A Double-blind, Randomized, Placebo-controlled, Parallel Group Trial on the Efficacy and Safety of PanhematinTM in the Treatment of Acute Attacks of Porphyria
Phase: PHASE2
Conditions: Acute Porphyrias
Sponsor: The University of Texas Medical Branch, Galveston

RDCRN Protocol # 7203                         Panhematin™ Phase 2              Version Date: 28SEP2015 
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Rare Diseases Clinical Research Network 
 
Porphyrias Consortium 
 
Clinical Study Protocol 
 
 
A double-blind, randomized, placebo-controlled, parallel group trial 
on the efficacy and safety of PanhematinTM in the treatment of 
acute attacks of porphyria 
 
Trial phase: II 
 
 
 
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 
 
 
 
Participating Institutions/Investigators Table  
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. 
NIH Approved 12-02-15

RDCRN Protocol # 7203                         Panhematin™ Phase 2              Version Date: 28SEP2015 
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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: 
Ilona Nekayeva, MD,PhD, Linda Ede, MD 
 
 
Data Management and Coordinating Center Principal Investigator: Jeffrey Krischer, PhD 
Contact: 
Carrie Light, Research Project Manager 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NIH Approved 12-02-15

RDCRN Protocol # 7203                         Panhematin™ Phase 2              Version Date: 28SEP2015 
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Table of Contents 
1. 
Introduction ............................................................................................10 
1.1 
Description of acute porphyrias and current treatment .....................10 
1.2 
Description of the drug under study .....................................................17 
1.3 
Rationale for this clinical trial .................................................................17 
2. 
Objectives ...............................................................................................18 
2.1 
Endpoints. .................................................................................................18 
3. 
Trial Design .............................................................................................20 
3.1 
Type of Trial .............................................................................................20 
3.2 
Rationale for the trial design ..................................................................20 
3.3 
Treatment of Subjects and Rationale for Treatment .........................21 
4. 
Trial Population .....................................................................................21 
4.1 
Number of patient and sites ...................................................................21 
4.2 
Recruitment of Subjects .........................................................................22 
4.3 
Inclusion Criteria ......................................................................................22 
4.4 
Exclusion Criteria ....................................................................................23 
4.5 
Withdrawal Criteria ..................................................................................23 
4.6 
Subject Replacement .............................................................................24 
5. 
Study materials ......................................................................................24 
5.1 
Study drug reconstitution and administration .....................................24 
5.2 
Placebo preparation and administration ..............................................25 
5.3 
Timing of administration of Panhematin™ or placebo ......................26 
5.4 
Glucose administration ...........................................................................26 
5.5 
Blinding .....................................................................................................27 
5.6 
Rescue treatment ....................................................................................27 
5.7 
Randomization .........................................................................................28 
6. 
Methods and Assessments ................................................................28 
6.1 
Visit Procedures ......................................................................................28 
6.1.1 Visit 1a Screening ...................................................................................29 
6.1.2 Visit 1b: Treatment Day 1: .....................................................................30 
6.1.3 Visit 1c, d, etc. Treatment Days 2-4 etc. .............................................30 
6.1.4 Visit 2a, b, etc. daily  Observation after treatment, until discharge .30 
6.1.5 Visit 3: Follow-up 7-10 days after completion of treatment ..............30 
6.1.6 Visit 4. Follow-up 6 months after completion of treatment ...............31 
6.1.7 Visit 5. Follow-up one year after completion of treatment ................31 
6.2 
Assessments for Efficacy .......................................................................31 
6.2.1 Clinical improvement ..............................................................................31 
6.2.2 Rescue treatment ....................................................................................32 
6.2.3 Biochemical measures of improvement ...............................................32 
6.2.4 Recurrent attacks and continued symptoms .......................................32 
6.3 
Safety Assessment .................................................................................32 
6.3.1 Symptoms .................................................................................................32 
6.3.2 Physical Examination .............................................................................33 
6.3.3 Blood counts and chemistries ...............................................................33 
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RDCRN Protocol # 7203                         Panhematin™ Phase 2              Version Date: 28SEP2015 
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6.3.4 Urinalysis ..................................................................................................33 
6.3.5 Pregnancy test .........................................................................................33 
6.3.6 Adverse Events........................................................................................33 
7. 
Adverse Events......................................................................................33 
7.1 
Definitions (ICH) ......................................................................................33 
8. 
Case Report Forms ...............................................................................36 
8.1 
Rules for Completing CRFs ...................................................................37 
8.2 
Corrections to CRFs ...............................................................................37 
8.3 
CRF Review and Data Entry .................................................................37 
9. 
Monitoring Procedures ........................................................................37 
10. 
Data Management .................................................................................39 
11. 
Evaluability of Subjects for Analysis ...............................................40 
12. 
Statistical Analyses ..............................................................................40 
12.1 Purposes ...................................................................................................40 
12.2 Variables for statistical analyses ...........................................................41 
12.2.1 Efficacy variables ....................................................................................41 
12.2.2 Safety variables .......................................................................................42 
12.3 Statistical Methods ..................................................................................43 
12.4 Sample size determination ....................................................................43 
12.5 Interim analyses ......................................................................................44 
13. 
Ethical considerations .........................................................................44 
13.1 Assessment of Risks ..............................................................................44 
13.2 Assessment of benefits ..........................................................................47 
13.3 Research consent ...................................................................................48 
13.4 Institutional Review Boards ...................................................................48 
13.5 Regulatory Authorities ............................................................................48 
14. 
Premature Termination of the Trial ..................................................48 
15. 
Deviations from the Protocol .............................................................49 
16. 
Essential Documents ...........................................................................49 
17. 
Reports and Publication......................................................................50 
18. 
Retention of Clinical Trial Documents ............................................50 
19. 
Indemnity Statement ............................................................................50 
20. 
Quality Control and Quality Assurance ..........................................50 
 
 
NIH Approved 12-02-15

RDCRN Protocol # 7203                         Panhematin™ Phase 2              Version Date: 28SEP2015 
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Protocol Synopsis 
Interventional Synopsis 
Protocol Number: 
7203 
Protocol Title: 
A double-blind, randomized, placebo-controlled, parallel group trial 
on the efficacy and safety of PanhematinTM in the treatment of 
acute attacks of porphyria 
Study Chair: 
Karl E. Anderson, MD 
Statistician: 
Kristofer Jennings, PhD 
Consortium: 
Porphyrias Consortium 
Participating Sites: 
The University of Texas Medical Branch, Galveston, TX 
Activation Date: 
 
Current Status: 
Awaiting approval 
Sample Size: 
Patients to be studied and randomized: 30-40 
Patients to be evaluated and screened: 60-80   
30-40 patients with well-documented acute porphyria (AIP, HCP or 
VP) 
Target Enrollment Period: 
11/1/2013-10/31/2018 
Study Design: 
Interventional multi-centre, double-blind, randomized, placebo-
controlled, parallel group trial 
Primary Study Objective: 
Primary Objectives:  
 
To evaluate the clinical efficacy of Panhematin™ 
compared to glucose treatment started early for acute 
attacks of porphyria 
 
To evaluate the safety of Panhematin™, compared to 
glucose started early for acute attacks of porphyria 
Secondary Study 
Objective(s): 
Secondary Objectives:  
 
To evaluate the biochemical effects of Panhematin™ in 
patients treated early for attacks of acute porphyria 
Exploratory Objectives:  
 
To evaluate effects of clinical features, such as sex, age 
and the factors that precipitate attacks of porphyria on 
response to Panhematin™ 
 
To evaluate effects of genetic features, including the 
nature or the PBGD, CPO or PPO mutation on treatment 
response to Panhematin™ 
 
To evaluate the use of Panhematin™ reconstituted with 
25% human albumin in patients with acute attacks of 
porphyria  
Study Population and Main 
Eligibility/ Exclusion 
Criteria: 
Inclusion Criteria 
1. Male or female aged 18 years 
2. Willing to provide written informed consent  
3. Acute symptoms (14 days duration or less to time of 
enrollment) such as abdominal, back and/or limb pain, 
diagnosed by the investigator as caused by porphyria after 
initial evaluation has excluded other causes.   
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RDCRN Protocol # 7203                         Panhematin™ Phase 2              Version Date: 28SEP2015 
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4. Diagnosis of acute porphyria documented by a substantial 
increase in urinary or serum PBG.   
5. Type of acute porphyria confirmed by additional testing (in 
addition to increased PBG), which may be completed before or 
after treatment begins using pretreatment samples: 
a. For AIP: Normal or only slight increases in plasma 
and fecal porphyrins.  Most (~90%) will have 
deficient activity of erythrocyte PBGD, and almost 
all (>95%) will have a demonstrable disease-
causing PBGD mutation.  
b. For HCP: Substantial increases in fecal porphyrins 
(almost entirely coproporphyrin III).  In the 
absence of skin photosensitivity, most will have 
normal or only slight increases in plasma 
porphyrins.  Almost all (>95%) will have a 
demonstrable disease-causing CPO mutation. 
c. For VP: Substantial increases in fecal porphyrins 
(mostly coproporphyrin III and protoporphyrin), 
increased plasma total porphyrins and a 
fluorescence emission maximum of diluted plasma 
at neutral pH near 626 nm (18, 19, 22).  Almost all 
(~95%) will have a demonstrable disease-causing 
PPO mutation.   
Start of treatment will be as soon as possible after enrollment, and 
may be before Inclusion Criterion 5 is fully met.  This approach 
avoids delay in instituting treatment after a substantial increase in 
PBG is documented, and is consistent with standard of care.  All 
inclusion criteria must be met for inclusion of a patient in the 
efficacy analysis.   
Exclusion Criteria 
1. Symptoms such as abdominal, back or limb pain are explained 
by another condition, as judged by the investigator 
2. Known or suspected allergy to Panhematin™ or related 
products 
3. Any disease or condition that the investigator judges would 
lead to an unacceptable risk to the patient or interfere with the 
successful collection of data for the trial 
4. Previous randomization in this trial 
Treatment  
Agent- 
Panhematin™ 
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Dosage, schedule, route of 
administration- 
Panhematin™ dose of 4 mg/kg body weight by intravenous 
infusion.  Representative calculated dosages are shown in the 
Table, below. 
 
Table.  Volumes of heme–albumin solution needed for each 
dose based on representative body weights 
Body Weight 
(kg) 
Hemin dosage  
(4 mg/kg) 
Heme–Albumin 
Mixture (mL) 
50 
200  
83 
60 
240  
100 
70 
280 
117 
80 
313*  
132 
* No more than 1 vial of Panhematin™ (313 mg hemin) should 
be used per single dose. 
Safety Issues- 
Risks related to the randomized study design and other study 
procedures:  
 
Progression of symptoms due to initial randomization to 
placebo and treatment at least initially with glucose rather 
than Panhematin™.  (Treatment is started early, glucose is 
sometimes sufficient treatment; the study design provides 
rescue Panhematin™) 
 
Blood drawn could contribute to iron deficiency.  (The 
volume of blood drawn will total <160 mL if the patient is 
treated for 4 days, or <260 mL if treatment is required for 10 
days; iron status will be assessed and treatment given if 
needed.)  
 
