and reports results with a clinically 
useful interpretation (70-72).  Other laboratories can be used if equivalent results can be 
obtained.  Although results from different laboratories are likely to be comparable, this has not 
been verified.  Normal ranges are likely to be less comparable between laboratories than 
elevated abnormal values.  It is desirable to use the same laboratory for porphyrin testing 
throughout the study.  In general, Quest, LabCorp, ARUP or Mayo are suitable for urine and 
plasma porphyrin measurements. However plasma porphyrin fluorescence peak testing is only 
done at UTMB and ARUP.  The treatment outcomes are based on criteria stated in this protocol 
rather than on normal ranges stated by different laboratories, which may vary considerably.   
Molecular analyses to identify UROD mutations are provided by the Genetic Testing 
Laboratory at the Icahn School of Medicine at Mount Sinai in New York City.   
4.B. Design.  This is an open-label comparative study of the two standard treatments for PCT.  
Participants will be assigned to the treatment for which they are eligible, as determined by strict 
medical criteria as outlined in this protocol.  Participants eligible and willing to receive either 
treatment will be randomized across sites; however the majority of participants are expected to 
be assigned a treatment based on their medical indications and preference.  Based on many 
decades of clinical experience, both treatments are accepted as effective and safe.  Therefore, 
comparing efficacy and safety will not be an objective of these standard of care treatments.  
Rather, the main objectives will be to compare time needed to achieve remission, as assessed 
by documented primary and secondary biochemical and clinical outcomes, and the durability 
(i.e. lack of disease recurrence) after each treatment.  Since phlebotomy and low dose 
hydroxychloroquine are both considered accepted alternatives for treatment of PCT, costs will 
be either considered standard of care and charged to insurance or supported by the Porphyrias 
Consortium grant for those participants without insurance.   
4.C. Treatment definitions. For participants assigned to Group 1, the treatment regimen will be 
hydroxychloroquine 100 mg twice weekly until at least one month after plasma porphyrin levels 
are normal and other biochemical outcomes (absence of a plasma fluorescence peak at ~619 
nm, a normal total urinary porphyrin level and a normal pattern of individual urinary porphyrins 
by HPLC) are achieved, with a maximum of 24 months of treatment.   
Hydroxychloroquine is available only as 200 mg unscored tablets.  Participants in Group 
1 will be supplied with half tablets containing hydroxychloroquine 100 mg and instructed to take 
one half tablet twice weekly, and on a specific schedule, such as every Monday and Thursday, 
or Tuesdays and Friday.  Participants will be supplied with tablets that have been halved with a 
razor blade by the Pharmacy at UTMB and supplied to each of the study sites.  The FDA CDER 
has suggested that with regard to the proposed strength of the half tablet, we follow the 
procedures outlined for the physical test for the “Uniformity of Dosage Limits” found in the USP, 
as follows: 
• 
Weigh and record the weight of each whole tablet 
• 
Split the tablet and reweigh each tablet half and record those weights 
• 
Follow the USP physical test for Uniformity of Dosage Units, such that each tablet 
half should be within a range of 85-115% of the intended 100 mg 
This procedure will better assure uniformity of the half tablets used in this study.  The UTMB 
Investigational Drug Pharmacy will supply half tablets to be dispensed to patients at the other 
sites.   

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V3 Date: 25FEB2020 
Page 22 
For Group 2, treatment by phlebotomy will consist of removal of one unit (450 ml) of 
whole blood at intervals of ~2 weeks or as tolerated until a target serum ferritin concentration of 
≤20 ng/ml is reached.  A serum ferritin of ≤25 ng/ml on the same day as the last phlebotomy will 
also be regarded as a satisfactory target ferritin concentration.  The time to achieving this target 
ferritin level will depend on the initial ferritin level and the participant’s compliance with the 
scheduled treatment visits.  Suitable sites for phlebotomies may include 1) an outpatient clinic, 
2) a blood bank that performs therapeutic phlebotomies or 3) a clinical research center.  The 
phlebotomy site must provide documentation of the procedure to the site investigator.  A site 
that can obtain a sample for a serum ferritin concentration is most desirable.   
4.D. Recruitment and availability.  Participants with PCT will be obtained primarily by referral 
to the participating centers.  Physicians in primary care and specialty clinics such as 
dermatology and gastroenterology are made aware through personal contacts and notices of 
this treatment study and asked to refer participants.  Notices are also sent to primary physicians 
and specialists in the referral area for each center in order to attract additional participants.  We 
anticipate enrolling ~60 additional participants over the second 5-year cycle of funding of the 
Porphyrias Consortium to bring the total enrollment to at least 100.  Thus the total target 
enrollment period will be 10 years.   
Feasibility of recruitment is based on data from UTMB, which has been studying PCT 
and capturing all patients seen at that institution for many years.  On average, we expect to 
enroll 8-10 patients with new onset or recurrent PCT per year at UTMB.  Over the second 5-
year period of Porphyrias Consortium funding we can expect to enroll a total of 40-50 patients at 
UTMB.  With contribution from the other 6 centers, we expect to achieve the recruitment 
objective of ~60 new patients.   
4.E. Enrollment and treatment assignment.  Subjects will be enrolled if they meet the 
inclusion and exclusion criteria shown in Table 1, which should allow inclusion of the great 
majority of individuals who present with PCT.  PCT patients are often unsponsored, and may be 
unable to afford either of the standard treatments in this study or to attend scheduled study 
visits.  To assure both study adherence and optimal management, treatment and study costs 
will be covered either by participants’ insurance or other funding if the participant does not have 
insurance, at the discretion of the study site.  Reimbursement for travel and time lost for study 
participation will be at the discretion of each study site.  This will help to enable all who need 
therapy for PCT to be treated within the study.   
A history and physical examination will be carried out, which will help document the 
diagnosis and identify susceptibility factors such as alcohol and estrogen use and smoking, 
which will then be assessed in more detail by alcohol and smoking questionnaires.  The results 
of the history, physical examination and screening laboratory tests will be recorded on Case 
Report Forms (CRFs) prepared for this study.   
PCT will be documented by appropriate laboratory measurements carried out in the 
Porphyria Laboratory at UTMB or another reliable clinical laboratory.  This can be done before 
or after enrollment in an outpatient clinic or at an initial visit to a Clinical Research Center 
(CRC).  Participants are considered to be enrolled after they complete the informed consent 
process, and will be assigned a Patient Number.  Subjects found to be not eligible after 
enrollment will be recorded as screening failures to be replaced.  A recruit to replace approach 
will be utilized to achieve final recruitment goals. A relapse during follow up can be treated 
within the study, but will not be part of the primary analysis. 
 
 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 23 
 
Table 1.  Inclusion and exclusion criteria for initial and continued enrollment in the study.   
Inclusion Criteria: 
1. Willing to give informed consent 
 
2. Willing to return to clinic at time points deemed appropriate by the investigator or 
work with a local physician to have necessary labs done and samples sent to study 
site 
 
3. Age 18 or greater 
 
4. Women of child-bearing potential must be willing to avoid pregnancy and use an 
accepted and effective contraceptive method during treatment.   
 
5. Well-documented PCT: 
i. 
Clinical features- A history of blistering cutaneous photosensitivity and/or skin 
fragility.  Subjects with subclinical PCT who have diagnostic porphyrin 
elevation but do not have symptoms may also be included.   
ii.Biochemical and molecular findings – a and b are required 
a. A substantial increase in urinary porphyrins [>450 nmol/24 hours or g of 
creatinine, or more than 1.5-fold increase (relative to ULN of 300 nmol/24 
hours or g of creatinine or >300 ug/24 hours or g of creatinine, or more than 
1.5-fold increase (relative to ULN of 200 ug/24 hours or g of creatinine)] 
and/or plasma porphyrins [>2.7 ug/dL, or >3-fold increase (relative to ULN of 
0.9 ug/dL), and a fluorescence peak at ~619 nm], with a predominance of 
uroporphyrin and heptacarboxylateporphyrin in urine or plasma, and normal 
or only slightly elevated urine ALA and normal PBG.   
b. Normal or only slightly elevated erythrocyte porphyrins [<200 ug/dL, or less 
than 1.5-fold increase (relative to ULN of 80 ug/dL)], unless elevated 
erythrocyte protoporphyrin are due to a non-porphyric condition in the opinion 
of the investigator. This is to exclude mild cases of CEP and HEP, which may 
have urine findings similar to PCT.  
 
iii. 
 
Exclusion Criteria: 
1. Evidence for another cause of blistering skin lesions, such as another type of 
cutaneous porphyria, or pseudoporphyria 
2. Pregnancy 
3. Prior treatment by phlebotomy, hydroxychloroquine or chloroquine within one 
month, unless all appropriate lab results from before treatment was started can be 
obtained, to document baseline porphyrin levels.  
4. Unwillingness to comply with the protocol and required visits 
5. Previous treatment as a participant in this protocol. 
Pregnant women will not be included in the study, because it is generally recommended 
that treatment of PCT be delayed in pregnant women until 1-2 months after delivery.  
Phlebotomies may induce borderline iron status during pregnancy, which may compromise fetal 
health.  Usage of 4-aminoquinoline compounds during pregnancy should be avoided because 
these drugs cross the placenta and accumulate in ocular tissues of the fetus.  

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 24 
In very rare instances a subject that is an excellent candidate for the study may not meet 
all inclusion/exclusion criteria. If the investigator feels the subject may still be a good candidate 
for the study, entrance to the study will be reviewed with the Study Chair and the site’s IRB to 
determine participation. Reasons for the exception must be recorded on the CRF.   The 
objective is to include in the study all patients who need to be treated and obtain information 
and experience to better define future treatment guidelines. 
Documentation of PCT will include consistent cutaneous symptoms and signs, increases 
in urinary total porphyrins with a predominance of highly carboxylated porphyrins (uroporphyrin, 
hepta-, hexa- and pentacarboxylate porphyrin) and increased plasma total porphyrin with a 
plasma fluorescence emission spectrum at neutral pH at 619~620, which is consistent with 
PCT.  Participants with subclinical PCT (i.e. without skin manifestations) and biochemical 
documentation can also be included.  Additional testing will exclude other blistering cutaneous 
porphyrias such as variegate porphyria, and erythrocyte total porphyrin measurement will 
exclude congenital erythropoietic porphyria, which rarely mimics PCT.  Samples required for 
these tests prior to treatment include a 24 hour urine collection or a spot urine sample, a blood 
sample; a random fecal sample is optional but recommended.  Testing and laboratory methods 
will include the following:   
• Plasma total porphyrins (25, 26, 64) 
• Urinary δ-aminolevulinic acid and porphobilinogen (73) 
• Urinary porphyrins (total, and separation by high performance liquid chromatography) 
(64, 74) 
• Erythrocyte protoporphyrin/total porphyrins (75) 
• Erythrocyte uroporphyrinogen decarboxylase (76) 
• Fecal porphyrins (total, and separation by high performance liquid chromatography) 
(64, 77) – desirable but not required at baseline 
DNA studies to identify heterozygous UROD mutations, which are found in ~20% of PCT 
participants and represent a genetic susceptibility factor, will be done at baseline at the 
molecular resource for the Porphyrias Consortium at the Icahn School of Medicine at Mount 
Sinai.   
Susceptibility factors that will be assessed and their prevalence observed previously in a 
series of 143 patients (mean age 52 years, 66% male, 88% Caucasian) seen at UTMB(14) are 
listed in Table 3.   
 
Table 2.  Susceptibility factors to be identified in this study and their prevalence reported 
in a previous study at UTMB of 143 patients with PCT.   
Susceptibility factors 
Prevalence(14) 
1. Ethanol usage, including amount, duration and how recent 
(alcohol consumption questionnaire) 
87% 
2. Smoking history, including amount, duration and how recent 
(tobacco use questionnaire) 
81% 
3. Estrogen use, including type, dose, duration and how recent 
66% of females 
4. Hepatitis C (serum anti-HCV) 
69% 
5. HIV (serum anti-HIV) 
13% 
6. HFE mutations (C282Y and H63D)  
53% (14% with 2 
mutations) 
7. Inherited UROD deficiency  
            (a) by measuring erythrocyte UROD activity, or 
 
13% 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 25 
            (b) by screening for UROD mutations 
20%* 
*UROD mutations were found in 25 of 126 UTMB PCT patients (unpublished) 
Given the high prevalence of many of these susceptibility factors, it is not surprising that 
3 or more were identified in 70% of patients.  HCV infection was significantly associated with 
other behavior-related factors such as ethanol use (odds ratio [OR], 6.3) and smoking (OR, 
11.9) (14).  However, there is a biological rationale for increasing susceptibility with each of 
these behavior-related factors, and it is unlikely that some are confounding.   
As shown in Table 3, gene sequencing has been found to be more reliable than 
measuring erythrocyte UROD for identifying patients with UROD mutations, since the 
erythrocyte enzyme activity is subject to change; it is higher in younger erythrocytes and can be 
increased with unapparent stimulation of erythropoiesis.   
In assessing the effects of susceptibility factors and required sample sizes in this study, 
we will focus on those of most clinical interest, namely alcohol, hepatitis C and UROD 
mutations, with estimated prevalence of 87, 69 and 20%, respectively.   
Other testing.  Because PCT participants typically have abnormalities in liver function 
tests, other causes of liver disease such as hepatitis B, diabetes mellitus, etc. will be looked for 
by appropriate laboratory testing as standard of care, and charged to health insurance.   
1. Hepatitis B will be screened for by HBsAg testing.   
2. Fatty liver disease will be screened for by hepatic ultrasound, if clinically indicated, 
recognizing that increased echogenicity is consistent with but not specific for hepatic 
steatosis and lacks sensitivity.  
3. Liver biopsy will be recommended, if clinically indicated.   
4. Conditions sometimes associated with PCT, such as end stage renal disease and 
myelofibrosis or other bone marrow disorders impairing erythropoiesis, will be screened 
for as reasons for selecting therapy.   
Additional testing will be done, unless results are already available from within the 
previous month, to include complete blood counts, serum ferritin, iron, iron binding capacity, 
transferrin percent saturation and a screening chemistry panel (to include sodium, potassium, 
chloride, carbon dioxide, blood urea nitrogen, creatinine, total protein, albumin, total bilirubin, 
glutamic oxaloacetic transaminase [aspartate aminotransferase], serum glutamic pyruvic 
transaminase [alanine aminotransferase], glucose, uric acid, calcium, and phosphorous).   
Liver ultrasound and biopsy will be recommended to participants based on clinical 
indications per the investigator, these tests will not be done solely for the study. If completed at 
an outside institution records will be obtained.  Tissue will be examined microscopically, and 
iron content will be measured if possible.  Evaluation of liver histology is not required for this 
study because the results are usually not essential for diagnosis or classification of PCT 
participants, identifying risk factors, or deciding on treatment options.  However, liver biopsy is 
the best means of assessing liver iron concentration, and is often recommended for assessing 
the degree of pretreatment damage to the liver associated with hepatitis C, alcohol, steatosis, 
etc.  Results of liver biopsy, when available, will be recorded on the CRFs and tabulated and 
analyzed with other clinical information that pertains to PCT.   
Treatment assignment.  Before assigning treatment, subjects will be evaluated for the 
contraindications to treatment with hydroxychloroquine and phlebotomy listed in Table 3 and 4.  

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 26 
If one of these treatments is contraindicated, the reason(s) will be recorded, and the subject will 
be assigned to the other treatment.  Participants eligible for both will be assigned by 
randomization.   
 
Table 3.  Contraindications to treatment with hydroxychloroquine.   
1. 
Unwillingness to consider this form of treatment 
2. 
Lactating women 
3. 
Psoriasis 
4. 
Significant retinal disease 
5. 
Glucose-6-phosphate dehydrogenase deficiency 
6. 
Recent and continued heavy use of alcohol (defined as 28 or more drinks per 
week) 
7. 
Recent and continued use of hepatotoxic drugs such as acetaminophen, isoniazid 
or valproic acid 
8. 
Marked abnormalities in liver function tests at baseline, such as serum bilirubin 
>3mg/dL, serum alanine aminotransferase >200 U/L, or prothrombin time >16 
seconds (or INR >1.4) 
9. 
Advanced renal disease, with serum creatinine >3 mg/dL 
10. Poor tolerance or poor response to this treatment in the past 
11. HFE genotypes C282Y/C282Y or C282Y/H63D and serum ferritin above the 
normal range (>336 ng/mL) 
12. Substantial iron overload, with serum ferritin >500 ng/mL, in the absence of these 
HFE genotypes 
13. Marked iron overload (3+ or 4+) on liver biopsy, if available 
Continued heavy use of alcohol is unusual in most PCT participants.  Most were 
moderate rather than heavy drinkers, and in our experience most discontinue or greatly reduce 
their intake of alcohol when so advised during the study.  Therefore, we seldom need to exclude 
hydroxychloroquine treatment in PCT because of heavy use of alcohol.  Most participants also 
smoke cigarettes, and are less successful in reducing or stopping this addiction.   
Participants with serum ferritin concentrations >500 ng/mL or with marked iron overload 
on liver biopsy will not be considered for treatment with hydroxychloroquine, since they will be 
considered clinically to likely have substantial iron overload and require treatment by 
phlebotomy.  Participants with the C282Y/C282Y or C282Y/H63D HFE genotypes often have 
serum ferritin concentrations in the normal range, do not have iron overload and will be eligible 
for either treatment.  Those with these genotypes and ferritins >336 ng/mL (the upper limit of 
normal) will not be randomized, since we consider that phlebotomy is indicated with these 
genotypes when iron overload is evidenced by a high ferritin level, and PCT participants with the 
C282Y/C282Y genotype and high ferritin are reported to be resistant to low dose 4-
aminoquinolines (48).   
Table 4.  Contraindications to treatment with phlebotomy.   
1. 
Unwilling to consider this form of therapy 
2. 
Severe bone marrow dysfunction manifested by anemia 
3. 
Poor venous access 
4. 
Poor tolerance in the past, such as frequent syncopal episodes, or poor response 
Most participants with HIV infection and PCT will be eligible for either treatment.  HIV 
participants with PCT generally tolerate phlebotomy and can be assigned to this treatment 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 27 
unless there is evidence of bone marrow failure, in which case they would be eligible for 
treatment with low-dose hydroxychloroquine.   
Participants with chronic hepatitis C (HCV) and PCT will be eligible for either treatment. 
Prospective participants will be evaluated for inclusion in PC7210 for HCV treatment first. If they 
are not eligible or decline participation in PC7210, they will be offered enrollment in PC7206, 
Patients who are eligible for PC7210 will include PCT patients >18 years old with HCV genotype 
1. Major exclusion criteria for this study include patients who are currently receiving PCT 
treatment by phlebotomy or hydroxychloroquine, alcohol abuse, amiodarone use, other 
comorbid conditions.  
4.F. Treatment Phase.  The treatment phase of this study will continue until treatment is 
completed and all primary and secondary outcomes have been achieved.  
Group 1: Assigned treatment with low-dose hydroxychloroquine.  Half tablets of 
hydroxychloroquine (100 mg for each half tablet) will be prepared as described above in the 
UTMB Investigational Drug Pharmacy and supplied to the other sites.   
Participants assigned to Group 1 will be instructed to record when they take each half 
tablet on a diary sheet that is provided to them (see Appendix B), and to bring the record and 
the bottle of half tablets back to the study site at the time of each visit.  Compliance will be 
assessed at the time of each visit by the dosing record and by counting the half tablets 
remaining in the medication bottle.  Given the convenience of this regimen, we expect good 
adherence to the regimen, but this will be monitored.   
As noted above, it is permissible to take a twice weekly dose of hydroxychloroquine up 
to one day late, and this should be recorded.  The next dose should be taken 3 days later or as 
scheduled, with an interval no greater than 3 days.  If a dose is not taken for longer than one 
day, that dose should omitted and recorded as noncompliance.  
Group 2: Assigned treatment with phlebotomy.  Participants in Group 2 will undergo 
repeated phlebotomies with removal of one unit (~450 ml) of whole blood at intervals of ~2 
weeks at a suitable facility at the study site or elsewhere, such as 1) an outpatient clinic, 2) a 
blood bank that performs therapeutic phlebotomies or 3) a clinical research center.  Efforts will 
be made to identify a suitable facility that is most convenient for the individual subject, in part to 
encourage compliance with the regimen.  It is advantageous to choose a study site that can 
obtain samples for serum ferritin measurements.   
The phlebotomy site must issue a report to document the date of each phlebotomy and 
the volume of blood removed, and provide a copy to the study site investigator.  The information 
will be recorded in the CRF.  If a scheduled phlebotomy is not done (e.g. hematocrit is below the 
permissible level), the reason should be recorded on the report to the site investigator.  It must 
be determined in advance for each participant how documentation of each phlebotomy will be 
provided, as customary practices may vary among blood banks and other facilities that do 
therapeutic phlebotomies.  Copies of this documentation will be retained at each site as source 
documents to verify each phlebotomy.  Source documentation will need to be specified if 
phlebotomies are performed at other sites, such as CRCs and outpatient clinics.  If such 
documentation is not received at the site, the coordinator will reach out to the outside facility to 
follow up appropriately.  If an outside facility is being used for phlebotomies and does not 
provide documentation of the procedures, the participant will be given such a form to have 
completed by medical staff at the facility and will be responsible for sending this to the site 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 28 
coordinator (see Appendix C).  The cost of the phlebotomies will be considered standard of care 
and covered by the patient’s insurance or by the Porphyrias Consortium if the patient has no 
insurance.  
At each session, a hematocrit or hemoglobin determination will be done prior to the 
phlebotomy to assure this is high enough for tolerating phlebotomy.  The permitted lowest value 
for each patient will be specified in advance and prerecorded, and will be no more than 10 
points below the starting hematocrit, and no less than ~33.  This value will be adjusted upward if 
there are concurrent medical conditions that need to be considered.  The permitted hematocrit 
value is specified in advance to enhance safety and is not a therapeutic target.   
During the course of treatment by phlebotomy, samples for measuring serum ferritin and 
plasma total porphyrins will be obtained at baseline and at intervals of 2 weeks, or as needed to 
document achieving the target serum ferritin of ≤20 ng/mL.  Documenting a serum ferritin of ≤25 
ng/mL on the same day as the last phlebotomy will satisfy this requirement.  Ferritin levels may 
not be needed every 2 weeks early in the course of treatment, but should be measured most 
frequently (biweekly) once the ferritin falls below 60 ng/mL and is approaching the target value 
of ≤20 ng/mL.   
Samples for tests such as blood counts and serum chemistries will be obtained at 
baseline, during the treatment phase of the study only when clinically indicated, during the post 
treatment phase when clinically indicated, and at the end of the follow up phase. This is the 
standard approach to the treatment of PCT by repeated phlebotomy in the U.S. and other 
countries.   
It is best if therapeutic phlebotomies can be done at a site that can also send blood 
samples for ferritin, plasma porphyrins, blood counts and chemistries and urine porphyrins, 
when needed.  Otherwise, additional visits will need to be arranged for monitoring these test 
results.   
Phlebotomies will be discontinued once the target serum ferritin (≤20 ng/mL) is reached, 
which is before porphyrin levels and patterns normalize.  The ferritin level should be repeated 2 
weeks after the last phlebotomy, unless a ferritin of ≤25 ng/mL was documented on the same 
day as the last phlebotomy.  Porphyrin levels will continue to be monitored after phlebotomies 
have been discontinued in order to document times to each treatment outcome.   
Most facilities that do phlebotomies require that a consult request or orders be provided.  
Suggested wording for such requests is as follows, which will need to be modified for each site 
and permitted hematocrit (or hemoglobin) values specified for each participant:   
 
Please start repeated phlebotomies at intervals of approximately 2 weeks for treatment 
of porphyria cutanea tarda (PCT).  The treatment target is a serum ferritin from the 
previous visit of less than 25 ng/mL.   
1. Please call the patient to schedule the first visit.   
2. At each visit, please 
a. obtain an hematocrit 
b. send a blood sample to Clinical Chemistry for serum ferritin and 
c. obtain a blood sample for total plasma porphyrins (green top tube – call 
extension xxxx for pickup). 
3. At each visit, if the hematocrit is less than xxxx, omit the phlebotomy and just 
obtain the above samples.  Ask the patient to return in 1-2 weeks for the next 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 29 
phlebotomy.  By that time the hematocrit should increase to or above xxxx, and 
allow phlebotomies to continue until the target ferritin is reached.   
4. If the serum ferritin from the previous visit is less than 25 ng/mL (i.e. the target 
ferritin), omit the phlebotomy and just obtain the above samples.  After this target 
ferritin is reached, schedule or ask the patient to schedule a return visit to xxxx 
Clinic to see Dr. xxxx in 2 weeks.   
5. For each patient visit, please send a report recording the date and the amount of 
blood removed.  If a phlebotomy was not done, please state the reason on the 
report.  Reports should be sent to xxxx at xxxx.   
Note that the target ferritin for this treatment is ≤20 ng/mL.  However, a serum ferritin of 
≤25 ng/mL can satisfy this requirement if it is obtained on the same day as the last phlebotomy, 
because it can be assumed that an effect of the last phlebotomy will be to decrease the ferritin 
further by at least 5 ng/mL.  If a ferritin level is not obtained on the same day as the last 
phlebotomy, a ferritin level should be obtained ~2 weeks later to document a level of ≤20 ng/mL.  
If the target is not reached, another phlebotomy should be scheduled.   
Treatment failure.  A complete lack of response to either treatment is unlikely.  In the 
interim analysis (45), 30 participants with adequate numbers of observations achieved a normal 
plasma porphyrin concentration, and only 4 (2 on each therapy) did not. In 3 of these, partial but 
still substantial reductions in plasma porphyrin levels and symptomatic improvement occurred; 
their incomplete remissions were associated with continued use either of estrogen, a known 
susceptibility factor (1 patient treated with hydroxychloroquine), or carisoprodol, an inducer of 
hepatic heme and porphyrin synthesis, for chronic back pain (2 patients treated by phlebotomy).  
The fourth patient, who had HIV infection, anemia, and concurrent treatment with antiretroviral 
drugs, did not improve with hydroxychloroquine and died of an acquired immune deficiency 
syndrome–related infection.  Therefore, it is important to continue to record concomitant 
medications and clinical features during the study and determine if they correlate with 
incomplete responses to treatment.   
Change of treatment.  Treatment may need to be changed due to incomplete response 
or to side effects or intolerance of the initial treatment.  Change of treatment will be a clinical 
decision by the investigator and the patient, and the reasons will be recorded on the CRFs.  The 
second treatment will be monitored as part of the study with an additional set of the treatment-
related CRFs in the same manner as the first treatment.  Data collected after a change in 
treatment will be analyzed descriptively and separately from data collected during the first 
treatment.   
Treatment of recurrences.  Patients will be followed after completion of treatment in 
order to determine the frequency of recurrent disease, as indicated by increases in porphyrin 
levels with or without recurrent cutaneous manifestations.  These recurrences will be monitored 
as part of the study.  Data collected during treatment of recurrences will be analyzed 
descriptively and separately from data collected during the first treatment. These provisions will 
provide information about all treatment that is needed for this disease, since repeated courses 
of treatment greatly increase the impact of the disease.  
4.G. Study visits during the Treatment Phase.  During the Treatment Phase, participants will 
be scheduled to return to the study site or be contacted by the study site by telephone at 2 week 
intervals.  A study visit can be scheduled after longer than 2 weeks based on careful review of 
data from the last visit. If this is contemplated, the investigative team should evaluate clinical 
features and laboratory results within 1 week, to be sure that a longer visit interval will not impair 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 30 
capturing timely data within a documentation window.  Sometimes study information can be 
collected by telephone, including recording of patient-reported skin manifestations, and by 
special arrangements study samples collected locally and shipped to the study site.   
The treatment outcomes for this study are documentation of times to normalization of 
several porphyrin laboratory measurements, which occur in sequence at different times during 
the Treatment Phase.  Study performance will be assessed by whether or not primary study 
outcomes are documented within specified time windows.  Documenting the time to each 
outcome requires an abnormal result followed by a normal result within a specified time window.  
The windows of documentation for each treatment outcome are shown in Table 5.  Experience 
to date indicates that these outcomes are usually achieved in the order shown.  All outcome 
measures may not be documented in all patients, but with four rather than one outcome 
measure it is more likely that each patient will achieve documentation of at least some of these 
outcomes. 
 