Risks of Panhematin™ and other human hemin 
preparations 
o 
Reversible renal shutdown with excessive dosage.  
(Not observed with usual dosages.) 
o 
Phlebitis at the site of intravenous infusion is common 
can lead to loss of venous access.  (Risk reduced 
with use of albumin.)   
o 
Other risks associated with intravenous infusions, 
such as pain, infiltration and infection.   
o 
Transient anticoagulant effect.  (Risk reduced with 
use of albumin.)   
o 
Fever, aching, malaise, headache, migraine 
o 
Rare hemolysis, anaphylaxis, and circulatory 
collapse.   
o 
Infectious agents, such as disease-causing viruses, 
the Creutzfeldt-Jakob disease (CJD) agent, and 
unknown infectious agents, since Panhematin™ is 
made from human blood.  (Never reported, and 
manufacturing process should eliminate such agents.)   
 
Risks of glucose infusions:   
o 
Elevated blood glucose 
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RDCRN Protocol # 7203                         Panhematin™ Phase 2              Version Date: 28SEP2015 
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o 
Hyponatremia, seizures and fluid overload 
 
Risks from infusion of albumin:   
o 
Rare allergic reactions 
o 
Blood product, may contain infectious agents 
o 
Blood volume expansion could worsen heart failure, 
significant chronic anemia or advanced kidney 
disease.   
o 
Malaise or headache 
 
Loss of confidentiality 
Primary Outcome 
Measures: 
The primary efficacy endpoint will be the change from baseline in 
pain at 12 hours as assessed by a numeric rating scale (NRS) on a 
0-10 scale.  Pain will be assessed at other intervals to include 24, 
48, 72 and 96 hours after start of treatment are:  
Primary safety endpoints will include:  
 
Occurrence of phlebitis 
 
Occurrence of coagulopathy 
o 
Coagulation panel (platelets, prothrombin time and 
partial thromboplastin time) 
 
Secondary Outcome 
Measures: 
Secondary efficacy endpoints will include:  
 
Pain as assessed by 
o 
Change from baseline  in the NRS score for pain 
at later time intervals, namely 24, 48, 72 and 96 
hours after start of treatment 
o 
Use of morphine or other opioid in each 24 hour 
period 
o 
Time to last administration of opioid  
 
Other symptoms 
o 
NRS for nausea, vomiting and other symptoms will 
be recorded on a 0-to-10 scale over each 24 hour 
period 
o 
Use of medications for nausea or vomiting in each 
24 hour period 
 
Rescue treatment with open label Panhematin™ 
o 
Rescue treatment given 
o 
Time to rescue treatment 
 
Biochemical changes (analyzed at the Porphyria Laboratory of 
the University of Texas Medical Branch) will include:  
 
Serum (or plasma) ALA, PBG and total porphyrins  
 
Urinary ALA, PBG and total porphyrins, including 
fractionation of individual porphyrins by HPLC 
 
Fecal porphyrins, including fractionation of individual 
porphyrins by HPLC (if elevated initially) 
Secondary safety endpoints will include:  
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 
Symptoms 
 
Findings on physical examination including vital signs 
 
Routine clinical testing daily for days 1-4 and at day 7-10 
to include 
o 
Complete blood counts 
o 
Metabolic and liver panels 
Exploratory endpoints are:  
 
Length of hospital stay 
 
Time to occurrence of next attack 
Statistical Considerations 
(sample size and analysis 
plan): 
The main clinical efficacy variable, change in pain from baseline 
after commencement of treatment will be analyzed by analysis of 
covariance with treatment as a factor and baseline value as a 
covariate.  Length of hospitalization and total opioids received will 
be analyzed by exact two sample Wilcoxon tests. Rescue 
treatment with hemin within each treatment group will be analyzed 
by Fisher’s exact test.  Time to use of human hemin, the time to 
last administration of opioids and the time to new attack will be 
analyzed by exact log rank test.  Changes in biochemical 
parameters (AUC PBG reduction , etc.) will be an exact two sample 
Wilcoxon test and associated Hodges-Lehmann confidence 
interval for difference in medians.  Changes from baseline to end 
of treatment will be analyzed by analyses of covariance with 
baseline value as a covariate.  Pain intensity difference based on 
NRS for current pain will be analyzed by repeated measures 
analysis of variance.  Analyses of signs and symptoms will be 
descriptive.  Safety variables such as physical and laboratory 
findings will be analyzed descriptively, using shift tables – 
screening versus end of treatment or by repeated measures 
analysis of variance.  Adverse events will be coded and analyzed 
descriptively.   
It is anticipated that there will be large differences in pain and other 
efficacy parameters in this study, which increases the power to 
detect a treatment-related difference.  An interim analysis is 
planned after the first 15-20 subjects 
to determine a reasonable estimate of the variance. 
Sponsors (federal, state, 
foundation and industry 
support): 
U.S Food and Drug Administration Office of Orphan Product 
Development 
National institutes of Health (NIH) 
 
 
 
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Abbreviations:  
AE, adverse event 
ALA, 5-aminolevulinic acidADP 
ALA-dehydratase porphyria 
ALAS, ALA synthase 
ALAS1, ubiquitous or housekeeping form of 
ALAS 
ALAS2, erythroid form of ALAS 
APF, American Porphyria Foundation 
BMI, body mass index 
CPO, coproporphyrinogen oxidase 
CRF, case report form 
CYPs, cytochrome P450 enzymes 
DMCC, Data Management Coordinating Center 
FDA, Food and Drug Administration 
GCP, Good Clinical Practice 
HIPAA, Health Insurance Portability and 
Accountability Act 
HMBS, hydroxymethylbilane synthase 
HPLC, high-performance liquid chromatography 
IRB, Institutional Review Board 
NRS, numeric rating score, PBG, 
porphobilinogen 
PBGD, porphobilinogen deaminase 
PPO, protoporphyrinogen oxidase 
RDCRC, Rare Disease Clinical Research 
Consortium 
RDCRN, Rare Disease Clinical Research 
Network 
SAE, significant adverse event 
SIADH, syndrome of inappropriate antidiuretic 
hormone secretion 
SPID, sum of pain intensity differences 
UTMB, University of Texas Medical Branch.   
 
Introduction 
The trial will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP) and applicable regulatory requirements.  This is a single center study at the 
University of Texas Medical Branch (UTMB) in Galveston, Texas.  It is also a study 
of the Porphyrias Consortium , which is funded by a grant from the National Institutes 
of Health (NIH), and data will be uploaded to the Porphyrias Consortium database.   
1.1 Description of acute porphyrias and current treatment 
The acute porphyrias are four types of porphyria that can present with attacks of 
identical neurological symptoms.  Each is due to a deficiency of a different enzyme in 
the heme biosynthetic pathway (1).  Patients with the three most common of these 
disorders, namely acute intermittent porphyria (AIP), hereditary coproporphyria 
(HCP) and variegate porphyria (VP) will be eligible for inclusion in this study.  AIP, 
HCP and VP are autosomal dominant genetic diseases that are classified as hepatic 
porphyrias and cause symptoms most commonly in adult women.  The fourth acute 
porphyria, ALA-dehydratase porphyria (ADP), is extremely rare (only six well-
documented cases described) (2, 3).  In contrast to the other acute porphyrias, ADP 
is an autosomal recessive disorder, is perhaps more commonly symptomatic in 
males, and excess erythrocyte zinc protoporphyrin suggests a significant 
erythropoietic component.  Given these possibly significant dissimilarities, patients 
with ADP will not be included in this protocol.  Moreover, ADP is the rarest of the 
porphyrias, with only one known case in the U.S. (3), and it is unlikely that any 
patients would be available for inclusion.  Therefore, in this and other study 
documents “acute porphyria” will refer to AIP, HCP and VP.   
Molecular basis 
AIP is the most common of the acute porphyrias in most countries, with an estimated 
prevalence of 5-10 gene carriers per 10,000 in western countries (1, 4, 5).  AIP 
results from a deficiency of the third enzyme of the heme biosynthetic pathway, 
porphobilinogen deaminase [PBGD – also known as hydroxymethylbilane synthase 
(HMBS)].  Both affected individuals and asymptomatic carriers, who are said to have 
latent AIP, are heterozygous for mutations of the PBGD gene.  The disease is 
heterogeneous at the molecular level, with more than 250 mutations described in 
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different families.  Most known mutations cause the enzyme to be ~50% of normal in 
all tissues from birth, as most conveniently demonstrated in erythrocytes.  However, 
mutations affecting exon 1 may reduce enzyme activity only in nonerythroid tissues, 
and in these families erythrocyte PBGD activity is normal (4).   
HCP and VP are due to deficiencies of coproporphyrinogen oxidase (CPO) and 
protoporphyrinogen oxidase (PPO), the sixth and seventh enzymes in the heme 
biosynthetic pathway, respectively.  Like AIP, HCP and VP are genetically 
heterogeneous. Fewer mutations have been identified in HCP and VP, perhaps 
reflected their lower prevalence in most countries (1, 6).  VP is especially common in 
South Africans of Dutch ancestry, due to a founder effect, and the great majority of 
VP patients in that country share the same PPO mutation (6).   
Clinical presentation 
AIP can be considered the prototypic acute porphyria.  The majority of individuals 
who inherit PBGD mutations remain clinically unaffected throughout their lives, and 
most do not have elevations in porphobilinogen (PBG) and porphyrins.  Clinical 
expression of AIP is more common in women, and is determined by additional 
factors, including certain drugs, nutritional alterations, endogenous or exogenous 
hormones, infections and other stressful illnesses, and probably unidentified 
modifying genes (1).   
The most common presentation is an acute attack of neurological symptoms, 
including abdominal pain, vomiting, constipation, pain in the back, chest and 
extremities, muscle weakness and sensory loss.  Peripheral neuropathy may 
progress to quadriplegia and respiratory paralysis, especially if diagnosis and 
treatment are delayed.  Central nervous system manifestations may include mental 
symptoms, convulsions and hyponatremia from the syndrome of inappropriate 
antidiuretic hormone secretion (SIADH).  Some patients develop frequently recurring 
attacks or chronic symptoms (1).   
Blistering skin lesions on sun exposed areas of skin, which are identical to those 
found in porphyria cutanea tarda, are common in VP, much less common in HCP, 
and never occur in AIP (except rarely when there is concomitant end stage renal 
disease) (1, 6, 7).   
Many patients do well after one or a few attacks.  However, some develop frequently 
recurring attacks and more lasting symptoms, including depression and pain (8). 
Acute porphyria patients, and especially those with high excretion of urinary ALA and 
PBG are at increased risk for developing hepatocellular carcinoma, especially after 
40-50 years of age (9, 10).   
Pathogenesis 
These disorders are classified as hepatic porphyrias because the accumulation of 
pathway intermediates proximal to the deficient enzyme occurs initially in the liver, 
followed by excretion in urine or feces.  Excretion of products derived from 
intermediates distal to the deficient enzyme is also increased, which suggests that 
excess intermediates can be metabolized further, perhaps in nonhepatic tissues.  
AIP, HCP and VP are readily differentiated by distinctive patterns of excess 
porphyrin precursors and porphyrins in urine, plasma and feces.  A diagnosis should 
be confirmed by DNA studies.  The identified mutation can then be sought in 
relatives to detect those at risk for the disease (11).   
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In AIP, the accumulation of heme pathway intermediates, namely 5-aminolevulinic 
acid (ALA, also known as -aminolevulinic acid), PBG and porphyrins, results from 
the specific inherited enzyme deficiency as well as induction of hepatic ALA 
synthase, the first enzyme in the pathway (1).  PBGD is not genetically deficient in 
HCP and VP, but its normal activity may become rate-limiting when heme synthesis 
is stimulated.  Therefore, ALA and PBG are increased during attacks of HCP and 
VP, but the increases may be less than in AIP, and return to normal more quickly.   
Heme synthesis in the liver is controlled by the ubiquitous form of ALA synthase, 
termed ALAS1, which is the initial and rate-controlling enzyme of the pathway in the 
liver.  ALAS1 is inducible and subject to sensitive feedback repression by the end-
product heme.  A “free” pool of heme in hepatocytes down-regulates the synthesis of 
ALAS1.  (The erythroid form of ALAS, termed ALAS2, is produced only in erythroid 
cells, and is regulated quite differently by heme.)  Factors known to precipitate 
porphyric attacks include certain drugs and steroid hormones, alcohol, caloric or 
carbohydrate restriction, metabolic stress and infections.  Many of these factors are 
inducers of hepatic ALAS1.   
The inherited partial deficiencies of PBGD, CPO or PPO in these acute porphyrias 
limit hepatic heme synthesis sufficiently to make ALAS1 more inducible.  For this 
reason, gene carriers are susceptible to exacerbating factors that induce ALAS1 and 
heme synthesis in the liver.  Because most heme made in the liver is used for 
synthesis of cytochrome P450 enzymes (CYPs), drugs, hormones and other 
substances that induce both CYPs and ALAS1 in the liver are potentially dangerous 
in these disorders (12).  Hepatic induction of ALAS1 and CYPs is controlled by 
similar nuclear receptor-mediated mechanisms (1, 13, 14).   
The pathogenesis of the neurological symptoms and signs of the acute porphyrias is 
poorly understood (1, 4, 15).  A neurotoxic effect of ALA or one or more other 
intermediates or biproducts of the pathway seems most likely.  A role for PBG seems 
unlikely, especially after a recent study in which PBG was very effectively reduced by 
infusion of recombinant human PBGD demonstrated no clinical benefit (unpublished) 
(7).  Heme deficiency in the nervous system is also a possible cause of neurological 
damage, but is less supported in terms of evidence.  Chronic blistering skin lesions 
in HCP and VP, as in other cutaneous porphyrias, are due to accumulation of 
porphyrins, which are known to be photosensitizing.   
Biochemical findings  
During exacerbations of AIP, urinary excretion of PBG is typically in the range of 
20~200 mg/day (normal range, 0~4 mg/day), and ALA excretion is approximately 
half that of PBG (normal range, 0~7 mg/day) (11).  Urinary porphyrins are also 
markedly elevated, usually with a predominance of uroporphyrin (derived in part from 
nonenzymatic polymerization of PBG and also from enzymatic formation of 
uroporphyrinogen III from accumulated PBG), which accounts for reddish urine.  
Excess PBG can also form porphobilin, a brownish degradation product.   
Urinary ALA and PBG are often less elevated in HCP and VP than in AIP, and may 
decrease more rapidly to normal as the attack resolves.  Porphyrin measurements in 
urine, plasma and feces are sometimes needed for diagnosis of HCP and VP, and to 
differentiate these disorders from AIP (6, 11, 16, 17). Urinary porphyrin levels 
generally remain substantially elevated in HCP and VP, even after ALA and PBG 
become normal, and are usually predominantly coproporphyrin III.   
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Plasma porphyrins are substantially increased in symptomatic VP, and in many 
cases of latent VP, with a distinctive fluorescence emission spectrum at neutral pH 
(maximum at ~626 nm) (18, 19).  Plasma porphyrins are usually normal or slightly 
elevated in AIP and HCP, but are expected to be substantially elevated in the small 
number of HCP patients with cutaneous manifestations.  Fecal porphyrins are 
substantially increased in HCP and VP, and are predominantly coproporphyrin III in 
HCP, and approximately equal amounts of coproporphyrin III and protoporphyrin in 
VP (6, 11, 16, 17).   
Diagnosis 
A rapid, accurate diagnosis is paramount because delayed treatment of an attack 
can result in neurologic damage and even death.  Acute porphyria should be 
considered in any patient with symptoms that are prominent in these conditions, 
particularly abdominal pain, when initial clinical evaluation does not support another 
cause (11).  No single sign or symptom is universal, and 5% to 10% of patients may 
not have the most common features, such as abdominal pain and tachycardia.  The 
family history may be unrevealing because most carriers of the trait are 
asymptomatic.   
Rapidly excluding acute porphyrias also avoids delay in establishing an alternative 
correct diagnosis.  Misdiagnoses of porphyrias are common, so it cannot be 
assumed that a reported history of porphyria is accurate.  It is important to obtain the 
original evidence for the diagnosis, and to repeat testing if that evidence is not 
convincing.   
Biochemical diagnostic testing 
A substantial increase in urinary PBG establishes the diagnosis of acute porphyria – 
either AIP, HCP or VP.  Because increases in PBG are so substantial during acute 
attacks of AIP, HCP and VP, measurement of PBG even on a spot urine sample is 
often diagnostic.  Further testing on the same spot urine sample, and on plasma, 
feces and erythrocytes (obtained prior to initiating treatment) differentiates AIP, HCP 
and VP (11).   
Initial rapid testing for increased urinary PBG is recommended for initial diagnosis of 
these acute porphyrias, especially at or near the time of symptoms.  This will miss 
the diagnosis only in patients who have already received hemin (which can rapidly 
decrease PBG), in the very rare patient with ADP and in some cases of HCP and VP 
with more transient increases in ALA and PBG.  Therefore, ALA and total porphyrins 
should also be measured, which will enable diagnosis of ADP, in which ALA and 
coproporphyrin are markedly elevated, and HCP and VP, in which porphyrins 
commonly remain increased even after ALA and PBG decrease to normal (11).   
Most tests for PBG, a colorless pyrrole, rely on formation of a violet pigment with 
Ehrlich’s reagent (p-dimethylaminobenzaldehyde).  PBG must be separated from 
other urinary substances, principally urobilinogen, that also react with Ehrlich’s 
aldehyde.  The Mauzerall–Granick and closely related anion exchange methods are 
most reliable and are used for quantitative determination of ALA and PBG (20).  For 
rapid detection of increased PBG levels in urine, a commercially available kit 
(Thermo Scientific, 1-800-640-0640), which detects PBG levels at concentrations 
greater than 6 mg/L and has a color chart for semi-quantitative estimation of higher 
levels, is recommended (11, 21). 
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Because excretion of these porphyrin precursors is so high when symptoms are 
present, differences in reference ranges between laboratories are of little 
consequence, and collection of urine for 24 hours, which delays diagnosis, is 
unnecessary for diagnosis.  Urinary results expressed per gram of creatinine are 
readily compared with reference ranges for 24-hour excretion.  Decreases occur with 
clinical improvement and are dramatic (but usually not long-lasting) after hemin 
therapy. After recovery from an attack of AIP, levels of ALA and PBG generally 
remain increased, except immediately after hemin therapy or with prolonged latency.  
But in HCP and VP, ALA and PBG levels may be less markedly increased and may 
decrease more rapidly.  All major medical facilities should provide for in-house 
determination of urinary PBG levels within hours of obtaining the sample, preferably 
by using the Trace PBG Kit, because life-threatening progression of the disease may 
occur with a delay of several days in testing. The single-void urine sample is tested, 
it should be refrigerated or frozen without additives and shielded from light for 
subsequent quantitative ALA, PBG, and total porphyrin determinations (which can 
detect HCP or VP when ALA and PBG levels have already decreased to normal). In 
patients with substantial renal dysfunction, ALA and PBG levels can be measured in 
serum (11).   
If PBG is increased in urine or serum, second-line testing will differentiate AIP, HCP 
and VP, although treatment (which is the same regardless of the type of acute 
porphyria) should not be delayed pending these results.  Second-line tests include 
measurement of erythrocyte PBGD activity, as well as urine, plasma, and fecal 
porphyrin levels, measured in samples collected before beginning hemin therapy.  
Marked increases in urinary and fecal total porphyrin levels and relative, rather than 
absolute, amounts of the individual porphyrins [separated by high-performance liquid 
chromatography (HPLC)] are of greatest diagnostic importance.  Therefore, spot 
urine and fecal samples are suitable for second-line testing. Total plasma porphyrin 
levels are best measured fluorometrically either by acidification and solvent 
extraction or in diluted plasma at neutral pH (11, 19, 22).   
These second-line tests should not be relied upon for initial diagnosis of an acutely ill 
patient before treatment because they lack either sensitivity, specificity, or both. 
Urinary porphyrin levels, for example, can be increased in many nonporphyric 
conditions. Coproporphyrin is the predominant porphyrin in normal urine.  But 
because coproporphyrin is also partially excreted in bile, even minor liver dysfunction 
may reduce biliary and thus increase urinary coproporphyrin excretion (11, 23).   
Diagnosis of the acute attack 
The diagnosis of an acute attack in a patient with documented AIP, HCP or VP is 
made on clinical grounds.  While urinary ALA, PBG and porphyrins are higher during 
attacks than before or between attacks, there are no defined laboratory criteria for 
deciding that a patient is having an acute attack.  Recurrent attacks are often similar 
over time and biochemical reconfirmation of the diagnosis of AIP, HCP or VP is not 
required for each attack.  Treatment should be initiated immediately, after exclusion 
of other causes of symptoms (for example, pancreatitis and appendicitis) (11).  
Criteria for diagnosis of an acute attack should be defined in clinical trials.   
Enzymatic and DNA testing 
Enzyme activity measurement and DNA testing help to confirm the type of acute 
porphyria and enable identification of asymptomatic but at-risk relatives.  For 
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example, half-normal activity of erythrocyte PBGD helps confirm a diagnosis of AIP 
in patients with increased PBG.  This assay is also useful for screening family 
members once an index case has been identified.  However, normal erythrocyte 
PBGD activity does not exclude AIP because 1) some mutations in the PBGD gene 
lead to a deficiency of the enzyme in the liver and other organs but not in 
erythrocytes (24, 25); 2) the normal range for erythrocyte PBGD activity is wide (up 
to 3-fold) and low-normal and high-carrier values overlap; and 3) the enzyme activity 
is much higher in younger than older erythrocytes and therefore enzyme activity in 
whole blood increases when erythropoiesis is stimulated (26).  A falsely low enzyme 
activity may be due to improper processing, storing, and shipping of blood samples.  
Assays of the enzymes deficient in HCP and VP are technically difficult, must be 
performed in extracts of cells with mitochondria, such as lymphocytes or cultured 
fibroblasts, and are not widely available (11).   
Once biochemical studies have determined the type of acute porphyria, DNA studies 
can identify the disease-causing mutation in the defective gene.  This further 
confirms the diagnosis, and permits rapid and accurate testing of asymptomatic at-
risk family members by DNA studies.  Patients with porphyria should have genetic 
counseling and should be encouraged to inform family members about the disease 
and its genetics.  Counseling enables family members to make informed decisions 
about lifestyle and to know the potential risks of certain drugs, preferably before the 
development of an acute illness (11).   
Acute porphyria may be diagnosed prenatally with enzymatic and molecular studies, 
but this is seldom indicated because the outlook for most carriers is favorable (1).   
Treatment of the acute attack 
Precipitating factors, such as drugs, dietary restrictions, alcohol, metabolic stress, 
infection, and exogenous hormones should be identified and removed whenever 
possible.  Treatment of symptoms such as pain, nausea, vomiting, agitation, etc. are 
important.  Specific treatments include human hemin, which must be administered 
intravenously, and carbohydrate loading, given by mouth (if tolerated) or 
intravenously.  Glucose is often given in amounts of 200-400 g per day.   
Intravenous administration of heme (as human hemin) is regarded as the most 
effective treatment for acute attacks of porphyria (1, 11).  After intravenous 
administration heme binds to hemopexin and albumin in plasma, and is then taken 
up primarily in hepatocytes, where it reconstitutes a “free” heme pool that regulates 
ALAS1.  In patients with AIP, HCP and VP, heme promptly (within 24-48 hours) 
reduces excretion of ALA and PBG to normal or near-normal levels.   
Human hemin (hemin for injection)1 is approved in the U.S. as lyophilized hematin 
(Panhematin™, Recordati, the first drug approved under the U.S. Orphan Drug Act) 
and in Europe and South Africa as heme arginate (Normosang™, Orphan Europe).  
Approval of human hemin in these countries was based on biochemical efficacy and 
  