Table 5.  Treatment outcomes and windows for documentation 
Treatment Outcomes 
Windows for 
Documentation of 
Outcomes 
Normal plasma porphyrin level 
4 weeks 
Disappearance of plasma fluorescence peak 
at ~619 nm 
8 weeks 
Normal urine total porphyrins 
8 weeks 
Normal pattern of urinary porphyrins 
8 weeks 
Time to achieving each of these treatment outcomes and the location of each of these 
outcome windows in time during the Treatment Phase will vary among individual participants. 
For this reason, regular visits should be scheduled based on these windows, and less frequent 
visits scheduled only after examination of the most recent laboratory results.   
4.H. End of treatment.  The maximum duration of treatment will be 24 months, but is expected 
to be shorter for most participants.  Treatment by phlebotomy will end when the target ferritin 
value is reached (≤20 ng/mL, or ≤25 ng/mL on the day of the last phlebotomy).  Therefore, it is 
advantageous, if possible, to obtain ferritin measurements on the days of phlebotomy.  
Porphyrin levels will start to decrease, but will not be normal when phlebotomies are ended.  
Therefore the Treatment Phase of the study extends beyond the last phlebotomy until all 
treatment outcomes are documented.  Factors that may lengthen the duration of phlebotomy 
treatment include marked iron overload, some loss of venous access and difficulty adhering to 
treatment visits.    
Hydroxychloroquine treatment will end after the plasma total porphyrin concentration and 
other porphyrin abnormalities have been normal for at least one month (i.e. at least one month 
after all treatment outcomes are achieved).  Treatment may be stopped for poor tolerance or 
other medical reasons, and these reasons will be recorded.  For hydroxychloroquine, the 
desirable length of this treatment and factors that delay response are less well understood, and 
will be clarified by the results of this study.  For this protocol, the duration of hydroxychloroquine 
treatment will not exceed 24 months.   
Either treatment will be discontinued if a participant no longer meets the inclusion criteria 
or develops one of the exclusion criteria for the assigned treatment.  A treatment will also be 
stopped if an adverse event occurs that is regarded as a reason for stopping the current 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 31 
treatment or in the judgment of the investigators on clinical grounds is a reason for stopping the 
current treatment in the best interest of the patient.  The reasons for discontinuing treatment will 
be recorded on the CRFs. If a participant is discontinued from one treatment, they may be 
switched to the alternate treatment if deemed appropriate by the investigator. Should this 
happen their information will still be collected according to the schedule described in this 
protocol and analyzed as part of this study.   
4.I. Follow Up Phase.  Determining durability of treatment after achieving a complete 
biochemical remission of PCT is an important objective of this study.  Therefore, subjects will be 
observed long term during the Follow Up Phase for clinical and biochemical recurrences of 
PCT.  This phase will begin after treatment is completed and all treatment outcomes are 
achieved.  These visits will occur, either on site or remotely, every 3-6 months for up to 5 years, 
or possibly longer, depending on the availability of funding for the study.  Symptoms will be 
monitored, and porphyrin levels measured for early detection of recurrence.  Determinations on 
these visits will include total plasma and urinary porphyrin concentrations, plasma porphyrin 
neutral pH fluorescence emission peak, urinary porphyrin HPLC, ferritin and liver function tests.  
These samples may be obtained at the study site or elsewhere as part of standard of care.  This 
will provide information on both clinical and subclinical biochemical recurrence after remission 
with both types of treatment. If a subject has a recurrence of symptoms their treatment will be 
followed clinically and they will continue with this follow up visit schedule.  
It is important to assess both symptoms and porphyrin levels during follow up.  In our 
experience patient reports of recurrence of skin manifestations are not always reliable, and can 
be discounted if evaluation at the time finds that porphyrin levels remain normal and no 
objective skin changes consistent with PCT are present.  Conversely, biochemical recurrence 
with small or large increases in porphyrins can occur in the absence of symptoms.  It is 
suspected that subclinical PCT may be especially common in patients with UROD mutations, 
but this is not well documented.   
4.J. Study duration and end of study.  The duration of the study including the Follow Up 
Phase is at least five years.  It is possible that the study will be extended further depending on 
results and the availability of funding.  Subjects will enter the study needing treatment, and 
require up to 24 months of treatment and observation to document achieving the treatment 
outcomes, followed by at least 3 years of follow-up.  Therefore, the most frequent study visits 
will occur during the Treatment Phase and generally the first ~12 months of the study, which 
includes active treatment and the treatment outcome windows to document biochemical 
remission.  Based on the interim analysis (45) it is anticipated that the first outcome (a normal 
plasma porphyrin concentration) will be reached within 6-7 months, on average.  Other 
treatment outcomes should be achieved within ~12 months, although this is uncertain at 
present, since such observations were not part of the interim analysis.   
4.K. Treatment outcomes and schedule of events.  A schedule of events in tabular form and 
a study flow diagram are shown below.  This study compares time to reaching certain efficacy 
outcomes with the two treatments and documents durability of treatment in terms of absence of 
increases in porphyrins and recurrence of symptoms.   
The primary efficacy outcome is achieving a normal plasma porphyrin concentration 
(<0.9 mcg/mL).  Secondary efficacy outcomes include achieving (1) absence of a fluorescence 
peak in diluted plasma at neutral pH; (2) a normal level of total urinary porphyrins; (3) a normal 
pattern of individual porphyrins in urine (defined as total highly carboxylated porphyrins less 
than coproporphyrin); (4) times to achieving intermediate improvements in these porphyrin 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 32 
measures, which will be defined during data analysis; (5) absence of new skin lesions for at 
least 3 months; and (6) effects of susceptibility factors such as hepatitis C, inherited UROD 
deficiency, etc. on achieving these treatment outcomes.  
Durability of treatment (i.e. absence of recurrence) is recorded as beginning with the 
time that treatment achieves the treatment outcomes, and extends to the time of repeat 
documentation of a normal plasma porphyrin concentration, assuming there have been no 
interim recurrences of skin manifestations.   
4.L. Safety.  Safety parameters are based on known side effects of both treatments and include 
suggestions of the UTMB IRB and the FDA CDER.  Participants will be evaluated at the 
beginning of the study to ensure that they meet the entry criteria and are informed about risks 
and precautions.  They will then be monitored at study visits for assessment of safety.  Close 
monitoring of hemoglobin or hematocrit may occur as a part of standard treatment by 
phlebotomy.  This is not the case for hydroxychloroquine, because initiation of treatment in 
clinical practice requires only one visit to prescribe the drug, and continued visits are not needed 
to administer treatment.  Therefore, safety monitoring will be as good or better than in clinical 
practice.   
1.  History and physical examination 
History and physical examination (including height and weight) will be performed at the 
beginning and end of the study.  Results will be recorded on CRFs.   
 
 
Schedule of Events 
 
Baseline 
(Day -60 to Day 
-1)  
Treatment Period 
(including all 
treatment outcomes) 
Follow Up Period  
(to monitor for 
recurrence) 
Visit frequency 
One visit or as 
needed 
Every 2-4 weeks until 
plasma porphyrin 
concentration 
normal, then every 4-
8 weeks 
Every 3-6 
months  
Medical History and physical examination 
X 
 
Annually & End 
of study 
Documentation of PCT & porphyrin testing- urine total 
porphyrins, plasma total porphyrins#, erythrocyte 
protoporphyrin, UROD mutation testing, erythrocyte 
UROD, urine ALA & PBG, fecal porphyrins (optional) 
X 
 
 
Lab assessment for susceptibility factors- serum anti-
HCV (with follow up HCV RNA if positive), serum anti-
HIV, HFE mutation testing 
X 
 
 
Screening Lab tests- serum ferritin, complete 
metabolic panel%, CBC with Diff, hemoglobin A1C, 
Erythrocyte glucose-6-phosphate dehydrogenase 
screening, PT, aPTT, serum iron & TIBC 
X 
 
 
Alcohol & Tobacco Use Questionnaires 
X 
 
 
History of Estrogen Use (type, dose, duration, how 
recent) 
X 
 
 
PCT Symptom Assessment  
X 
X 
X 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 33 
 
Liver ultrasound and/or liver biopsy (if clinically 
indicated) 
X 
 
 
Ophthalmologic Evaluation (only for HCQ 
participants)  
X 
Annually 
 
Plasma and urine (24 hour or spot sample) total 
porphyrins, quantified & plasma porphyrins 
fluorescent peak#  
 
X 
X 
 
Urine pregnancy test 
X 
X 
 
Follow Up Lab tests- Hepatic Function Panel with 
reflex to PT and aPTT if abnormal, HCV RNA if 
positive at baseline 
 
X 
X 
Serum Ferritin@ (follow up needed only for 
phlebotomy participants) 
X 
X 
X 
Dispense HCQ or begin phlebotomies 
 
X 
 
HCQ twice weekly or ~biweekly phlebotomies$ 
 
X 
 
Investigator review of labs to determine next visit 
 
PRN 
X 
Collection of urine for research testing 
X 
X 
X 
#Plasma porphyrin scan at neutral pH can be done at UTMB or ARUP, urine and plasma porphyrin measurements can be done at 
UTMB, ARUP, Mayo, Quest or LabCorp. During treatment phase once plasma levels drop to less than ~5 mcg/dL the test should be 
repeated biweekly  
%Complete Metabolic Panel should include- sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, total 
protein, albumin, total bilirubin, glutamic oxaloacetic transaminase [aspartate aminotransferase], serum glutamic pyruvic 
transaminase [alanine aminotransferase], glucose, uric acid, calcium, and phosphorous  
@ Serum ferritin should be done biweekly once the level drops below 60 ng/mL, until the target of ≤20 ng/mL is reached 
$ For participants on HCQ the coordinator will need to complete compliance forms monthly. For participants on phlebotomy the 
phlebotomy visit sheet will need to completed at every phlebotomy visit 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 34 
Study flow diagram:  
 
2.  Laboratory evaluations 
The tests listed below are required to assess safety of treatment or detect concurrent 
conditions that might affect treatment indications.  Examples of the latter include advanced liver 
disease, chronic renal disease and myelofibrosis and other bone marrow disorders.  The serum 
pregnancy test is needed in women of child-bearing potential to exclude pregnancy, because 
this is a reason for exclusion at the start of the study or for stopping treatment during the study.   
a.  The following will be measured by the hospital clinical laboratory.   
i) Tests done at baseline  
• Erythrocyte glucose-6-phosphate dehydrogenase activity 
 
Eligible Only for 
Phlebotomy 
Eligible for Either 
Treatment 
Eligible Only for 
Hydroxychloroquine 
Tests at Baseline visit: 
1.
Plasma porphyrins, urinary ALA, PBG, and 
porphyrins with HPLC, erythrocyte 
protoporphyrin & UROD, fecal porphyrins, DNA 
studies 
2.
Anti-HCV (viral load and genotype if positive), 
anti-HIV; HFE mutations; CBC, BMP, LFTs, ferritin 
and iron studies.  If clinically indicated: HBsAg, 
liver US and liver biopsy.   
Randomize  
Inclusion & Exclusion 
Criteria are Met 
Prescreening 
Baseline Visit: Consent, 
Assign Treatment 
Group 1 
Phlebotomies, 
biweekly 
Until ferritin ≤20 
ng/mL.  Treatment 
Hydroxychloroquine  
100 mg, twice weekly 
Until all treatment 
outcomes achieved 
Group 2 
1.  Visits every 2-4 weeks until plasma porphyrin 
concentration is normal (Documentation window is 4 
weeks) 
2.  Then every 4-8 weeks until other outcomes 
achieved (Documentation window 8 weeks) 
At each visit: plasma porphyrins (including spectrum), 
urine porphyrin with HPLC, serum ferritin.  CBC, LFTs, 
iron studies, HCV viral load optional.   
3.  Remote visits may be arranged.   
FOLLOW UP PHASE 
To assess for recurrences 
TREATMENT PHASE:  
Treatment to be completed and all outcomes achieved 
Visits on site or remotely every 3-6 months for at least 3 years   