1 Human hemin and hemin for injection refer to heme that is derived from human blood as a biological 
product for administration to humans, and are generic names for all heme preparations used for 
intravenous administration, including hematin and heme arginate.  Hemin is also a chemical term that 
refers to the oxidized (ferric) form of heme (iron protoporphyrin IX), and is usually isolated as hemin 
chloride.  Hemin is insoluble at neutral pH, but in alkaline solution (pH 8 or higher), the chloride is 
replaced by the hydroxyl ion, forming hydroxyheme, or hematin, which can be prepared for 
intravenous infusion.   
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evident benefit in numerous individual cases and case series, rather than 
randomized, controlled studies (27-37).  One small blinded study of heme arginate, 
in which treatment was delayed for 2 days, showed biochemical but not clinical 
efficacy (38).  That study, which was clearly underpowered, showed trends 
suggesting efficacy, and is not considered as having demonstrated evidence against 
efficacy.  This report contrasts with many case reports and series, including a large, 
uncontrolled case series that enrolled 22 patients who had 51 acute attacks, in which 
heme arginate was initiated within 24 h of admission in 37 attacks (73%).  All 
patients responded, including two with paresis, and hospitalization was less than 7 
days in 90% of cases (32).   
Human hemin has few side effects.  Hematin is unstable in water, and degradation 
products are formed which, when infused intravenously, can cause phlebitis at the 
site of infusion and a transient anticoagulant effect (39-43).  Reconstitution with 25% 
human albumin, which has become common in clinical practice, stabilizes hematin 
and prevents formation of degradation products, such that coagulopathy and 
phlebitis are prevented (7, 37, 44, 45).  This helps preserve peripheral venous 
access in patients who require repeated courses of hematin.  Heme arginate is more 
stable in solution (46), but is also often reconstituted with albumin (47).  Less 
common reported side effects of hemin have included fever, aching, malaise, 
hemolysis, anaphylaxis, and circulatory collapse (48, 49).  Excessive doses of 
hematin can cause acute renal tubular damage associated with excretion of heme in 
urine (50).  Clearance of drugs that are metabolized by hepatic CYPs is reduced in 
some patients with acute porphyrias (51) and rapidly restored after intravenous 
hemin (52-54).   
In the past glucose was recommended as first line therapy and human hemin as 
second line therapy.  Increasingly, hemin is used earlier, because it is considered 
more effective than glucose (11).  Moreover, clinical response to hemin may be 
delayed or incomplete when there is advanced neurologic damage, as may occur 
when treatment is started late (32).  Subacute or chronic symptoms, which may 
reflect persistent neurological damage after repeated or prolonged attacks, are 
unlikely to respond (29, 55).  Therefore, it is important to reverse an attack before 
advanced neuronal damage has occurred.  The standard regimen for hemin 
treatment of acute porphyric attacks is considered to be 3–4 mg/kg daily for 4 days 
(or sometimes longer for severe attacks with advanced neuropathy) (11, 32, 56), 
although product labeling for Panhematin™ recommends 1-4 mg/kg for up to 14 
days.  Doses lower than 3 mg/kg have less effect on porphyrin precursor excretion 
and probably less clinical benefit.  Prophylactic regimens of weekly or biweekly 
single doses have sometimes been useful in preventing attacks in patients prone to 
frequent exacerbations, but have been little studied (57, 58).   
The clinical benefits of hemin treatment described above remain under discussion 
because randomized, controlled trials with adequate power were not conducted prior 
to regulatory approval.  In a retrospective mortality study of AIP patients (referred to 
earlier), no statistically significant reduction in mortality was evident with the 
introduction of treatment with human hemin in 1971 (8).  Therefore, the level of 
evidence for efficacy of hemin treatment is not considered to be high, even though it 
is widely considered to be highly effective (59).   
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1.2 Description of the drug under study 
Panhematin™ is a sterile, lyophilized powder suitable for intravenous administration 
after reconstitution.  Each dispensing vial of Panhematin™ contains the equivalent of 
313 mg hemin, 215 mg sodium carbonate and 300 mg of sorbitol. The pH may have 
been adjusted with hydrochloric acid; the product contains no preservatives.   
When mixed as directed with sterile water for injection, USP, each 43 mL provides 
the equivalent of approximately 301 mg hematin (7 mg/mL).  When reconstituted 
with 132 mL of 25% human serum albumin instead of sterile water, which is an off-
label recommendation, the hemin concentration is 2.4 mg/mL. (44) 
In this study Panhematin™ will be reconstituted with 25% human albumin, which has 
been found to enhance stability and reduce side effects such as infusion site 
phlebitis and transient coagulopathy (37, 44, 45).  Phlebitis and coagulapathy after 
reconstitution with sterile water result from degradation products that bind to vascular 
endothelial cells, platelets and circulating coagulation factors.   
1.3  Rationale for this clinical trial 
The quality of the evidence base for diagnosis and treatment is becoming 
increasingly important in clinical practice, even for uncommon disorders.  Hemin 
treatment can be rated no higher than 1C based on current evidence-based 
evaluation (59).  The lack of strong evidence for efficacy makes it more difficult to 
convince practicing physicians that patients will benefit, and therefore limits 
availability of this treatment for patients with acute porphyrias.  Experience has 
shown that some physicians regard this treatment as still “experimental.”   
Because acute porphyrias are rare, there has been concern that an adequately 
controlled study of treatment of the acute attack was not feasible, and might be 
unethical.  But such a study of recombinant human PBGD for treatment of acute 
attacks of AIP was recently carried out at multiple centers in Europe and the U.S.  
There were no ethical concerns raised, and the study was encouraged by leading 
porphyria experts and patient support groups in many countries.  This trial aimed to 
enroll 36 patients, was able to enroll 26, and demonstrated that intravenous infusion 
of human genetically recombinant PBGD (Porphozym™, Zymenex) was in fact not 
effective clinically.  Although the scientific rationale for this drug was not considered 
strong (the enzyme deficiency within hepatocytes was not corrected), the study was 
well designed and carried out according to accepted industry standards with the aim 
of obtaining regulatory approval.  This study demonstrated that a blinded, controlled 
study of a treatment for acute attacks is ethical and feasible if multiple centers are 
involved.  Moreover, such a study can provide convincing evidence as to efficacy of 
a treatment for the acute attack.   
Therefore, an adequately powered clinical trial to provide definitive evidence for 
efficacy of hemin is now considered feasible.  We estimate conservatively that 
enrollment of 30-40 patients, as was intended in the Porphozym™ trial, would 
probably be required to achieve statistical significance.  The most desirable patients 
for such a study are those who can be treated soon after onset of an attack, as they 
can be expected to respond quickly to treatment or, if there was no improvement, be 
provided rescue treatment (with open-label human hemin) after 24-48 hours, or 
earlier if needed.   
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This study will not provide definitive evidence to support the changes in product 
labeling for Panhematin™ in the U.S., but will contribute significantly to the body of 
evidence to support current expert recommendations in the following areas.  1) 
Product labeling recommends treatment with Panhematin™ only after a trial of 
glucose for several days is not successful.  Current expert opinion is that hemin 
treatment should be started promptly, without an initial trial of glucose (11).  This 
study will likely provide evidence to support initial treatment with Panhematin™.  2) 
Although Panhematin™ labeling states that treatment is approved only for treatment 
of women with attacks of AIP related to the menstrual cycle, there is no evidence 
from previous cases series that treatment response to hemin is different in men, in 
women when the attack is not related to the cycle or in HCP and VP.  Therefore, this 
study will support the use of hemin in men and women with attacks of AIP, HCP or 
VP either related or unrelated to the menstrual cycle.  3) The study will provide 
evidence to support use of Panhematin™ reconstituted with 25% human albumin to 
enhance stability and reduce side effects (44) by demonstrating a low incidence of 
infusion site adverse effects.  This method has become widely used in clinical 
practice, but published data supporting its use is limited.  4) The study will also focus 
on a narrower dose range of 3-4 mg/kg rather than the 1-4 mg/kg daily 
recommended in product labeling.   
2. Objectives 
This blinded, randomized placebo-controlled trial in 30-40 patients with acute attacks 
of porphyria will compare early treatment with Panhematin™ and glucose with 
placebo and glucose, with Panhematin™ rescue available for both groups.   
Primary Objectives:  
 To evaluate the clinical efficacy of Panhematin™ compared to glucose 
treatment started early for acute attacks of porphyria 
 To evaluate the safety of Panhematin™, compared to glucose started early 
for acute attacks of porphyria 
Secondary Objectives:  
 To evaluate the biochemical effects of Panhematin™ in patients treated early 
for attacks of acute porphyria 
Exploratory Objectives:  
 To evaluate effects of clinical features, such as sex, age and the factors that 
precipitate attacks of porphyria on response to Panhematin™ 
 To evaluate effects of genetic features, including the nature or the PBGD, 
CPO or PPO mutation on treatment response to Panhematin™ 
 To evaluate the use of Panhematin™ reconstituted with 25% human albumin 
in patients with acute attacks of porphyria  
2.1 Endpoints 
The endpoints include primary endpoints that relate to clinical manifestations of the 
acute attack, which are the main focus of this study.  Pain is the primary symptom of 
the acute attack, and will be recorded every 4 hours and before scheduled or prn 
opioid dosing.  Pain will be assessed in terms of changes from baseline in pain score 
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and narcotic analgesic requirements.  Secondary and exploratory efficacy endpoints 
will include biochemical changes, genetic features, precipitating factors and other 
clinical findings, which may correlate with clinical response, and safety endpoints.    
The primary efficacy endpoint will be the change from baseline in pain at 12 hours as 
assessed by a numeric rating scale (NRS) on a 0-10 scale.   
Secondary efficacy endpoints will include:  
 Pain as assessed by 
 Change from baseline  in the NRS score for pain at later time 
intervals, namely 24, 48, 72 and 96 hours after start of treatment 
 Use of morphine or other opioid in each 24 hour period 
 Time to last administration of opioid  
 Other symptoms 
 NRS for nausea, vomiting and other symptoms will be recorded 
on a 0-to-10 scale over each 24 hour period 
 Use of medications for nausea or vomiting in each 24 hour 
period 
 Rescue treatment with open label Panhematin™ 
 Rescue treatment given 
 Time to rescue treatment 
 Biochemical changes (analyzed at the Porphyria Laboratory of the 
University of Texas Medical Branch) will include:  
 Serum (or plasma) ALA, PBG and total porphyrins  
 Urinary ALA, PBG and total porphyrins, including fractionation of 
individual porphyrins by HPLC 
 Fecal porphyrins, including fractionation of individual porphyrins 
by HPLC (if elevated initially) 
Exploratory endpoints are:  
 Length of hospital stay 
 Time to occurrence of next attack 
Primary safety endpoints will include:  
 Occurrence of phlebitis 
 Occurrence of coagulopathy 
o Coagulation panel (platelets, prothrombin time and partial 
thromboplastin time) 
Secondary safety endpoints will include:  
 Symptoms 
 Findings on physical examination including vital signs 
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 Routine clinical testing daily for days 1-4 and at day 7-10 to include 
o Complete blood counts 
o Metabolic and liver panels 
 Unexpected adverse events 
Patient characteristics, such as PBGD, CPO or PPO mutations and factors 
contributing to the attack being treated, will be collected and correlated with 
treatment endpoints.  Patients will be genotyped at the Mt. Sinai Porphyria Center in 
New York City.   
 
3. Trial Design 
3.1 Type of Trial 
The trial is a multi-centre, double-blind, randomized, placebo-controlled, parallel 
group trial investigating the efficacy and safety of Panhematin™ in the treatment of 
acute attacks in at least 30 patients with well-documented acute porphyria (AIP, HCP 
or VP).  An interim analysis may be carried out after enrollment of 15-20 patients for 
possible adjustment of the sample size.  The trial consists of the following: 
 A screening period lasting up to 4 hours 
 A treatment period lasting for 4 days, beginning with the first treatment dose, 
which may be extended if clinically indicated 
 A post-treatment, in-hospital observation period for patients who remain in the 
hospital after the treatment period and lasting until discharge from the hospital. If 
hospitalization is prolonged, the observation period may overlap with the follow-
up visits.   
 Follow-up visits or interviews by telephone 
o 7-10 days after treatment to assess clinical status 
o at 6 months and 1 year to assess time to next attack, if any 
The study will consist of two parts.  Part One will end after the 7-10-day follow-up 
visit, as this will complete the collection of data pertinent to efficacy and safety for 
treatment of the acute attack.  Part Two will end after the last visit at 1 year, and will 
determine if the treatment had any effect on recurrences.   
3.2 Rationale for the trial design 
The symptoms of acute porphyria, including pain, are highly variable and subjective. 
Physical signs other than pulse and blood pressure, are also at least somewhat 
subjective. Therefore, a double-blind study design is important for evaluate clinical 
efficacy of a treatment for acute porphyria.  A parallel control group is important 
because the acute porphyrias are conditions with intermittent symptoms, and attacks 
can resolve without treatment with glucose or hemin.  In this parallel study, one 
group will be treated with glucose, 300g daily, and Panhematin™ and the other with 
glucose and placebo.  Thus both groups will receive what can presently be 
considered standard treatment (i.e. glucose and/or human hemin).  Pretreatment 
with glucose prior to Panhematin™ is consistent with product labeling.  Rescue 
treatment with open-label Panhematin™, which can be started based on criteria 
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described in this protocol or at the decision of the treating physician or the patient, is 
also consistent with current product labeling for Panhematin™.  The study is 
expected to show that initial treatment with hemin and glucose is more effective than 
glucose alone, and if so will increase the quality of the evidence for efficacy, perhaps 
from 1C to 1B.   
Patients with frequently recurring attacks are most likely to be available for this 
study, and for many reasons are also most suitable. 1) These patients can be 
evaluated and enrolled in advance and optimal biochemical, genetic and clinical 
characterization assured.  2) Their recurrent attacks are usually predictable, and 
patients can be brought to a study site in advance of an attack, so that early 
treatment can be assured.  3) These patients are among the most severely affected 
by their disease, and it is reasonable to extrapolate evidence of efficacy to patients 
with less frequent attacks.  4) Most will have had prior experience with hemin 
treatment and will be favorable to participation.  Other patients may participate if the 
diagnosis of acute porphyria is well documented and they present within 14 days of 
onset of symptoms.  All documented patients registered or followed at participating 
centers or contacted through the American Porphyria Foundation will be contacted in 
advance and informed of the study, and will be asked to come to the center hospital 
as soon as their symptoms suggest that an attack is beginning.   
3.3 Treatment of Subjects and Rationale for Treatment 
Panhematin™ 4 mg/kg will be reconstituted with 25% human albumin (44) and 
infused over a 1 hour period once daily for 4 days.  Product labeling suggests that 
Panhematin™, after reconstitution with sterile water, be infused within 15 minutes. 
An infusion time of 1 hour is based on guidelines for infusion of the amount of human 
albumin used for reconstitution, which is based on achieving a 1:1 molecular ratio for 
hemin and albumin (37, 44).  The longer infusion time of 60-90 minutes is acceptable 
given the enhanced stability of hemin in the presence of albumin.  Experience 
indicates that a single infusion site can be used 4 or more times if Panhematin™ is 
reconstituted with albumin.   
Glucose will be infused intravenously as a 10% solution to total 300 grams of 
glucose daily (3 liters daily).  Although Panhematin™ product labeling suggests an 
initial trial of glucose at a higher dose of 400 grams daily, a dose of 300 grams daily 
as 10% glucose is generally accepted (11, 60, 61) and a higher dose given as 10% 
glucose would increase the risk of fluid overload and hyponatremia.  Smaller 
amounts (e.g. 200 grams as 2L 5% glucose in saline) have been recommended for 
meeting fluid, electrolyte and caloric needs, but not as an alternative to hemin 
therapy (62).   
Symptomatic treatment will be provided, including opioids, as needed to control pain 
and other symptoms of the attack.  Amounts of individual and daily doses of all drugs 
administered during the attack will be recorded.   
 
4. Trial Population 
4.1 Number of patient and sites 
Patients to be studied and randomized: 30-40 
Patients to be evaluated and screened  60-80   
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Approximately 2 patients will need to be evaluated for every patient found suitable 
for study and randomization.  Patients who do not complete the Part 1 of the study 
will need to be replaced.    
Study sites: One site at the University of Texas Medical Branch (UTMB) is 
participating in this study.  This study is a project of the Porphyrias Consortium. All 
current sites participating in the PC (8 additional sites to UTMB) will refer suitable 
patients to UTMB for this study.  Additionally, the American Porphyria Foundation 
(APF) is an active patient support group and is a supporting partner in the Porphyrias 
Consortium that will also refer potential participants for this study.  The Porphyrias 
Consortium is one of many NIH-funded consortia that comprise the Rare Disease 
Clinical Research Network (RDCRN).  Funds for the Porphyrias Consortium are 
provided by the NIH Office of Rare Diseases as well as the National Institute for 
Diabetes, Digestive and Kidney Diseases (NIDDK).   
4.2 Recruitment of Subjects 
Investigators will contact patients known to them who are likely to be eligible for the 
trial by phone or letter.  Additional patients will be referred by the American Porphyria 
Foundation (APF), which has been an important referral source for previous 
porphyria studies, and by the Porphyrias Consortium.  Those patients not previously 
known to the investigators or the APF will be contacted through their primary treating 
physician.  Patients newly referred will also be considered and enrolled for screening 
to determine if they meet the entry criteria.  Written material and transcripts of 
planned verbal descriptions of the study will be approved in advance by the 
Institutional Review Board (IRB) at UTMB as well as other centers.  A Screening Log 
will be kept of all subjects who are contacted by phone or letter.  Subjects will be 
enrolled in advance of an attack, especially if they have frequent, predictable attacks, 
or at the time of presentation to the study site.   
4.3 Inclusion Criteria 
1. Male or female aged 18 years 
2. Willing to provide written informed consent  
3. Acute symptoms (14 days duration or less to time of enrollment) such as 
abdominal, back and/or limb pain, diagnosed by the investigator as caused by 
porphyria after initial evaluation has excluded other causes.   
4. Diagnosis of acute porphyria documented by a substantial increase in urinary or 
serum PBG.   
5. Type of acute porphyria confirmed by additional testing (in addition to increased 
PBG), which may be completed before or after treatment begins using 
pretreatment samples: 
a. For AIP: Normal or only slight increases in plasma and fecal 
porphyrins.  Most (~90%) will have deficient activity of erythrocyte 
PBGD, and almost all (>95%) will have a demonstrable disease-
causing PBGD mutation.  
b. For HCP: Substantial increases in fecal porphyrins (almost entirely 
coproporphyrin III).  In the absence of skin photosensitivity, most will 
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have normal or only slight increases in plasma porphyrins.  Almost all 
(>95%) will have a demonstrable disease-causing CPO mutation. 
c. For VP: Substantial increases in fecal porphyrins (mostly 
coproporphyrin III and protoporphyrin), increased plasma total 
porphyrins and a fluorescence emission maximum of diluted plasma at 
neutral pH near 626 nm (18, 19, 22).  Almost all (~95%) will have a 
demonstrable disease-causing PPO mutation.   
Start of treatment will be as soon as possible after enrollment, and may be before 
Inclusion Criterion 5 is fully met.  This approach avoids delay in instituting treatment 
after a substantial increase in PBG is documented, and is consistent with standard of 
care.  All inclusion criteria must be met for inclusion of a patient in the efficacy 
analysis.   
4.4 Exclusion Criteria 
1. Symptoms such as abdominal, back or limb pain are explained by another 
condition, as judged by the investigator 
2. Known or suspected allergy to Panhematin™ or related products 
3. A known or suspected allergy to human albumin  
4. Any disease or condition that the investigator judges would lead to an 
unacceptable risk to the patient or interfere with the successful collection of data 
for the trial 
5. Previous randomization in this trial 
4.5 Withdrawal Criteria 
The subject may be withdrawn from the trial if judged non-compliant with the study 
procedures or if there is a safety concern, at the discretion of the investigator.   
The subject may withdraw from the study at any time. 
For subjects withdrawn prematurely, assessments should be completed up to the 
time of withdrawal.   
Patients who require rescue treatment with open label Panhematin™ are not 
withdrawn from the study.  Rescue treatment is completed as part of the study.   
Patients withdrawn will be offered standard of care treatment, which may include 
Panhematin™, at the study site or through their own physician.   
An intent to treat approach will be used. All data acquired prior to termination for the 
reasons listed below will be included in the primary analysis unless patient withdraws 
consent. Every effort will be made to conduct a final study visit with the participant 
and participants will be followed clinically until, if applicable, all adverse events 
resolve.  
 
 
 Withdrawal of consent 
 Withdrawal by the participant 
 Withdrawal by the investigator 
 Intercurrent illness or event that precludes further visits to the study site or 
ability to evaluate disease (e.g.-mental status change, large pleural effusion). 
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4.6 Subject Replacement 
Subjects who are enrolled initially and then found not to meet inclusion criterion will 
be replaced in order to provide 30-40 patients eligible for randomization. 
 