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 35 
• Prothrombin time 
• Partial thromboplastin time 
• Total protein 
• Albumin 
• Total bilirubin 
• Aspartate aminotransferase (glutamic oxaloacetic transaminase) 
• Alanine aminotransferase (glutamic pyruvic transaminase) 
• Iron 
• Iron binding capacity 
• Transferrin percent saturation 
• Ferritin 
• Complete blood cell count (to include hemoglobin, hematocrit, red blood cell 
count, red blood cell indices, white blood cell count, differential white blood 
cell count and platelet count) 
• Sodium 
• Potassium 
• Chloride 
• Carbon dioxide 
• Blood urea nitrogen 
• Creatinine 
• Glucose 
ii) Tests done at subsequent visits 
• Repeat baseline tests that were abnormal, or are clinically indicated 
• Total bilirubin 
• Aspartate aminotransferase (glutamic oxaloacetic transaminase) 
• Alanine aminotransferase (glutamic pyruvic transaminase) 
• Iron 
• Iron binding capacity 
• Transferrin percent saturation 
• Ferritin 
• Prothrombin time and partial thromboplastin time if liver function tests are 
abnormal 
 
A urine or serum pregnancy test will be done at baseline and every 2 months until the 
end of treatment in premenopausal females; pregnancy is a reason for exclusion at any time 
during the study.   
Hydroxychloroquine will be discontinued if there is worsening of liver disease, as 
determined by a rise in alanine aminotransferase to >300 U/L, or a two-fold increase from 
baseline in either total bilirubin or prothrombin time.  Participants will also be monitored at each 
visit for signs or symptoms of worsening liver disease.  Phlebotomy will be discontinued if 
participants are unable to tolerate this treatment at least monthly.  Randomized patients 
discontinued from either treatment may be treated with the alternative method, since an 
objective of this pragmatic study is to achieve remission in all patients.   
3.  Ophthalmologic examinations will be done in all participants treated with 
hydroxychloroquine at the beginning and end of treatment. This is consistent with the 
recommendations of the American Academy of Ophthalmology as updated in 2011 (Table 7) 
[78].  Because retinal damage from 4-aminoquinolines is very rare (especially with 
hydroxychloroquine), it is not expected that ocular effects will be observed in this small study 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 36 
employing a low dose regimen of relatively short duration.  The risk of retinal damage is very 
low even with the much higher doses used for prolonged treatment of rheumatoid disorders, 
with the risk increasing if treatment is continued for longer than 5 years or if the cumulative dose 
is high.  In this study, the dose of 100 mg twice weekly averages to a daily dose of less than 0.5 
mg/kg for a 70 kg patient, and the duration of treatment will be less than 5 years. Therefore, a 
second ophthalmological examination will be done at the end of treatment rather than 5 years.  
Each participating institution will have their own standard practices established by 
ophthalmology departments based on the guidelines shown in Table 7. 
 
Table 7.  Recommendations of the American Academy of Ophthalmology on screening patients 
treated with chloroquine and hydroxychloroquine [78].   
Timeline 
Baseline examination within first year of use 
 
Annual screening after 5 yrs of use 
Recommended Screening Procedures 
Ocular 
examination 
Dilated retinal examinations are important for detection of associated retinal 
disorders, but should not be relied on for screening (low sensitivity). 
Automated visual 
field 
White 10-2 threshold testing. Interpret with a low threshold for abnormality, and retest 
if abnormalities appear. 
In addition, if available, perform one or more of the following objective tests 
SD-OCT 
Rapid test that can be done routinely; can show abnormalities very early, even before 
field loss 
mfERG 
Valuable for evaluation of suspicious or unreliable visual field loss; may show 
damage earlier than visual field testing 
FAF 
May validate other measures of toxicity; can show abnormalities earlier than field loss 
Not Recommended for Screening 
Fundus 
photography 
Recommended for documentation, especially at baseline, but not sensitive for 
screening 
Time-domain OCT Insufficient resolution for screening 
Fluorescein 
angiography 
Use only if corroboration of pigmentary changes is needed 
Full-field ERG 
Important for evaluation of established toxicity, but not for screening 
Amsler grid 
Use only as adjunct test 
Color testing 
Use only as adjunct test 
EOG 
Questionable sensitivity 
Abbreviations: EOG = electro-oculogram; FAF = fundus autofluorescence; mfERG = multifocal 
electroretinogram; SD-OCT = spectral domain optical coherence tomography. 
 The recommendation in the product labeling for hydroxychloroquine for 
ophthalmological examination before and at 3 month intervals during treatment for lupus or 
rheumatoid arthritis is considered outdated and leads to unnecessary health care costs (50), 
and less frequent examinations are recommended in the recently revised guidelines of the 
American Academy of Ophthalmology (78).     
Participants will be questioned at each visit about specific eye symptoms, such as 
reading and seeing difficulties, missing objects or parts of objects, missing or blacked out areas, 
blurred vision, halos around lights, photophobia, light flashes or streaks.  Evidence of 
ophthalmic complications of hydroxychloroquine, although unlikely, will be reason for 
discontinuing the drug.  The patient may then be treated by phlebotomy.   

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 37 
4.  Neuromuscular symptoms.  Participants will be questioned at each visit regarding 
neuromuscular symptoms such as sensory changes and weakness, and examined for sensory 
changes, depression of deep tendon reflexes and loss of muscle strength, which are reported 
side effects of hydroxychloroquine.   
5.  Precautions for children.  Participants taking hydroxychloroquine will be warned to 
keep the medication out of the reach of children.   
6.  Harmful exposures.  Participants will be advised to avoid exposure to ultraviolet light 
(sunlight, tanning parlors, etc.) and alcohol, smoking, iron supplements, estrogens or other 
substances known to exacerbate PCT.  This is part of standard clinical advice given to 
participants with PCT.   
4.M. Efficacy.  Efficacy will be assessed primarily by laboratory results.  Information on 
symptoms and signs will also be recorded.   
1.  Laboratory Tests 
The primary measures of efficacy will be plasma total porphyrin concentration, the 
plasma fluorescence emission spectrum at neutral pH, and urinary porphyrins (total as well as 
fractionated).  The following will be measured at each visit.   
• 
Plasma total porphyrins  
• 
Plasma fluorescence emission spectrum at neutral pH 
• 
Urinary porphyrins (total, and separation of individual porphyrins by high performance 
liquid chromatography-HPLC) 
• 
Plasma and urinary exosomal ALAS1 mRNA 
The following will be done on an optional research basis based on preliminary results 
from the interim analysis (45):  
• 
Samples will be collected for measurement of urinary iron excretion will be done on a 
research basis, with precautions to avoid contamination, at baseline and at 1, 3 and 6 
months of treatment by graphite furnace atomic absorption mass spectroscopy or 
inductively coupled plasma mass spectrometry  (80, 81).   
• 
Serum HCV RNA – quantitative – will be determined on an optional basis before and at 
1, 2, 3, and 6 months (total = 5) in participants with PCT and hepatitis C on either 
therapy.   
2.  Cutaneous manifestations 
Symptoms related to PCT, such as appearance of new blisters or milia, as well as other 
symptoms that might result from concomitant conditions such as hepatitis C or from treatment, 
will be recorded on CRFs at each visit.   
At each visit, the number of new lesions, especially blisters and milia, will be counted.  
The backs of both hands will be photographed, if possible, and kept in the participants study 
chart to document any new lesions and improvement in the number of lesions.   

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 38 
Pain may occur as a result of cutaneous lesions, but is otherwise not a prominent or 
characteristic feature of PCT.  If participants have pain or other symptoms that can be graded, 
the following scale will be used.  This information will be recorded on CRFs.  
 
Scale 
Descriptions for pain and other symptoms 
Absent 
No pain 
Mild 
Awareness of pain but easily tolerated.   
Moderate 
Pain not easily tolerated and interferes with usual activities.   
Severe 
Pain incapacitating and prevents usual activities.   
4.N. Concomitant therapy.  Drugs other than hydroxychloroquine will not be allowed in this 
study for treatment of PCT.  Other drugs will be permitted if needed for symptomatic relief or 
other medical conditions, and will be recorded at the time of each study visit.  Estrogens will be 
stopped until a remission is achieved (30).  Iron-containing preparations will be discontinued.  
Participants will be recommended to stop use of alcohol and tobacco, as is standard for 
management of PCT.  There will be no dietary restrictions.  Compliance with these 
recommendations will be monitored during the study.   
4.O. Adverse experiences.  At the time of each visit it will be determined whether any adverse 
experiences have occurred.  The participants will be questioned in a general way and no 
specific adverse symptoms will be suggested, except in regard to the symptoms to be recorded 
on the CRFs or symptoms that are of particular importance in the clinical management of an 
individual patient.  Any clinical adverse experiences that have occurred will be recorded on the 
CRFs, and a judgment made regarding whether or not the adverse experience was related to 
study treatment. 
Any serious adverse experience (SAE), including death, due to any cause and occurring 
during the course of this investigation, whether or not related to the study treatments or 
procedures will be reported immediately to the Institutional Review Board (IRB) at the site, the 
IRB at UTMB, the Clinical Research Center at UTMB and the site, if required, and the US Food 
and Drug Administration.   
A SAE with respect to clinical experience includes any experience that is fatal or life-
threatening, is permanently disabling, or either requires or prolongs inpatient hospitalization.   
4.P. Patient withdrawal.  Every reasonable effort will be made to keep participants in the study.  
If a patient wishes to leave the study or is removed by the PI, a complete final evaluation will be 
performed.  A narrative description of the reason(s) for withdrawal from the study will be 
recorded in the source documents. 
The following are justifiable reasons for removing a patient from the study: 
1.  Development of a study exclusion criterion, as previously listed 
2.  If continuing the study presents an unacceptable risk or discomfort to the patient. 
3.  Violation of the study protocol. 
4.  The patient is uncooperative or noncompliant in study-related observations or in 
administration of study medication. 
5.  Consent is withdrawn. 
6.  The study is terminated. 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 39 
4.Q. Treatment failure or intolerance.  Participants who fail therapy are expected to be few.  
Participants who fail or develop contraindications to the treatment assigned will be switched to 
the alternate treatment and continue to be followed in the study.  Reasons for changing 
treatment will be recorded within the study. Participants who relapse and require retreatment will 
also remain in the trial.  Data from second or subsequent treatments will be collected, but 
analyzed separately from data obtained during the first treatment in the trial.  Rare patients who 
are not eligible for either treatment will continue to be followed, anticipating that their eligibility 
may change and treatment will be possible. There is no specific standard-of-care as to when 
participants are switched to alternate therapy, because failure of treatment is highly unusual and 
poorly documented with either type of therapy, except when there is noncompliance or other 
reasons for not completing the therapeutic procedures as planned. The study will provide 
important new information on patients who need to change therapy for PCT. Participants also 
have the option of withdrawing from the study at this or any other time.   
4.R. Data analysis and statistical considerations.  This was originally designed as a 
randomized noninferiority clinical trial, with inclusion of participants who could not be 
randomized in a substudy, but with the same treatment and follow up for all participants.  We 
had anticipated that 90% of participants could be randomized, and the intent was to include only 
randomized participants in the noninferiority analysis.  A planned interim analysis, which has 
been published (45) found that more than half the participants could not be randomized due to 
medical reasons or patient preference; therefore the interim data was analyzed for the 
randomized participants and for all participants.  Although the treatments appeared equivalent in 
terms of time to remission, statistical significance was not achieved.  Therefore, after formation 
of the Porphyrias Consortium (PC), the study was continued as a PC study with the goal of 
enrolling enough participants for a statistically significant result.  Based on the interim analysis, 
the PC investigators identified additional value in continuing this study to enroll a larger number 
of participants.  1.) Like the PC Longitudinal Study (LS), PC7201, this study enrolls participants 
with well documented PCT who are characterized for all of the known susceptibility factors, 
which are multiple but different for individual participants.  But unlike the LS, this study carefully 
documents treatment response and remission, and allows assessment of treatment response 
and durability as related to specific, multiple susceptibility factors, some of which may change 
over time.  2.) This study will allow examination of the importance of newly-identified or 
postulated susceptibility factors, not only for contributing to development of PCT but for affecting 
treatment responses.  3.) This study is developing for the first time reference information on time 
to remission for phlebotomy, presently for comparison with hydroxychloroquine.  But additional 
treatment arms may be added to the study as new therapeutic approaches are developed in the 
future.   
 