5. Study materials 
5.1 Study drug reconstitution and administration 
Panhematin™ (human hemin), a lyophilized preparation of hematin (hydroxyheme or 
heme hydroxide), is provided by Recordati Pharmaceuticals, and reconstituted with 
132 mL of 25% human serum albumin (37, 44).   
The patient’s body weight is provided to the Pharmacy, which prepares each 
Panhematin™ dose of 4 mg/kg body weight.  Representative calculated dosages are 
shown in the Table.  No more than one vial should be used for each administration, 
i.e. the dose is 4 mg/kg body weight, not to exceed a total of 313 mg.  After the first 
dose, the same calculated dosage is used for subsequent doses.   
The dose should be calculated and venous access obtained before reconstituting the 
study drug.  An existing central venous port may be used.  The venous access may 
be used for other medications and fluids, but only 0.9% sodium chloride should be 
infused simultaneously with reconstituted Panhematin™, as described below.   
Procedure for reconstitution of Panhematin™ (44).   
The following materials are needed:  
1. One 313-mg vial of Panhematin™.   
2. One 150-mL sterile empty glass bottle for infusion 
3. Three 50-mL vials of 25% albumin (only 132 mL will be used) 
4. One 5-micron filter needle  
5. One vent needle.   
To prepare Panhematin™ for infusion: 
1. Reconstitute the 313-
mg vial of 
Panhematin™ with 
132 mL of 25% 
albumin.  Because this 
volume will almost 
completely fill the vial, 
the albumin must be 
injected into the vial 
slowly and the vial 
must be vented.  Use 
a vented needle or 
make a vent with a separate needle to release the air pressure. 
2. Do not shake the mixture. Swirl the vial 15 to 20 times to ensure that it is 
thoroughly mixed (it will be difficult to see if the materials are blended because 
of the dark color of hemin). 
Table.  Volumes of heme–albumin solution needed 
for each dose based on representative body 
weights 
Body Weight 
(kg) 
Hemin dosage  
(4 mg/kg) 
Heme–Albumin 
Mixture (mL) 
50 
200  
83 
60 
240  
100 
70 
280  
117 
80 
313*  
132 
* No more than 1 vial of Panhematin™ (313 mg 
hemin) should be used per single dose. 
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3. After reconstitution, the hemin concentration is 2.4 mg/mL. The volume 
required to deliver the desired dose (usually 3 to 4 mg/kg of body weight) 
should be calculated according to representative volumes for corresponding 
body weights (see Table). 
4. Withdraw the required dose into a syringe by using a 5-micron filter needle. 
5. Inject the dose into a 150-mL empty sterile bottle. 
6. Label the bottle.  The label will be provided for the study.   
7. Place the bottle in an amber bag to protect the mixture from light.  Also place 
a vented spike adapter in the bag.  Affix a label provided.  [Customarily, a 
yellow Medication Administrations Recording blood products label (for both 
albumin and Panhematin™) would be attached to the amber bag.  This should 
be done only if the treatment is unblinded, i.e. for open label Panhematin™ 
rescue treatment.]  Then place the amber bag inside a STAT-labeled bag. 
8. Hand-deliver the bag to the clinical unit immediately.  The infusion should be 
started within 1 hour or less of preparation.  The heme–albumin complexes 
may be stable for much longer, but the solution does not contain bacteriostatic 
agents and therefore should be infused promptly. 
Procedure for administration of Panhematin™.   
1. Access a large peripheral vein using an indwelling intravenous catheter.  
Based on clinical indications, such as a need for frequent intravenous 
infusions or poor venous access, a peripherally inserted central line or a 
central line or port may also be used.   
2. Piggyback the Panhematin™-albumin dose to an intravenous line that is 
infusing 0.9% sodium chloride at a moderate rate (at least 100 mL/hr).  The 
piggyback site should be as close as possible to the venous access site.   
3. Infuse the dose over a period of 60-90 minutes or at a rate that should not 
exceed 1 mL/min, which corresponds to the recommendation for infusing 25% 
human albumin (37, 44).  A somewhat shorter infusion time may be 
acceptable but may entail some risks from intravascular volume expansion. 
Some patients have experienced headaches shortly after infusions of heme–
albumin, perhaps related to transient expansion of intravascular volume.   
4. After the heme–albumin is infused, continue the infusion of 0.9% saline for at 
least 10 minutes at a rate of at least 100 mL/hr to clear the line, catheter (or 
port) and vein of the drug.  Before and after the heme-albumin infusion, the 
infusion site can be used for infusion of 10% glucose, other fluids and 
electrolytes and intravenous medications needed for treating symptoms.   
The study drug is administered once daily for 4 days at a dose of 4 mg/kg body 
weight.  The infusion is given over one hour (44), after which the IV set and other 
materials are removed and discarded.   
5.2 Placebo preparation and administration 
It is not feasible to design a placebo for intravenous administration with the same 
appearance as Panhematin™ (human hemin), which is administered as a black 
solution.  The placebo for this study will be 117 mL of 0.9% sterile saline in the same 
150 mL sterile glass bottle used for the active drug, and labeled and delivered from 
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the Pharmacy in the same manner as the active drug.  The placebo will be infused in 
the same manner as the active drug by a research nurse who is unblinded. Other 
study personnel will remain blinded.  To maintain blinding in this study, study drug 
(reconstituted Panhematin™ or placebo) is delivered from the Pharmacy in a 
container that is not visible to study personnel or the patient.  One research nurse 
will have responsibility for the infusion and not be blinded.  This nurse will interact 
minimally with the patient and other study personnel and will drape the 
administration set and the IV site in a manner that will maintain blinding. The 
unblinded nurse will remain for the entire infusion time and assist in any manner 
necessary to maintain blinding of other study personnel and the patient, which may 
include adjusting drapes and the infusion set-up.  At completion of the one-hour 
infusion, the unblinded nurse will remove the IV set and other materials to another 
location for disposal.  To further reinforce blinding, the patient will also be blind-
folded before the study drug arrives and until the IV set and other materials are 
removed from the unit.  If a patient does not wish to be blinded (e.g. due to 
claustrophobia), this will be recorded, but he or she will not be excluded.  Visitors will 
not be allowed in the room during a blinded infusion.  Other research nurses who are 
blinded will carry out other study procedures that do not involve the infusion.   
5.3 Timing of administration of Panhematin™ or placebo 
Treatment with Panhematin™ or placebo should be started as soon as possible after 
enrollment and eligibility are determined.  Panhematin™ is FDA approved at the 
dosage level used in this study.  It is not necessary to time subsequent doses at 
exactly 24 hour intervals.  The second dose should be administered on the second 
study day and at least 12 hours after the first dose.  For example if the first dose is 
given in the afternoon or evening of the first day, the second dose can be given 
during the morning of the second day.  Panhematin™ or placebo administration on 
the third and fourth study days should be at about the same time as on the second 
day, but may be given at a later time if necessary.  Timing of all dose administrations 
will be recorded on the CRFs.   
5.4 Glucose administration 
All patients who are randomized to receive either Panhematin™ or placebo will also 
be treated intravenously with glucose 300 grams daily, which is considered the 
standard dosage for glucose loading (7, 11, 60, 61, 63).  Although larger amounts 
are sometimes recommended, this results in larger volumes of intravenous fluid and 
increased risk for fluid overload and hyponatremia.   
Glucose (10% solution) will be supplied in the usual manner by the hospital and 3 
liters (300 grams glucose) will be infused daily during the 4-day treatment period.  
Electrolytes may be added to correct imbalances or for other clinical indications.  The 
same intravenous access site may be used for glucose and for Panhematin™ or 
placebo, in which case the glucose infusion will be stopped and replaced with a 0.9% 
saline infusion during the time required for infusion of Panhematin™ or placebo.   
The amount of 10% glucose can be reduced if there are clinical findings such as 
hyponatremia or if needed to prevent severe hyperglycemia in diabetics, based on 
clinical judgment.  The amounts of glucose administered daily will be recorded on the 
CRFs.   
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5.5 Blinding 
Blinding of treatment with a darkly colored, intravenous drug poses significant 
challenges, but is feasible because the drug is administered only once daily, and 
personnel directly involved in drug reconstitution and administration will be different 
from those who establish intravenous access and are otherwise involved in the study 
patient’s care.  The PI, other physicians, study coordinators and nurses involved in 
patient care will remain blinded.  Pharmacy personnel (1-2 individuals) and one 
study nurse who will administer the drug will not be blinded.  The Pharmacy 
personnel will deliver the study drug or placebo in a non-transparent container to the 
unit and the unblinded study nurse who will administer the drug.  This nurse will be 
responsible for the infusion and for maintaining blinding at the bedside, but will not 
otherwise be involved in the patient’s care or in collecting data.  The drug or saline 
placebo will be administered through an already established intravenous access, 
with drapes to prevent the patient and blinded staff from viewing the drug 
administration.  Also, the patient will be blind-folded from before the study drug is 
delivered to the unit until after all administration material is removed from the unit.  
Blinded staff will not be in the room during study drug administration.  Every effort 
will be made to avoid compromise in blinding if, for example, there are problems with 
the infusion after it is started.  Problems with the infusion will be handled by the 
unblinded nurse without compromising blinding of other personnel.  If unblinding of 
additional personnel is required (e.g. for venous access problems), this will be 
recorded in the Case Report Forms.  If rescue treatment with Panhematin™ is 
required less than 12 hours after a blinded infusion, the first rescue infusion will also 
be blinded.  This will allow for the first rescue infusion to be saline, if the previous 
treatment infusion within the previous 12 hours was active drug, without 
compromising blinding of the assigned treatment.  Any difficulties that might 
compromise blinding will be recorded.   
5.6 Rescue treatment 
Rescue treatment for this study will be Panhematin™ 4 mg/kg body weight daily for 4 
days, or longer if clinically indicated.  Panhematin™ will be reconstituted with human 
albumin, as described above, since this is now considered optimal (11).  If rescue 
treatment is given, blinding will be maintained, unless doing so would compromise 
patient safety.   
If rescue treatment is necessary, it is not necessary to wait until the next day after 
the last dose of Panhematin™ or placebo.  Administration of two Panhematin™ 
doses of 4/mg/kg doses daily was common in the past, although a single daily dose 
for 4 days is now more commonly recommended (11).  When two doses are given, 
an interval of at least 6-8 hours is customary.  Provision is made in this study to 
avoid giving two doses of Panhematin™ within a period of 12 hours.   
If rescue treatment with Panhematin™ is required less than 12 hours after a blinded 
infusion, the first rescue infusion will also be blinded, and this will be so recorded on 
the CRFs.  This will avoid unblinding of the treatment given before rescue treatment.  
Subsequent rescue doses will not need to be blinded, since they will be administered 
at least 12 hours apart.   
Symptomatic treatment for pain, nausea and vomiting will be given as needed to 
control these symptoms of the porphyric attack, which can be severe.  These are 
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regarded as expected treatments rather than rescue treatments in this study, since 
they will be needed in varying amounts by all study patients.   
5.7 Randomization 
Randomized treatment in this is double-blind, symmetrically randomized, parallel 
group trial study will be assigned by the Data Management and Coordinating Center 
(DMCC) of the RDCRN at the University of South Florida in Tampa.  The 
randomization numbers will be a different series from the study enrollment numbers.  
Randomization will be done during the screening visit after the inclusion and 
exclusion criteria are satisfied.  Subjects will be randomized through an online data 
management system at the DMCC, and a subject is considered on therapy as soon 
as randomized.  Randomization can be accomplished automatically anytime by the 
research pharmacistvia the RDCRN website. .   
Labels showing the study randomization number will be generated to label all study 
samples and materials.   
The randomization code for a particular subject can be broken if knowing the identity 
of the treatment allocation is felt to be necessary for optimal management of the 
patient and the treating physician concludes that breaking the code is in the best 
interest of the patient.  This is most likely to be indicated if there is an allergic or 
other adverse reaction that might influence starting rescue treatment unless it is 
known whether the initial treatment was hemin or placebo.  Whenever a code is 
broken, the person breaking the code must record the time, date and reasons.  It 
must also be recorded who is unblinded as a result of breaking the code, i.e. specific 
study personnel and/or the patient.  The Data Management and Coordinating Center 
(DMCC) may unblind the data at any time during the study without unblinding others 
involved in the study.   
The site may decide to break the code at any time if this is necessary for benefit of 
the subject or to reduce undue risk.  Reasons for breaking the code are recorded in 
detail on the CRF.  Unblinded data will be identified, and may be excluded from the 
data analysis.   
 