The study will continue as a more pragmatic study relevant to clinical practice, with assignment 
to treatment based on uniform criteria and randomization only of participants eligible for both 
treatments, to avoid unnecessary bias.  Therefore, it will be a two-group study with no substudy.  
A descriptive approach to data analysis will be employed, with clinically relevant comparisons of 
the two treatments, rather than a noninferiority analysis.   
Inclusion of all available participants rather than just the minority that can be randomized has a 
number of advantages.  Participants eligible for both treatments (and therefore eligible for 
randomization) might respond differently than those who are not, since some of the reasons that 
make participants ineligible for one treatment relate to certain susceptibility factors and to prior 
treatment experience.  Exclusion of a majority of participants from treatment comparisons also 
would make the study less pragmatic and less clinically relevant.  In the interim analysis, 
randomized and nonrandomized participants did not differ in terms of clinical and demographic 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 40 
features, but such important comparisons would be more meaningful with a larger number of 
participants.   In the amended study, participants who are eligible for both treatments are to be 
randomized as a method for choosing between treatments that is needed in the study to avoid 
bias, but not as a study design feature.  Bias might arise, for example, from existing site-specific 
treatment preferences.   
A total of at least 100 participants will be assigned, based on medical criteria, preference, or (if 
eligible for both treatments) by randomization, to one of these standard treatment groups.  
CRFs will be completed for each patient, including porphyrin levels, and data entered into the 
study database.  This database is designed by and housed at the Data Management and 
Coordinating Center (DMCC) at the University of South Florida in Tampa.  The DMCC is 
supported by the NIH Rare Diseases Clinical Research Network and serves as the secure 
repository for de-identified data for all consortia in the Network. Upon approval from the UTMB 
IRB and the Porphyrias Consortium DSMB, data from patients previously enrolled in this study 
at UTMB starting in 2006 before the study was a RDCRN study will be entered into the 
database. Subjects will be contacted to give their consent for this data transfer to the DMCC 
and storage in a federal data repository.  For subjects who are now deceased consent will be 
obtained from next of kin.  For subjects who cannot be re-contacted or where the next of kin 
cannot be re-contacted, approval of the UTMB IRB and the Porphyrias Consortium DSMB will 
be sought for this data transfer. Transferring this previously collected de-identified data is not 
expected to cause any increased risks to subjects.  Data will be verified and edited where 
necessary for completeness and consistency by comparison with source documents.  Study 
outcomes, such as time to achieving biochemical endpoints, will be determined from this data.  
As was found in the interim analysis, assignment to the two groups is unlikely to be equal, and 
more will be assigned to phlebotomy than to hydroxychloroquine.  As in the interim analysis, 
times to achieving measures of remission are not expected to be substantially different for the 
two treatment groups.  Effects of multiple susceptibility factors and other clinical and 
demographic features on treatment response and durability will be further examined.  Outcome 
measures such as time to remission will be compared using Cox proportional models to study 
the effects of susceptibility factors on the hazard ratio to compare the two treatments. All 
patients who start treatment will be included in the analysis.  Safety measures will be compared 
more descriptively where the adverse effects of each type of treatment are different.   
The following susceptibility factors for PCT will be summarized and tabulated, and examined for 
balance across treatment groups.  Differences in response based on susceptibility factors will 
be examined by multivariate analysis.  The following susceptibility factors will be emphasized in 
this analysis:  
1. 
Alcohol use (presence or absence) 
2. 
Smoking (presence or absence) 
3. 
Estrogen use (presence or absence) 
4. 
Hepatitis C (presence or absence) 
 
5. 
HIV (presence or absence) 
6. 
UROD mutations (presence or absence) 
7. 
HFE mutations (presence or absence of C282Y and H63D, and specific genotype 
combinations) 
The analysis regarding susceptibility factors will take into consideration that some (e.g. 
homozygotes for HFE mutations with high ferritin levels) are medical reasons for assignment to 
one treatment group and not the other.  We recognize that because the number of participants 
in subgroups based on susceptibility factors or combinations of susceptibility factors will be 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 41 
relatively small, and it may not be possible to detect or exclude statistically significant 
differences for all susceptibility factors.  The data is expected to support continuing this study 
with larger numbers of participants, or to suggest whether other studies should be designed to 
clarify the effects of these factors on treatment response and durability.  
Additional modeling will assess factors affecting the frequency of recurrence and seasonality 
effects using logistic regression modeling and log-rank testing, respectively. 
Sample Size and Power.  A sample size calculation was performed to assess power for a study 
assessing the effect of factors on time to remission.  Extremely common or rare factors are 
detected with 80% power for 90 subjects (and some dropout) when the hazard ratios are 2.3 
(alcohol consumption and UROD deficiency), 2.2 (smoking history), 3.2 (estrogen usage), 2.0 
(hepatitis C), and 1.9 (HFE mutations).  In summary, this approach for times to remission leads 
to a sample size of approximately 50 subjects per group.  All analyses were conducted in 
nQuery Advisor Version 5.0 (Janet Elashoff (2002); nQuery Advisor Version 5.0 User's Guide.  
Los Angeles, CA).  
 
5. PROTECTION OF HUMAN SUBJECTS 
 
 
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. 
5.A.  RISKS TO THE SUBJECTS 
Human Subjects Involvement and Characteristics.  The study will enroll up to 100 
subjects age 18 or greater, including nonpregnant females, with well-documented PCT selected 
as described above.  Criteria for inclusion and exclusion are listed above in Research Design 
and Methods.  
Sources of Materials.  Research material will be laboratory information collected before 
and during treatment, as detailed under Methods.  While samples of blood, urine and feces are 
ordinarily collected for clinical purposes in PCT, the number and frequency of urine and blood 
samples in this study will exceed somewhat those usually obtained.   
Potential Risks.  The study involves physical risks.  Risks from phlebotomy and 
venipuncture include pain, bruising, infection, and syncope.  There is a risk of iron deficiency, 
which may cause mild symptoms in the absence of anemia.  Risks from hydroxychloroquine, 
which are generally seen with use of higher doses than in this study, include side effects such 
as nervousness, nightmares and other psychiatric changes, headaches, dizziness, muscle 
weakness, blurred vision, other visual disturbances, nausea, vomiting, diarrhea, abdominal pain 
and hematological changes.  Chloroquine (and presumably hydroxychloroquine) overdose is 
especially dangerous in children.  Hydroxychloroquine poses a risk of retinal damage to the 
fetus, and phlebotomy might impair iron status in both the fetus and the mother, so pregnancy is 
a contraindication for entry into the study.  Specifically in PCT patients, low-dose 
hydroxychloroquine can result in transient increases in photosensitivity and slight increases in 
liver function tests and porphyrin levels.  These are normal and expected in PCT patients being 
treated with hydroxychloroquine. 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 42 
There is also risk of loss of confidentiality.  These risks are not greatly increased 
compared to those involved in standard treatment of PCT.   
5.B.  ADEQUACY OF PROTECTION AGAINST RISKS 
Recruitment and Informed Consent.  Participants with PCT will be recruited for these 
studies through referrals from their physicians and by notices sent to physicians in appropriate 
specialties, as described in Research Design and Methods.  Some participants may be self-
referred or be referred through agencies such as the American Porphyria Foundation and the 
Porphyrias Consortium.  Written informed consent will be obtained using a consent form 
approved by each sites’ Institutional Review Board.   
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 investigator or delegate will explain all aspect of the study 
to the participant and the participant will be given adequate time to read the consent form. The 
participant will have an opportunity to have all their questions answered before signing the 
consent form. The participant’s willingness to participate in the study will be documented in 
writing on the 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.  An additional copy will be placed in the participant’s medical 
record.  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. 
Protection Against Risk.  Potential risks will be minimized by close monitoring by the 
investigators and other study personnel.  Venipuncture and phlebotomy will be carried out only 
by trained personnel.  Participants treated with hydroxychloroquine will be instructed in detail 
about keeping the drug away from children.  Confidentially will be maintained by identifying data 
by Patient Number rather than by participants' names, and by storing study records and any 
copies of medical reports in locked cabinets.  Participants will not be identified by name in 
published reports or presentations.  Any adverse effects that do occur will be managed by a 
study investigator or the patient's physician.  A Data and Safety Monitoring Board will also 
monitor progress of the study and review all adverse events, as described below.   
The PI has obtained an IND (66,042) for use of hydroxychloroquine in the study 
described in this proposal.   
5.C.  POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND 
OTHERS 
Benefits to study subjects.  No benefit for the research subjects in this study can be 
assured, because both treatments offered are available as standard of care treatments without 
enrolling in the study.  It is possible that a better understanding of treatment of PCT will benefit 
the subjects should their disease recur in the future.  The frequent study visits could also 
provide some clinical benefit.   
Potential benefit to society.  The study is likely to benefit future participants and society 
by establishing better guidance for choosing either phlebotomy of low-dose hydroxychloroquine 
for treating PCT, which will enhance health care delivery and lower health care costs.   

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5.D.  IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
This study involves a comparison of two therapies already used for clinical management 
of PCT, and the risks of the two therapies, while different, are generally equivalent, based on 
present knowledge.  Therefore, the study does not involve a degree of risk that is greater than 
standard clinical care.  Moreover, these risks are small relative to the potential benefits to 
participants with PCT individually and as a group and to society.   
The study will lead to improved guidelines for the use of 4-aminoquinolines in treating 
PCT and hopefully in the future product labeling for this indication.   
5.E.  INCLUSION OF WOMEN 
The study will not exclude participants based on gender or ethnicity. PCT is more 
common in men than women, and in women is almost always associated with estrogen use.  
Because we are studying a rare condition, we will have little influence over the gender 
composition of the participants who participate, but will endeavor to include all women with PCT 
who are eligible, including women with child-bearing potential.  Pregnant women will be 
excluded, because there is potential risk to the fetus with either of the treatments under study, 
and we generally recommend delaying treatment until after delivery.  There is no evidence to 
our knowledge that treatment responses are different in women and men with PCT, and we 
expect that the results of this study will be relevant to women even if the subjects are mostly 
men.   
5.F.  INCLUSION OF MINORITIES 
PCT occurs in all races, but in a multiracial population such as ours may be more 
common in light-skinned individuals, who are less protected because they have less melanin 
pigment in the skin.  Blacks may develop manifest PCT less frequently because their greater 
skin pigmentation provides considerable protection against photosensitivity.  Racial or ethnic 
background may also influence the many risk factors, such as ethanol use and hepatitis C, that 
contribute to development of PCT.  Because recruitment for a rare condition such as PCT is 
difficult, we will endeavor to recruit all available participants without regard to race and ethnic 
background.  Our clinical experience indicates that there will be fewer Blacks recognized with 
PCT and entered into the study, but Hispanics will be well represented.  Previous experience 
and published information indicates that race and ethnicity are unlikely to influence 
responsiveness to treatment of PCT, and results in the subjects enrolled in this study will be 
applicable to participants with PCT from any ethnic background.   
The anticipated gender, racial and ethnic composition of the 100 study subjects is shown 
in the table below.   

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Total Planned Enrollment: 100 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
13 
27 
40 
Not Hispanic or Latino 
20 
40 
60 
Ethnic Category Total of All Subjects* 
33 
67 
100 
Racial Categories 
 
American Indian/Alaska Native 
0-1 
0-1 
0-1 
Asian 
0-1 
0-1 
0-1 
Native Hawaiian or Other Pacific Islander 
0-1 
0-1 
0-1 
Black or African American 
3 
7 
10 
White 
30 
60 
90 
Racial Categories: Total of All Subjects * 
33 
67 
100 
*The “Ethnic Category Total of All Subjects” must be equal to the “Racial Categories Total of All 
Subjects.” 
5.G.  INCLUSION OF CHILDREN 
No children with PCT who are less than age 18 will be enrolled into this study.  Younger 
children are expected to be less tolerant of repeated phlebotomies.  Published information 
indicates that treatment methods used in adults with PCT are applicable to children, and there is 
no indication that treatment responses are different.  Therefore, even though the study 
population is mostly adult, the results will be of benefit to children with the disease under study.   
5.H.  DATA AND SAFETY MONITORING PLAN 
The study protocol including amendments will be reviewed and approved by the National 
Institutes of Health (NIH) and by individual center IRB’s.  Participant enrollment may only begin 
with IRB approved consent forms.  
 
This is an interventional phase II study that meets the federal definition of low risk. 
The PI and the investigative team will be primarily responsible for day-to-day data and 
safety monitoring.  Adverse events will be reported to the IRB in accordance with the regulations 
of the IRB at each participating institution, the Data Management and Coordinating Center, the 
DSMB, NIDDK/NCATS and also to the FDA in accordance with IND regulations.   
Observations on participants in the study will be made through scheduled visits, and 
study results and reports of symptoms reviewed as soon as the information is available by the 
PI and research team.  The safety observations are described in detail under Research Design 
and Methods.  The study involves two treatment regimens that are commonly used in clinical 
practice for PCT and already considered safe and effective.  The major emphasis is on 
comparing time to remission rather than overall safety and efficacy.  The primary experimental 
intervention in the study is randomization of participants who are eligible for both treatments.  
The frequency and methods of monitoring are adequate in terms of the risks and complexity of 
the study, which are both relatively low.   

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A Data and Safety Monitoring Board (DSMB) is organized by the NIDDK and the Data 
Management and Coordinating Center (DMCC) for the Rare Diseases Clinical Research 
Network.  The DSMB will review information on study progress and safety information at 6-
month intervals, and may elect to do so more frequently.  Any Significant Adverse Events or 
other information that is reported to the IRB will also be reported to members of the DSMB.  The 
DSMB review every 6 months will include information from the CRFs that are compiled for 
review:  
• 
Number of enrolled subjects and the number providing evaluable data for specific 
study outcomes.   
• 
Efficacy of treatment as recorded on CRFs in all participants to date, to assure 
that participants in the study are making expected progress toward remission of 
PCT 
• 
Safety information recorded on CRFs, including all adverse events (whether 
considered significant or not), side effects, and laboratory safety information 
• 
Any additional information provided by the investigators, the GCRC Research 
Subjects Advocate and others related to the study 
Members of the DSMB will have the opportunity to ask questions of the PI and other 
members of the study team and raise any additional concerns.  The Board deliberations at 6 
month intervals will include presentations by the investigators regarding study progress and 
compiled information, and also discussions that exclude the investigators before final 
recommendations are made.  The Board will be asked to specifically approve continuation of the 
study with or without changes, and whether alternative monitoring plans should be instituted.  
Minutes and other records of the DSMB deliberations will be recorded. 
  
5.H.1. Study Oversight 
 
The Study Chair has primary oversight responsibility of this clinical trial. The NIH 
appointed Data (Observational) and 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, protocol compliance every 6 
months. The D/OSMB makes recommendations to the NIH regarding the continuation status of 
the protocol. 
 
 
Each site’s Primary Investigator and their 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 site 
review.  Adverse events will be reviewed at least every 6 months by the research team.   A 
separate report detailing protocol compliance will also be available from the DMCC for site 
review on a monthly basis. The research team will then evaluate whether the protocol or 
informed consent document requires revision based on the reports. 
 
5.H.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.” 

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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 of 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 by the site investigator using the current 
version of the Common Terminology Criteria for Adverse Events (CTCAE) developed and 
maintained by CTEP at National Cancer Institute. 
 
 
5.H.3. Expected/Known Risks/Discomforts/Adverse Events Associated with Study Intervention 
and Procedures: Definition of Expected Adverse Events 
Hydroxychloroquine.  In PCT, a low-dose regimen of hydroxychloroquine may cause the 
following transient side effects before remission occurs:   
• 
worsening of photosensitivity  
• 
slight increases in liver function tests and porphyrin levels   
Other reported side effects include those listed below, which are generally seen with use of 
higher doses than in this study in patients without PCT.     
• 
headache 
• 
dizziness 
• 
loss of appetite 
• 
nausea 
• 
diarrhea 
• 
abdominal pain 
• 
vomiting 
• 
skin rash 
• 
reading or seeing difficulties (words, letters, or parts of objects missing) 
• 
sensitivity to light 
• 
blurred distance vision 
• 
seeing light flashes or streaks 
• 
difficulty hearing 
• 
ringing in ears 
• 
muscle weakness 
• 
bleeding or bruising of the skin 
• 
bleaching or loss of hair 
• 
mood or mental changes 
• 
irregular heartbeat 
• 
drowsiness 
• 
convulsions 
• 
nervousness 
• 
nightmares 

RDCRN Protocol # 7206                        PCT Treatment               
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• 
other psychiatric symptoms 
• 
muscle weakness 
• 
hematological changes 
• 
overdose is especially dangerous in children 
• 
retinal damage to the fetus if taken during pregnancy 
Other Study Procedures:  
Venipuncture for therapeutic phlebotomies and for obtaining samples for testing:  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.   
Therapeutic phlebotomy might impair iron status, but iron status will be monitored to avoid iron 
deficiency anemia.   
Both hydroxychloroquine and iron deficiency entail risks for the fetus, and iron deficiency is a 
risk to the mother, so pregnancy is a contraindication for entry into the study.   
 
5.H.4. Reporting Timeline 
 
• Within 24 hours (of learning of the event), investigators must 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 must report all other reportable SAEs within 5 working days (of learning of the 
event). 
• All other (suspected) reportable AEs must be reported to the RDCRN within 20 working days 
of the notification of the event or of the site becoming aware of the event. 
 
Local institutional reporting requirements to IRBs, any CRC oversight committee and the FDA, if 
appropriate, remain the responsibility of the treating physician and the Study Chair. 
 
5.H.5. RDCRN Adverse Event Data Management System (AEDAMS) 
Upon entry of a serious adverse event, the DMCC created Adverse Event Data 
Management System (AEDAMS) will immediately notify the Study Chair, site PIs, the Medical 
Review Officer, and any additional agencies  of any reported adverse events via email.  
 
Serious adverse events: There will be an SAE adjudication committee comprised of the site 
investigator where the SAE occurred, the study chair, and the Consortium PI. They will review 
any SAEs that are deemed at least possibly related (possibly related, probably related, definitely 
related) to the study by the site investigator, and will present recommendations for protocol 
changes or ICF changes to NIDDK and the DSMB for consideration if necessary. The SAE 
adjudication committee policy will be reviewed and approved by NIDDK and the DSMB prior to 
initiation. Any changes or modifications to the policy will be submitted for review and approval 
by NIDDK and the DSMB. 
The NIH appointed Medical Review Officer (MRO) reviews the site investigator’s 
assessment of causality of the serious adverse event. The MRO and the sponsor may request 
further information if necessary and possibly request changes to the protocol or consent form as 

RDCRN Protocol # 7206                        PCT Treatment               
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Page 48 
a consequence of the adverse event. A back-up notification system is in place so that any 
delays in review by the MRO beyond a specified period of time are forwarded to a secondary 
reviewer. The Adverse Event Data Management System (AEDAMS) 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 expected adverse events  that are reported to or observed by the 
investigator or a member of his research team will be submitted to the DMCC in a timely fashion 
(within 20 working days). The events will be presented in tabular form and given to the MRO 
and RDCRN DSMB on a bi-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 site investigators and IRBs. 
 
5.H.6. Study Discontinuation  
The NIH, RDCRN DSMB and local IRB's (at their local site) have the authority to stop or 
suspend this trial at any time. This study may be suspended or closed if: 
• 
Accrual has been met 
• 
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 
 
5.H.7. 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.H.8. Data Management 
The results of the history, physical examination and screening laboratory tests will be 
recorded on Case Report Forms (CRFs) prepared for this study.  Information obtained at each 
study visit and from telephone will also be recorded on the CRFs.  The CRFs will incorporate all 
the data needed for final analysis of study results.   
 

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Page 49 
As much as possible data quality is assessed at the data entry point using intelligent on-
line 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.  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. 
 
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.   
 
5.H.9. 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. IRB approval for the protocol must be on file at the DMCC before 
accrual can occur from the clinical site. 
 
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.  When the participant is registered to participate in the study, 
using the DMCC provided web-based registration system; the system will assign a participant ID 
number.  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 code assigned by the DMCC.  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.  In this fashion, no personal identifiers would be accessible to 
the DMCC.  
 
5.H.10. Data Entry 
Data collection for this study will be accomplished with online electronic case report 
forms.  Using encrypted communication links, on-line forms will be developed that contain the 
requisite data fields.   
 
5.H.11. Data Quality Control 
As much as possible data quality is assessed at the data entry point. 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 

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Page 50 
to build these checks into the initial tables and cross tabulations that should reveal any 
remaining data quality issues. 
 
 
 

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Adjarov D, Ivanov E. Clinical value of serum g-glutamyl transferase estimation in 
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Cortés JM, Oliva H, Paradinas FJ, Hernandez-Guío C. The pathology of the liver in 
porphyria cutanea tarda. Histopathology. 1980;4:471-85. 
42. 
Chlumsky J, Malina L, Chlumská A. The effect of venesection therapy on liver tissue in 
porphyria cutanea tarda. Acta Hepato-Gastroenterol. 1973;20:124-30. 
43. 
Seubert S, Seubert A, Stella AM, Guzman H, Batlle A. [Results of treatment of porphyria 
cutanea tarda with bloodletting and chloroquine]. Z Hautkr. 1990;65:223-5. 
44. 
Cainelli T, Padova CD, Marchesi L, Gori G, Rovagnati P, Podenzani SA, et al. 
Hydroxychloroquine versus phlebotomy in the treatment of porphyria cutanea tarda. Br J 
Dermat. 1983;108:593-600. 
45. 
Singal AK, Kormos-Hallberg C, Lee C, Sadagoparamanujam VM, Grady JJ, Freeman 
DH, Jr., et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of 
patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2012;10(12):1402-9. 
46. 
Rocchi E, Gibertini P, Cassanelli M, Pietrangelo A, Borghi A, Pantaleoni M, et al. Iron 
removal therapy in porphyria cutanea tarda:  phlebotomy versus slow subcutaneous 
desferrioxamine infusion. Br J Dermatol. 1986;114:621-9. 
47. 
Rocchi E, Cassanelli M, Ventura E. High weekly intravenous doses of desferrioxamine in 
porphyria cutanea tarda. Br J Dermatol. 1987;117:393-6. 
48. 
Stolzel U, Kostler E, Schuppan D, Richter M, Wollina U, Doss MO, et al. 
Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria 
cutanea tarda. Arch Dermatol. 2003;139(3):309-13. 
49. 
Valls V, Ena J, Enriquez-De-Salamanca R. Low-dose oral chloroquine in patients with 
porphyria cutanea tarda and low-moderate iron overload. J Dermatol Sci. 1994;7(3):169-
75. 
50. 
Easterbrook M. An ophthalmological view on the efficacy and safety of chloroquine 
versus hydroxychloroquine. J Rheumatol. 1999;26(9):1866-8. 
51. 
Thornsvard MAJCT, Guider BA, Kimball DB. An unusual reaction to chloroquine-
primaquine. JAMA. 1976;235:1719-20. 
52. 
Liu AC. Hepatotoxic reaction to chloroquine phosphate in a patient with previously 
unrecognized porphyria cutanea tarda. West J Med. 1995;162(6):548-51. 
53. 
Sweeney GD, Jones KG. Porphyria cutanea tarda: clinical and laboratory features. 
Canad Med Assn J. 1979;120:803-7. 
54. 
Felsher BF, Redeker AG. Effect of chloroquine on hepatic uroporphyrin metabolism in 
patients with porphyria cutanea tarda. Medicine. 1966;45:575-83. 
55. 
Taljaard JJF, Shanley BC, Stewart-Wynne EG, Deppe WM, Joubert SM. Studies on low 
dose chloroquine therapy and the action of chloroquine in symptomatic porphyria. Br J 
Derm. 1972;87:261-9. 
56. 
Kordac V, Semradova M. Treatment of porphyria cutanea tarda with chloroquine. Br J 
Derm. 1974;90:95-100. 
57. 
Ashton RE, Hawk JLM, Magnus IA. Low-dose oral chloroquine in the treatment of 
porphyria cutanea tarda. Br J Dermatol. 1984;3:609-13. 

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58. 
Malkinson FD, Levitt L. Hydroxychloroquine treatment of porphyria cutanea tarda. Arch 
Dermat. 1980;116:1147-50. 
59. 
Vizethum W, Dahlmann D, Bolsen K, Goerz G. Influence of chloroquine (Resochin) on 
hexachlorobenzene (HCB) induced porphyria of the rat. Arch Dermat Res. 
1979;264:125. 
60. 
Goerz G, Bolsen K, Merk H. Influence of chloroquine on the porphyrin metabolism. Arch 
Dermatol Res. 1985;277:114-7. 
61. 
Goerz G, Bolsen K, Seuwen P, Schmitter H, Merk H, Lissner R. Effects of chloroquine 
and hydroxychloroquine on hexachlorobenzene-induced porphyria in rats. IARC Sci 
Publ. 1986;77:513-5. 
62. 
Cohen SN, Phifer KO, Yielding KL. Complex formation between chloroquine and 
ferrihaemic acid in vitro, and its effect on the antimalarial action of chloroquine. Nature. 
1964;202:805-6. 
63. 
Scholnick PL, Epstein J, Marver HS. The molecular basis of the action of chloroquine in 
porphyria cutanea tarda. J Invest Dermatol. 1973;61:226-32. 
64. 
Egger NG, Goeger DE, Anderson KE. Effects of chloroquine in hematoporphyrin-treated 
animals. Chemico-Biological Interactions. 1996;102:69-78. 
65. 
Egger NG, Pow-Sang M, Johnson SA, Motamedi M, Anderson KE, Orihuela E. 
Accumulation of porphyrins in plasma and tissues of dogs after ∂-aminolevulinic acid 
administration: implications for photodynamic therapy. Pharmacology. 1996;52:362-70. 
66. 
Pimstone NR, Mukerji SK, Saicheur T, Lee J. Utility of chloroquine therapy in two 
patients with congenital erythropoietic porphyria (CEP). In: Blake D, McManus J, 
Ratnaike S, Hill J, Poulos V, Rossi E, eds. Porphyrins, Porphyrias and Photodynamic 
Therapy (Conference Proceedings), 1993. Melbourne, Australia, November 22-26. 
67. 
Elder GH. Porphyria cutanea tarda. Semin Liver Dis. 1998;18(1):67-75. 
68. 
Kordac V, Jirsa M, Kotal P, Kalab M, Cervinka J, Kotyk A, et al. Agents affecting 
porphyrin formation and secretion: Implications for porphyria cutanea treatment. Semin 
Hematol. 1989;26:16-23. 
69. 
Chlumska A, Chlumsky J, Malina L. Liver changes in porphyria cutanea tarda patients 
treated with chloroquine. Br J Dermatol. 1980;102:261-6. 
70. 
Daniell WE, Stockbridge HL, Labbe RF, Woods JS, Anderson KE, Bissell DM, et al. 
Environmental chemical exposures and disturbances of heme synthesis. Environmental 
Health Perspectives. 1997;105, Suppl 1:37-53. 
71. 
Bonkovsky HL, Barnard GF. Diagnosis of porphyric syndromes: a practical approach in 
the era of molecular biology. Semin Liver Dis. 1998;18(1):57-65. 
72. 
Hahn M, Bonkovsky HL. Multiple chemical sensitivity syndrome and porphyria. A note of 
caution and concern. Arch Intern Med. 1997;157:281-5. 
73. 
Mauzerall D, Granick S. The occurrence and determination of δ-aminolevulinic acid and 
porphobilinogen in urine. J Biol Chem. 1956;219:435-46. 
74. 
Schwartz S, Edmondson P, Stephenson B, Sarkar D, Freyholtz H. Direct 
spectrofluorophotometric determination of porphyrin in diluted urine. Ann Clin Res. 
1976;8:156-61. 
75. 
Sassa S, Granick JL, Granick S, Kappas A, Levere RD. Studies in lead poisoning. I. 
Microanalysis of erythrocyte protoporphyrin levels by spectrofluorometry in the detection 
of chronic lead intoxication in the subclinical range. Biochem Med. 1973;8:135-48. 
76. 
McManus J, Blake D, Ratnaike S. An assay of uroporphyrinogen decarboxylase in 
erythrocytes. Clin Chem. 1988;34:2355-7. 
77. 
Lockwood WH, Poulos V, Rossi E, Curnow DH. Rapid procedure for fecal porphyrin 
assay. Clin Chem. 1985;31:1163-7. 