6. Methods and Assessments 
This study will be carried out in an inpatient setting and will consist of a brief period 
of screening and enrollment (designated Visit 1a), a treatment period of 4 days or 
longer (Visits 1b, etc), an optional period of observation until discharge (Visit 2), a 
short term observation period of 7-10 days after discharge (Visit 3), and long term 
follow-up at 6 months (Visit 4) and one year (Visit 5).   
6.1 Visit Procedures 
Visits are designated as shown below to facilitate scheduling of procedures and 
recording of study-related data.   
Visit 1 
a 
Screening, 0-4 hours  
 
b 
Treatment Day 1  
 
c 
Treatment Day 2  
 
d 
Treatment Day 3 
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e 
Treatment Day 4 
 
f, 
etc. 
Additional treatment days, beyond the standard treatment of 4 days, 
may be added if clinically indicated, at the discretion of the 
investigator.   
Visit 2 
a, 
etc. 
Post-treatment observation period until discharge from the hospital 
(duration will depend upon need for continued hospitalization, and 
will be omitted if discharge occurs at completion of treatment or may 
overlap with Visit 3 if hospitalization is prolonged)  
Visit 3 
 
7-10 days after treatment 
Visit 4 
 
6 months after treatment  
Visit 5 
 
One year after treatment 
 
6.1.1 Visit 1a Screening  
Eligible patients will be fully informed, orally and in writing, about the purposes and 
procedures of the study, and asked to sign a research consent form approved by the 
IRB, which describes study procedures and risks and potential benefits of the study.   
Procedures: 
After informed consent is obtained each subject will be allocated a unique study 
enrollment number.  If the inclusion and exclusion criteria (see below) are satisfied, 
the patient will be randomized during the screening visit or before and assigned a 
unique study randomization number.  The following will be performed and recorded 
in the CRF: 
1. Checks of Inclusion and Exclusion Criteria. 
Demographic Information, to include: 
- Date of Birth 
- Sex 
- Race and ethnicity 
History, to include:  
- Year of first porphyria attack 
- Number of attacks during the past year 
- Attacks related to the menstrual cycle or not 
- Attacks related to other precipitating factors (harmful drugs, nutritional 
alterations, etc. or not 
- Time of onset of present attack 
- Previous treatment with Panhematin™ 
2. Concomitant illnesses 
3. History of allergy 
4. Concomitant medications 
5. Use of opioid agonists during the previous 24 hours 
6. Physical Examination, including:  
a. Body height and weight 
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b. Vital Signs 
7. Vital capacity measurement 
8. Electrocardiogram, if clinically indicated 
9. Recording of porphyria-related signs and symptoms 
10. Completion of NRS for pain and other symptoms 
11. Blood samples will be drawn for testing, to include erythrocyte PBGD, serum or 
plasma ALA, PBG and porphyrins, complete blood counts, metabolic and hepatic 
panels, and serum progesterone (females only) 
12. Urine sample will be collected for assessment of urine ALA, PBG, and porphyrins.   
13. Fecal sample will be collected for porphyrins.   
14. Blood sample for DNA isolation and mutation analysis (unless done previously) 
15. Urine pregnancy tests (for females of childbearing potential only). 
6.1.2 Visit 1b: Treatment Day 1:  
Procedures: 
The following will be performed and recorded in the CRF (at initiation of treatment): 
1. Concomitant medications, and any changes not recorded previously 
2. Vital Signs 
3. Recording of porphyria-related signs and symptoms 
4. Vital capacity measurement 
5. Completion of NRS for pain and other symptoms 
6. Begin continuous recording of use of opioids preceded by assessment of current 
pain  
7. Urine, blood and fecal samples for ALA, PBG and porphyrins (pretreatment) 
8. Recording of adverse events 
9. Administration of study treatment 
6.1.3 Visit 1c, d, etc.: Treatment Days 2-4 etc. 
Procedures: 
These will be the same as for Visit 1b.  Additional treatment days may be added if 
clinically indicated, at the discretion of the investigator.   
6.1.4 Visit 2a, b, etc.: Daily observation after treatment, until discharge 
Procedures: 
These will be the same as for Visits 1b, c, d, etc., except that there will be no study 
treatment.  Additional observation days may be added if clinically indicated, at the 
discretion of the investigator.   
6.1.5 Visit 3: Follow-up 7-10 days after completion of treatment 
Procedures: 
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These will be the same as for Visits 2b, c, d, etc., except that biochemical 
measurements are not required.  Unless clinical indications require the patient to 
come to the site, this visit can be completed by telephone.  Additional observation 
days may be added if clinically indicated, at the discretion of the investigator, and 
labeled 3a, etc.   
6.1.6 Visit 4. Follow-up 6 months after completion of treatment 
Procedures: 
These will be the same as for Visit 3   
6.1.7 Visit 5. Follow-up one year after completion of treatment 
Procedures: 
These will be the same as for Visits 3 and 4.     
6.2 Assessments for Efficacy 
6.2.1 Clinical improvement 
These assessments will be performed at each visit.   
6.2.1.1 Pain related to the attack of porphyria 
Current pain and average pain over the last 24 hours will be assessed during the trial 
using a numerical rating scale (NRS) ranging from 0-10.  The source(s) of pain will 
also be documented on the CRF.  Study personnel will be educated on completion of 
the NRS. 
Current pain will be assessed by the NRS and recorded every 4 hours and before 
scheduled or prn opioid dosing.  
For average pain over the last 24 hours the patient will be asked how much pain 
he/she has experienced as an average during the past 24 hours, and this will be 
recorded using the NRS.   
6.2.1.2 Use of opioids during the past 24 hours 
Use of potent opioid agonists during the last 24 hours will be recorded during 24 
hours prior to enrollment and during each day in Visits 1-3 or until discharge from the 
hospital.  The generic and trade names, dose, route of administration and time of 
each dose will be recorded.  
In past studies of treatment of acute porphyries it has not been possible to use one 
opioid drug, such as morphine, for all patients, because some patients have side 
effects from morphine but not certain other opioids.  A standard opioid conversion 
table will be used to express data in morphine equivalents, in order to combine data 
for all patients.  The results of calculating morphine equivalence will be entered on 
the CRF page after collection of the page from the site and prior to data entry.  The 
major treatment-related comparison will be change in opioid requirements, rather 
than comparing requirements between patients.   
6.2.1.3 Other porphyria-related signs and symptoms 
Other signs and symptoms will be recorded at the times stated above, and rated for 
severity using a NRS of 0 to 10.  These will include nausea, vomiting, constipation 
and specified neurological and psychiatric symptoms.   
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6.2.2 Rescue treatment 
Rescue treatment will be given when needed and recorded as part of the trial.  
Rescue treatment can be started if one of the following criteria is met, in the 
judgment of the investigators:  
 no improvement in symptoms after 48 hours 
 worsening in symptoms after 24 hours 
 development or worsening of hyponatremia 
 other findings that place the patient at undue risk 
 the patient requests rescue treatment due to worsening symptoms 
No improvement after 48 hours is an indication for rescue treatment because 
continuing placebo beyond this time is considered to place the patient at undue risk.  
Patients with hyponatremia may be started on blinded treatment, but rescue 
treatment will be started if there is worsening of hyponatremia.  Blinding up to rescue 
treatment will be maintained until the end of the study, and rescue treatment will be 
continued for the standard 4 days, or for a shorter period if there is rapid 
improvement, at the judgment of the study physician.  Rescue treatment may be 
continued longer than 4 days, if clinically indicated.  Patients will remain in the study 
during and after rescue treatment.   
6.2.3 Biochemical measures of improvement 
Biochemical measures, to include urinary ALA, PBG and porphyrins, plasma PBG 
and porphyrins and fecal porphyrins will be measured daily during Visits 1 and 2, and 
at Visits 3-5 only if the patient visits a study site.  Analyses will be performed at the 
Porphyria Laboratory of the University of Texas Medical Branch.  Procedures for 
obtaining, handling and storage of samples will be described in a trial laboratory 
manual. All results will be provided to the RDCRN Data Management and 
Coordinating Center during the trial.   
Baseline biochemical measurements obtained before initiation of treatment with 
Panhematin™ or placebo will not be blinded and will be recorded as usual in the 
subject’s medical record.  Biochemical data during blinded treatment will be remain 
blinded until the end of the study, and will not be provided to the medical record.    
These results will be maintained in the laboratory separately from other laboratory 
results to avoid inadvertent unblinding of other study personnel.  This blinded 
laboratory data will be entered into the database at the end of the study and only 
whether the sample was collected or not will be recorded on the CRFs at the time of 
the study visit.  
6.2.4 Recurrent attacks and continued symptoms 
Occurrences of new attacks and continued symptoms will be recorded at Visits 3-5.   
6.3 Safety Assessment 
6.3.1 Symptoms 
Any new symptoms not related to porphyria will be recorded during and after 
treatment.   
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6.3.2 Physical Examination 
Physical examination, to include vital signs, weight, body mass index (BMI) and 
evaluation of the major systems will be recorded daily during Visits 1 and 2, and at 
Visits 3-5 only if the patient visits a study site.  Height will be recorded at Visit 1.   
6.3.3 Blood counts and chemistries 
Blood samples will be drawn for complete blood counts and metabolic, hepatic and 
coagulation panels daily during Visits 1 and 2, and at Visits 3-5 only if the patient 
visits a study site.  Analyses will be performed either by the hospital laboratory or a 
central laboratory.  The site investigator will review the report, sign and date it, and 
comment on any laboratory abnormality that is judged to be clinically relevant.  A 
clinically relevant abnormality is defined as one that suggests a disease or organ 
toxicity and is of a severity that requires active management (e.g. change in 
treatment, more frequent follow-up or diagnostic investigation).  
6.3.4 Urinalysis  
A standard urinalysis will be performed at the site, using a urine strip, at Visit 1.   
6.3.5 Pregnancy test 
For women of childbearing potential a pregnancy test (urine hCG) will be performed 
at the site at Visit 1.  Since pregnancy is not a reason for avoiding treatment with 
hemin or glucose, a positive pregnancy test will not exclude a patient.  Pregnancy 
will be recorded as a concomitant condition.   
6.3.6 Laboratory data flow 
The DMCC will provide the site with on-line forms and/or electronic data exchange 
mechanisms - depending on their capabilities and needs - to enter, update and 
obtain relevant data.  On-line forms exist to perform specimen receipts, report 
specimen issues and submit test results for specimens.  The preferred method to 
exchange data electronically is through the Specimen Management System Web 
Service.  The Web Service allows laboratories to obtain specimen shipment 
information, receive individual specimens or specimen shipments, report specimen 
issues and communicate specimen aliquots in a secure manner (test result 
submission is planned).  The DMCC will also support uploading of files 
electronically.  All transactions are logged and validated for both methods.  As noted 
above, laboratory data that would result in premature unblinding will be entered  at 
the end of the study.   
 