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78. 
Marmor, M. F., U. Kellner, T. Y. Lai, J. S. Lyons, W. F. Mieler and O. American Academy 
of (2011). "Revised recommendations on screening for chloroquine and 
hydroxychloroquine retinopathy." Ophthalmology 118(2): 415-422  
79. 
Kellner U, Kraus H, Foerster MH. Multifocal ERG in chloroquine retinopathy: regional 
variance of retinal dysfunction. Graefes Arch Clin Exp Ophthalmol. 2000;238(1):94-7. 
80. 
Alcock NW. A hydrogen peroxide digestion system for tissue trace metal analysis. Biol 
Trace Elem Res. 1987;13:363-70. 
81. 
Liang L, D'Haese PC, Lamberts LV, De Broe ME. Direct determination of iron in urine 
and serum using graphite furnace atomic absorption spectrometry. Analyst. 
1989;114(2):143-7. 
 
 
 

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7. Appendices 
A. Informed Consent Template: 
 
You are being asked to participate as a subject in this research project because you have 
porphyria cutanea tarda (PCT).   
 
The title of the project is "Therapeutic Studies in Porphyria Cutanea Tarda.”  The study is 
directed by Karl E. Anderson, M.D.  The Sponsor of the study is the National Institutes of Health 
(NIH).  Portions of Dr. Anderson’s and his research team’s salaries may be paid by this grant.  
This study is a multi-center study directed by the Rare Diseases Clinical Research Network, 
Porphyria Consortium. UTMB is the lead center and there are 5 other porphyria centers 
participating: 1. The University of California, San Francisco; 2. The University of Alabama, 
Birmingham; 3. Carolinas Medical Center, Charlotte, NC; 4. Mount Sinai School of Medicine, 
New York; 5. The University of Utah, Salt Lake City. 
 
1.  PURPOSE OF STUDY 
 
The purpose of this study is to compare two treatments for PCT.  Phlebotomy (removal of blood) 
is considered the preferred treatment at most centers.  Treatment with hydroxychloroquine is an 
alternative that might be used more widely if more information were available comparing the two 
treatments.  The study aims to compare how rapidly PCT improves with the two treatments, and 
determine how frequently PCT recurs after each.   
 
2.  PROCEDURES 
 
The study will be carried out at UTMB in the outpatient part of the Institute for Translational 
Sciences- Clinical Research Center (ITS-CRC) or in another UTMB clinic, such as the GI Clinic.   
At the beginning of the study, there will be a screening visit to be sure you are eligible.  You can 
enter the study if you are eligible for either treatments.  The screening visit will include recording 
your medical history, a physical examination and blood, urine and stool tests that are standard 
for documenting a diagnosis of PCT and evaluating the stage of the condition.   
 
The following conditions are needed for you to enter the study:  
 
• 
age 18 or greater 
• 
well documented PCT 
• 
you are willing to consent, after you are provided with the information you need 
• 
if you are a woman capable of becoming pregnant, you are willing to avoid becoming 
pregnant during treatment and use an effective contraceptive method 
 
The following are reasons for you to be excluded from the study: 
 
• 
skin problems due to a type of porphyria other than PCT 
• 
pregnancy 
• 
previous treatment as a participant in this protocol. 
• 
prior treatment by phlebotomy, hydroxychloroquine or chloroquine within one month, 
unless baseline labs are available before treatment was started 
• 
unwilling or unable to comply with the protocol 

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The following will exclude you from being treated with hydroxychloroquine, but you may still be 
treated by phlebotomy:   
 
• 
unwilling to consider this form of treatment 
• 
psoriasis (a skin disease) 
• 
lactation (nursing mothers) 
• 
significant disease of the retina (light-sensitive part of the eye) 
• 
glucose-6-phosphate dehydrogenase deficiency (a genetic condition of the blood 
that is possibly made worse by hydroxychloroquine) 
• 
advanced liver disease or substantially abnormal liver tests 
• 
advanced kidney disease 
• 
recent and continued heavy use of alcohol  
• 
recent and continued use of drugs toxic to the liver, such as acetaminophen, 
isoniazid or valproic acid 
• 
marked excess body iron or certain genetic features associated with an iron overload 
condition called hemochromatosis 
• 
poor tolerance of hydroxychloroquine in the past 
 
The following will exclude you from being treated with phlebotomy, but you may still be treated 
with hydroxychloroquine: 
 
• 
unwilling to consider this form of treatment 
• 
bone marrow disease and anemia 
• 
very poor veins 
• 
poor tolerance of phlebotomies in the past 
 
If you have exclusions for both treatments, you may still be treated by the method that your 
doctors think is most likely to be safe and effective.   
Patients who have already started treatment may enter the study if there is sufficient information 
about the start of treatment and their treatment regimen is consistent with what is provided in 
this study.   
 
PCT is always associated with some liver abnormalities, which can resemble those due to other 
liver conditions.  Therefore, tests will be done as part of your medical care to rule out other liver 
diseases, including other types of hepatitis (such as hepatitis B) and diabetes.  A liver 
ultrasound and a liver biopsy are not required as a part of this study, but may be recommended 
as part of your medical care.   
 
You will also be tested for other conditions that would make treatment of PCT less effective, 
such as diseases affecting the kidneys or bone marrow.   
 
As part of your treatment for PCT, you have been advised to avoid things that make PCT worse, 
such as drinking alcohol, smoking, estrogens, iron pills and certain drugs.  You should also avoid 
ultraviolet light (sunlight, tanning studios, etc.) until your condition has been successfully treated.  
You can avoid sunlight by wearing protective clothing or remaining indoors during the day.   
 
Entering the study.  When you enter the study, samples will be obtained to document the 
diagnosis of PCT.  This will require samples of blood, urine (24 hour) and stool for tests that are 

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standard for diagnosing PCT.  Also, a history and physical examination will be done.  In 
addition, follow-up visits will be scheduled every 2 months for an additional 6 months. 
Information will be collected and laboratory tests done to see which of the following risk factors 
for PCT are present:  
 
1. Alcohol usage, including amount, duration and how recent 
2. Smoking, including amount, duration and how recent 
3. Estrogen use 
4. Hepatitis C (blood tests) 
5. HIV (blood test for the virus that causes AIDS) 
6. Genetic test for hemochromatosis (an iron overload condition) 
7. Enzyme test for UROD in red blood cells.  (UROD, or uroporphyrinogen decarboxylase, 
may be in part an inherited deficiency in about 20% of PCT patients.)   
8. Genetic test for UROD deficiency.   
 
Genetic testing for UROD will be done at Icahn School of Medicine at Mt. Sinai in New York 
City.  The purpose is to look for changes in DNA (mutations in the genetic material) in PCT.  
You may be asked to sign a separate consent form from that institution.   
 
Your DNA sample: 
• 
will have your name on it 
• 
may be stored indefinitely 
• 
can be used only by the porphyria research team at UTMB or another institution 
researching porphyria 
• 
may be used in the future to identify other mutations that are not anticipated now, 
but may lead to a better understanding of porphyria 
 
Any research done on your DNA now or in the future must have the approval of the 
UTMB Institutional Review Board (IRB), which oversees research on humans.  You may 
request that your DNA sample be withdrawn or destroyed at any time. 
 
You will be tested for HIV as part of the screening process and have appropriate 
counseling regarding HIV testing.  If you unexpectedly test positive, you will be 
contacted by a qualified medical provider and receive counseling regarding the impact of 
HIV on your physical, mental, and social well-being and be given help in finding further 
medical care for HIV infection.  The results of your HIV test and other tests will be 
confidential, but will appear in your UTMB hospital medical records.  Positive results will 
be reported to appropriate state and local agencies as required by law.   
 
Assigning treatment.  You will either be treated by low-dose hydroxychloroquine or repeated 
phlebotomy.  The treatments to be compared in this study are both considered effective, but it is 
not known how quickly each of these treatments works. You will be assigned to one of these 
treatments based on your preference and whether you are medically eligible for one treatment 
but not the other.  If you are eligible and willing to consider either treatment, you will be 
assigned by randomization.  (Like the flip of a coin.)  The purpose of randomization is to avoid 
introducing unnecessary bias into the study.   
 
If your treatment needs to be changed during the study, you will be assigned the other treatment 
and continue in the study.   
 

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Phlebotomy.  “Phlebotomy” means removing blood through a needle that is inserted into a vein.  
If you are treated by this method, the standard method will be followed.  One unit (450 ml, which 
is approximately one pint) of whole blood will be removed from an arm vein at the Blood Bank or 
the ITS-CRC at intervals of approximately 2 weeks.  This will be like donating blood, except that 
the blood removed will be discarded.  This is the most effective way of removing iron from the 
body, because the red blood cells contain large amounts of iron.  As blood is removed, more red 
blood cells are made in your bone marrow, which gradually uses up excess iron in your body.   
A needle will be inserted into an arm vein each time a unit of blood is removed.  Phlebotomies 
will be repeated until a blood test (serum ferritin) shows that enough iron has been removed.  
This test is a good indicator of how much iron is in your body.  The aim is to reduce the ferritin 
value to about 15 ng/ml.  At this point phlebotomies are stopped.   
 
To avoid your becoming anemic during this treatment, a hematocrit or hemoglobin test will be 
done before each phlebotomy.  If these are considered to be too low, removing a unit of blood 
will be postponed until the next visit in 1-2 weeks.   
 
Hydroxychloroquine.  If you are treated with hydroxychloroquine, the standard treatment by this 
method will be followed.  The dose will be 100 mg twice weekly until at least one month after the 
porphyrins in your blood plasma and urine become normal.  You will be provided this medication 
as part of the study.  You will be provided a diary to record when you take each dose.  At each 
study visit, you will bring the medication bottle with you to see if you have missed any doses and 
to be sure you have an adequate supply to last until the next visit.  The maximum duration of 
treatment with hydroxychloroquine will be 12 months.   
You will be supplied with tablets of hydroxychloroquine that have been cut in half.  Each half 
tablet is 100 mg.  So the dose will be one of these half-tablets taken twice weekly.   
Hydroxychloroquine sometimes causes damage to the retina of the eye, although this is rare 
and usually only with larger doses for longer periods of time than in this study.  As a precaution, 
your eyes will be examined for retinal damage before starting hydroxychloroquine, and then at 
least yearly and at the end of treatment.    
 
Hydroxychloroquine is much more toxic in children than in adults.  Therefore, you are advised to 
keep the drug out of the reach of children.   
 
The effect of hydroxychloroquine on the unborn child is not known.  But studies in animals 
suggest that it may be harmful to the eyes.  Therefore, you should not take chloroquine if you 
are pregnant or intend to become pregnant during the study.  Women who are capable of 
becoming pregnant will be tested for pregnancy every month during the study if they are taking 
chloroquine.  The drug will be stopped if you become pregnant.   
 
Study visits during treatment.  You will be asked to return to the ITS-CRC or to another UTMB 
clinic for study visits to provide a blood sample and a urine sample and determine the progress 
of the treatment.  Visits will be every 2-4 weeks until the amount of porphyrins in your plasma is 
normal.  After that, visits will be every 4-8 weeks, until the porphyrins in both plasma and urine 
are completely normal.  The number of visits will be approximately the same with either 
treatment.   
 
At each visit you will complete a questionnaire about your symptoms and progress.  The skin 
will be examined and the nature and severity of any lesions recorded.  Photographs of the skin 
may be taken.  Blood and urine samples will be obtained at each visit to determine the course of 
treatment and look for adverse effects.   
 

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Optionally, patients with both PCT and hepatitis C may have another tube of blood drawn on 5 
visits to see the effect of treatment for PCT on the amount of hepatitis C virus in the blood.  
Optionally, urine samples may be collected to measure iron concentration in urine.   
 
End of treatment.  Treatment by phlebotomy will end when the target ferritin value is reached.  
Hydroxychloroquine treatment will end at least one month after the plasma and urine porphyrins 
are completely normal.   
 
After the end of treatment.  After treatment is completed, you will be asked to return for follow-
up visits every 3-6 months for at least 5 years.  The purpose of these later visits is to see if PCT 
recurs more or less frequently depending upon which treatment has been given.   
 
No more than 30 mL (one tablespoon) of blood will be taken every 2 weeks during this study.  
Also, if you are treated by phlebotomy, one unit of blood will be removed at approximately 2-
week intervals until that treatment is completed.   
 
3.  PROCEDURES RELATED ONLY TO THE RESEARCH 
 
This study compares two accepted treatments for PCT, to see which acts more quickly and how 
often PCT recurs after each.  Because both treatments are accepted, many procedures are 
considered standard of care, and would be done if you were not in the study.  The following is a 
list of the procedures, which are already described above, that might not be done if you were 
not in the study.   
1.  Assignment to treatment at random, if you are eligible for and willing to consider both 
treatments.   
2.  More tests may be done to be sure you are suitable for either treatment, rather than just one 
treatment.  However, the same tests might be done outside the study to decide which treatment 
should be chosen.   
3.  Visits during and after treatment are considered standard of care, but might be somewhat 
more frequent than would always be done if you were not in the study.   
 
4. PROCEDURES NOT RELATED TO THIS RESEARCH (i.e., standard of care) 
 
Tests that are important for proper diagnosis and treatment of porphyria are considered 
standard of care. These tests and procedures that would otherwise be required for evaluation 
and treatment of your condition will be your responsibility or will need to be covered by your 
health insurers.  
 
5.  RISKS OF PARTICIPATION 
 
The study involves potential risks and discomforts.  But these risks will not be very different from 
standard treatment by either method.   
 
Risks from phlebotomy and venipuncture include pain, bruising, dizziness, fainting and infection.  
There is a risk of iron deficiency, which may cause mild symptoms even without causing 
anemia.   
 
Hydroxychloroquine removes porphyrins from the liver into the blood stream, so the porphyrins 
can then be excreted in the urine.  As a result, in the first few weeks of treatment, porphyrin 
levels and skin symptoms may increase before they start to decrease.  Liver function tests may 

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also worsen somewhat during this time.  Therefore, you should avoid sunlight during the first 
few weeks of treatment.   
 
Side effects from hydroxychloroquine, which are generally seen with use of higher doses than in 
this study, can include nervousness, nightmares and other psychiatric changes, headaches, 
dizziness, muscle weakness, blurred vision, other visual disturbances that are sometimes long 
lasting, nausea, vomiting, diarrhea, abdominal pain and hematological changes.  Blurring, 
trouble reading, eye pain and other disturbances may be due to effects of the drug on the back 
of the eye (retina).  If eye disturbances occur, you should notify the study team immediately.  
This drug can cause permanent damage to the retina, although this is rare, and unlikely at the 
dosage used in this study.   
 
Hydroxychloroquine may also be harmful to the unborn child, especially to the eyes, although 
this risk is not known with certainty.  Hydroxychloroquine overdose is very dangerous for young 
children.  Therefore, it is important we discuss with you how to keep it away from children.   
 
The investigative team will make every effort to rapidly identify and treat any undesirable effects.  
In the event of any unusual reaction you will be medically managed by the investigators and 
other physicians at UTMB.   
 
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.  
There is also risk of loss of confidentiality of sensitive personal, medical and genetic information.  
However, the investigative team will take precautions to keep all personal information about you 
confidential and be sensitive to any findings that might cause mental or social discomfort.   
 
6.  NUMBER OF SUBJECTS PARTICIPATING AND THE DURATION OF YOUR 
PARTICIPATION 
 
A total of up to 100 patients with PCT will participate at UTMB and up to 5 other centers in the 
United States.  Both women and men will be included.  Pregnant women will not be included.   
The length of time needed to complete the treatment itself will be the same as if you were not in 
the study, and should be within 12 months.  You will participate in the study with visits to the 
ITS-CRC or an outpatient clinic every 2-4 weeks until the plasma porphyrin concentration 
becomes normal, then every 4-8 weeks until plasma and urine porphyrins are completely 
normal.  After that, visits will continue every 3-6 months for the at least 5 years to compare how 
often PCT recurs after each treatment.   
 
7.  BENEFITS TO THE SUBJECT 
 
There may be no direct benefit to you for participating in this research study.  Either treatment 
might be available to you if you are not in the study.  The study is likely to lead to a better 
understanding of the treatment of PCT, which may benefit you in the future.   
Some of the laboratory information obtained during these studies may be used to manage your 
medical condition, and you can give your doctor permission (through a “release of information” 
form) to request this information.   
 
8.  BENEFITS TO SOCIETY 
 

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The findings of this study may benefit other patients with PCT and society by providing a better 
understanding of the treatment of this disease and by determining how quickly these two 
treatments work and how often PCT recurs after each treatment.   
 
9.  OTHER CHOICES (ALTERNATIVE TREATMENT) 
 
You may choose to not participate in this study, and either of these treatments 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.   
 
10.  REIMBURSEMENT FOR EXPENSES 
 
You will be reimbursed for parking with a parking token, and offered reimbursement for travel 
costs based on mileage driven at 45¢ per mile up to $90. 
 
11.  COMPENSATION FOR RESEARCH RELATED INJURY 
 
If you are physically injured because of any substance given to you or procedure performed on you 
under the plan for this study, UTMB will provide you with the appropriate medical treatment. Your 
insurance company will be billed and any charges not covered by your own insurance or health 
care program will be provided at no cost to you.  You will be responsible for paying any costs related 
to illnesses and medical events not associated with being in this 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. Questions about compensation may be directed to the study doctor.   
 
12. COSTS OF PARTICIPATION 
 
There will be no charge to you for any tests and procedures directly related to the study.  Tests 
and procedures, including phlebotomies, that would otherwise be required for evaluation and 
treatment of your condition will be your responsibility or will need to be covered by your health 
insurers.  Additional funds may be available for such costs for patients without insurance.  
Hydroxychloroquine half tablets will be provided at no cost.   
 
13.  USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
 
Study records that identify you will be kept confidential as required by law. Federal privacy 
regulations provided under the Health Insurance Portability and Accountability Act (HIPAA) 
provide safeguards for privacy, security, and authorized access of your records.  These 
regulations require UTMB to obtain an authorization from you for the use and disclosure of your 
health information.   By signing this consent form, you are authorizing the use and disclosure of 
your health information for the purpose of completing the research study.  Except when required 
by law, you will not be identified by name, social security number, address, telephone number, or 
any other direct personal identifier in study records disclosed outside of the University of Texas 
Medical Branch (UTMB). For records disclosed outside of UTMB, you will be assigned a unique 
code number. The key to the code will be kept in a locked file in the office of Dr. Anderson and 
his coworkers.   
 
As part of the study, the study team may report the results of your study-related tests to a drug 
company, regulatory agencies or other recipients.  While these recipients may understand the 
importance of protecting the confidentiality of your health information, UTMB cannot guarantee 

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the confidentiality of your health information or protect from further disclosures once these 
recipients receive your health information.   
 
If you sign this form, you are giving us permission to collect, use and share your health 
information.  You do not need to sign this form.  If you decide not to sign this form, you cannot 
be in the research study.  We cannot do the research if we cannot collect, use and share your 
health information.  Whether or not you agree to the research project or give us permission to 
collect, use or share your health information will not affect the care you will be given at UTMB.   
 
Dr. Anderson and his coworkers will use and disclose your study related test results both to 
treat you and to complete the research study.  These would include laboratory tests such as 
your blood counts and tests to measure the function of your liver and kidneys, for example. 
Some of these tests would have been done as part of your regular care.  These test results will 
be recorded in your medical record. You may see or receive a copy of any research information 
that will be included in your medical record.  For all other health information we collect on you 
that will not be included in your medical record, you may not be allowed to access or receive a 
copy of the information until the conclusion of the study. 
 
Your records may be reviewed in order to meet federal or state regulations.  Reviewers may 
include, for example, representatives of a drug company that might be interested in developing 
a treatment for your type of porphyria, the Food and Drug Administration and UTMB.  This 
authorization for the use and disclosure of your health information as described above expires 
upon the conclusion of the research study except for FDA regulated studies.  For FDA regulated 
studies, the study sponsor and government agencies, such as the FDA may review your records 
after the study ends.   
 
If you change your mind later and do not want us to collect or share your health information, you 
need to contact the researcher listed on the attached consent form by telephone or by letter.  You 
need to say that you have changed your mind and do not want the researcher to collect and share 
your health information.  You may also need to leave the research study if we cannot collect any 
more health information.  We may still use the information we have already collected.  We need to 
know what happens to everyone who starts a research study, not just those people who stay in it. 
The results of this study may be published in scientific journals without identifying you by name.   
 
We will keep your study records confidential.  However, certain people may need to see your 
study records.  By law, anyone who looks at your records must keep them completely 
confidential.  The only people who will be allowed to see these records are: 
• 
The research team, including the Principal Investigator, study coordinator, research 
nurses, and all other research staff.   
• 
The UTMB Institutional Review Board (IRB) and the staff that work for the IRB.  
• 
People from the federal Food and Drug Administration (FDA). 
• 
People from the National Institutes of Health (NIH), who sponsored this study.  
• 
People from the Department of Health and Human Services (DHHS).    
 
 
Transfer of Data to DMCC 
 
The clinical information collected for this study will be stored at the National Institutes of Health 
Office of Rare Diseases Research designated Rare Diseases Clinical Research Network Data 
Management Center and also sent to a Federal data repository. The data management center 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 64 
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 only using a 
study ID. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website 
will include a summary of the results. You can search this website at any time. 
 
14.  ADDITIONAL REQUIRED CLAUSES 
 
1. 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 adverse reaction (bad side effect), you 
should immediately contact Dr. Karl E. Anderson or Dr. Csilla Hallberg at 409-772-4661 or, if 
after normal office hours, at 409-772-1218.   
 
2. Your participation in this study is completely voluntary and you have been told that you may 
refuse to participate or stop your participation in this project at any time without penalty or loss 
of benefits and without jeopardizing your medical care at UTMB.  If you decide to stop your 
participation in this project and revoke your authorization for the use and disclosure of your 
health information, UTMB may continue to use and disclose your health information in some 
instances.  This would include any health information that was used or disclosed prior to your 
decision to stop participation and needed in order to maintain the integrity of the research 
study.  If there are significant new findings or we get any information that might change your 
mind about participating, we will give you the information and allow you to reconsider whether 
or not to continue.   
 
3. If you have any complaints, concerns, input or questions regarding your rights as a subject 
participating in this research study or you would like more information, you may contact the 
Institutional Review Board Office , at (409) 266-9475. 
 
The purpose of this study, procedures to be followed, risks and benefits have been explained to 
you.  You have been allowed to ask questions and your questions have been answered to your 
satisfaction.  You have been told who to contact if you have additional questions.  You have read 
this consent form and voluntarily agree to participate as a subject in this study.  You are free to 
withdraw your consent, including your authorization for the use and disclosure of your health 
information, at any time.  You may withdraw your consent by notifying Dr. Anderson at 409-772-
4661.  You will be given a copy of the consent form you have signed.   
 
Informed consent is required of all persons in this project.  Whether or not you provide a signed 
informed consent for this research study will have no effect on your current or future relationship 
with UTMB. 
 
 
 
 
Date 
 
Signature of Subject 
 
Using language that is understandable and appropriate, I have discussed this project and the items 
listed above with the subject and/or his/her authorized representatives. 
 
 
 
 
Date 
 
Signature of Person Obtaining Consent 
 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 65 
 
 
 
 

RDCRN Protocol # 7206                        PCT Treatment               
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Page 66 
B. Patient Compliance Chart for Hydroxychloroquine Use 
 
 
Name_________________________
UH # _________________________
Date of Birth___________________________
Hydroxychloroquine Use Record
Month
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
GCRC Protocol 682
Mark an 
X
the day you take your medication
IRB # 92-435
Bring this chart with you during each clinic visit to schedule next visit.

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 67 
C. Report Form for Phlebotomies 
 
 
Phlebotomy facility: ________________________________ Date of Phlebotomy : ________ 
 
Hematocrit or Hemoglobin level documented prior to phlebotomy (include reference range): 
__________________________________________________ 
Volume of blood removed: __________mL 
Venous access: _________________________ 
Other tests/samples collected: _________________________________________________ 
Side effects: _______________________________________________________________ 
Other comments or observations: ______________________________________________ 
_________________________________________________________________________ 
 
 
Signature of medical personnel overseeing phlebotomy: ___________________ 
 
 

RDCRN Protocol # 7206                        PCT Treatment               
V3 Date: 25FEB2020 
Page 68 
D.  Patient Compliance Chart for Phlebotomies 
 
Name_________________________
UH # _________________________
Date of Birth___________________________
Phlebotomy Record
Month
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
X
Bring this chart with you to each clinic visit.
Mark an 
on each day that a phlebotomy is done