6.3.7 Adverse Events 
Adverse Events will be recorded during Visits 1-5.   
 
7. Adverse Events 
7.1 Definitions (ICH) 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have 
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a causal relationship with this treatment. The following should not be recorded as 
AEs, if recorded at screening: 
Pre-planned procedure, unless the condition for which the procedure was planned 
has worsened from the first trial related activity after the subject has signed the 
informed consent. 
Pre-existing conditions found as a result of screening procedure 
Clinical Laboratory Adverse Event: 
A clinical laboratory AE is any clinical laboratory abnormality that suggests a disease 
and/or organ toxicity and that is of a severity that requires active management (i.e. 
change of dose, discontinuation of drug, more frequent follow-up or diagnostic 
investigation). Clinical laboratory abnormalities that are found at screening and that 
fall under the above description should be recorded as a concomitant illness. 
Serious/Non-Serious Adverse Event Definitions: 
Serious Adverse 
Event 
(SAE) 
An SAE is any untoward medical occurrence that at any 
dose:  
- 
results in death, 
- 
is life-threatening*, 
- 
requires inpatient hospitalization or prolongation of 
existing hospitalization, 
- 
results in persistent or significant 
disability/incapacity, 
or 
- 
is a congenital anomaly/birth defect 
- 
is an important medical event that may not result in 
death, be life-threatening*, or require hospitalization  
when, based upon appropriate medical judgment, it 
may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Non-Serious 
Adverse Event 
A non-serious adverse event is any AE which does not 
fulfill the definition of an SAE 
Unexpected 
Adverse Event 
Any adverse experience…the specificity or severity of 
which is not consistent with the risks of information 
described in the protocol. 
Expected Adverse 
Event 
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. 
* The term life-threatening in the definition of serious adverse event refers to an 
event in which the subject was at risk of death at the time of the event. It does not 
refer to an event which hypothetically might have caused death if it was more 
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severe. 
In the present trial a prolongation of hospitalization caused by lack of effect of the 
trial drug should not be reported as an SAE, unless one of the other criteria for an 
SAE is fulfilled.   
All reported adverse events will be classified using the current version of the 
Common Terminology Criteria for Adverse Events (CTCAE) developed and 
maintained by CTEP at National Cancer Institute. 
 
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 CTSA oversight committee, 
the Data and Safety Monitoring Board (DSMB) and the FDA, if appropriate, remain 
the responsibility of the treating physician and the Study Chair. 
 
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, the  
Medical Review Officer, and any additional agencies (if applicable- industry sponsor, 
CTEP, etc) of any reported adverse events via email.  
 
Serious adverse events: The NIH appointed Medical Review Officer (MRO) reviews 
the site investigator’s report and determines causality (definitely not related, probably 
not related, possibly related, probably related, definitely related) of the adverse 
event. The MRO may request further information if necessary and possibly request 
changes to the protocol or consent form as a consequence of the adverse event. 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. Any follow 
up reports or requested additional participant data will be entered into the AEDAMS 
system by the reporting site and reviewed by the MRO. Completed AE reviews by 
the MRO will sent to Study Chair, site PIs, and the appointed NIH officers. 
 
If warranted, the MRO may request an ad hoc call with the DSMB to review the 
adverse event. All reported AE’s will be reviewed during the regularly scheduled 
DSMB call. 
 
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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 and for review by the DSMB. 
 
8. Case Report Forms 
Case Report Forms (CRFs) will be prepared at the Coordinating Center at the 
University of Texas Medical Branch and supplied to other participating centers.   
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. 
 
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.  
 
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8.1 Rules for Completing CRFs 
CRFs may be completed by investigators, coordinators and study nurses at each 
site.  They will print legibly using a black ballpoint pen, and ensure that all relevant 
questions are answered and that no data entry spaces are left empty. 
Any assessment or test data that was not done and will not be available is indicated 
by writing “N/D” (Not Done) in the answer field.  If the question is irrelevant or not 
applicable, this is indicated by writing “N/A” (Not Applicable) in the field. 
The investigator and site study team must ensure that all information derived from 
source documentation is consistent with the source information. By signing the 
Affirmation Statement, the Investigator confirms that the information in the CRF is 
complete and correct. 
8.2 Corrections to CRFs 
Corrections to the data on the CRFs must only be made by drawing a straight line 
through the incorrect data and then writing the correct value next to data that has 
been crossed out.  Each correction must have initials of the individual who made the 
correction and the date of the correction.  An explanation for the correction should 
also be written next to the correction, if necessary for clarity.  If corrections are made 
after the date of the Investigator’s signature on the Affirmation Statement, the 
Statement must be signed and dated again by the Investigator. 
Corrections necessary after the CRFs have been removed from the Investigator’s 
site must be documented on a Query Resolution Form, and can be approved only by 
the Investigator. 
8.3 CRF Review and Data Entry 
The original CRFs are reviewed by the Monitor at the time of monitoring site visits, 
and photocopies made for storage at the study site and the Coordinating Center.  
The Monitor removes the original CRFs after no further corrections or amendments 
to the content are expected. 
The Coordinating Center will enter data from the original CRFs into the RDCRN 
DMCC database.  After all necessary database verification, the original CRFs will be 
archived at a secure archiving location.  Other copies may be destroyed after a 
comprehensive Clinical Trial Report has been finalized, and in accordance with 
practices approved at each site.   
 
9. Monitoring Procedures 
Study Oversight 
The Study Chair has primary oversight responsibility of this clinical trial. The NIH 
appointed Data (Observational) Safety Monitoring Board (D/OSMB) has oversight 
responsibility of the Data Safety Monitoring Plan (DSMP) for this clinical trial. The 
D/OSMB will review accrual, patterns and frequencies of all adverse events, 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 
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adverse events. Aggregate report- 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 3 
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. 
 
Safety Monitoring Plan 
The study protocol has been reviewed and approved by the National Institutes of 
Health (NIH) and a DSMB formed by NIH to oversee all Porphyrias Consortium 
studies.  Participant enrollment may only begin after IRB approval of consent forms 
and other study documents.   
This is an interventional phase II study that meets the federal definition of low risk. 
The risk level for this study is judged to be low, since the treatment modalities are 
already part of clinical practice, and no investigational products are involved.  
Although use of albumin for reconstituting Panhematin™ is an off-label method, 
there is strong evidence and considerable experience to suggest that this increases 
safety.  Potential risks of the study are described in detail under Assessment of 
Risks (See 13.1 below).  Although this is not a Phase III clinical trial, the DSMB 
formed by NIH will oversee the study.   
Recruitment, enrollment, retention, adverse events, and study procedures will be 
monitored carefully by the PI and the investigator at each site.  The investigators will 
review individual subjects’ study records to ensure that appropriate safety 
procedures are being followed, that protocol requirements are being adhered to, and 
that data is accurate, complete, and secure.  Study records include consent forms, 
case report forms, flow charts, data forms, laboratory specimen records, inclusion 
and exclusion criteria forms, adverse event logs, and medical charts.  Investigators 
will review available data at weekly investigators meetings or conference calls, and 
discuss any instances of adverse events or unexpected problems encountered 
regarding patient safety or data collection.  The DSMB will review data safety and 
data collection records at least every 6 months.   
Plan for Adverse Event (AE) Reporting. See Section 7.  The PI and site investigator 
will be notified immediately if an AE occurs, and a medical member of the team will 
evaluate the patient and enter a note into the medical chart.  The investigators will be 
responsible for notifications to the IRB and others, as appropriate.  In particular, all 
unanticipated, serious, fatal and/or life-threatening adverse events will be reported to 
the IRB, the DSMB and others as required, within 24 h of occurrence. The 
investigators, the DSMB and the IRB are primarily responsible for determining 
whether modifications to the protocol and consent form are required.  If a 
determination is made that participants are found to be exposed to excessive risks in 
relation to anticipated benefits, the study will be immediately suspended.  Studies will 
not resume until modifications are made that are deemed to result in an acceptable 
risk/benefit ratio. Aggregate reports of adverse events will be prepared on an annual 
basis and forwarded to the IRB and others as required.  Aggregate reports will be 
provided to the DSMB at six-month intervals. Plan for Safety Review. Every effort will 
be undertaken to monitor and minimize the risks to subjects.  Prior to obtaining 
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informed consent, subjects will be encouraged to thoroughly read the informed 
consent form and ask questions regarding the outlined procedures and risks, and be 
informed of all tests involved in the screening process.  
Data Monitoring Plan  
To ensure data quality and study integrity, all study data will be collected by the 
research team, recorded on data flow sheets or case report forms, and stored in 
locked file cabinets or secure electronic databases.   
Data monitoring for this Phase II study will be carried out by a Monitor from the Data 
Management Coordinating Center (DMCC) of the RDCRN, who will visit the trial 
sites at regular intervals and be available for discussions by telephone.  The 
purposes of these visits are to verify that the rights and well-being of study subjects 
are protected, reported trial data are accurate, complete, and verifiable from source 
documents and that the conduct of the trial is in compliance with the currently 
approved protocol and any amendments, and with applicable regulatory 
requirements.  
The Monitor must be given direct access to source documents (original documents, 
hospital charts – including electronic medical records, and other pertinent data and 
records).  Direct access includes permission to examine, analyze and verify any 
records and reports that are important to the evaluation of the clinical trial.  If these 
are removed from the site, identifying information other than initials and date of birth 
must first be removed.   
The following items must be verifiable in source documentation other than the CRF: 
- 
Existence of subject (initials, date of birth) 
- 
Confirmation of participation in trial (subject ID, trial ID and signed and dated 
research consent form) 
- 
Diagnosis/indication under investigation 
- 
Visit dates 
- 
Adverse events or signs and symptoms (description and duration) 
- 
Relevant medical history and/or concomitant illness(es) 
- 
Concomitant medication 
- 
Blood pressure, pulse, weight and height  
- 
Reason for exclusion or withdrawal 
For all other items the data recorded in the CRF are considered as source data.  The 
Monitor will ensure that the CRFs are collected.   
10. Data Management 
Data Management will be through the DMCC of the NIH RDCRN, which will design a 
secure web-entry database for this study.  Data will be entered at the Porphyria 
Center at the University of Texas Medical Branch or other sites.  Data downloaded 
from the database for further analysis will identify subjects by study number, without 
personal identifiers.  The identity of subjects will be excluded from all presentations 
and publications.   
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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. 
 
All study data will be collected via systems created in collaboration with the RDCRN 
DMCC and will comply with all applicable guidelines regarding patient confidentiality 
and data integrity. 
 
11. Evaluability of Subjects for Analysis 
The data analysis for efficacy will include all randomized subjects who were 
randomized and exposed to the study drug or placebo, fulfilled inclusion and 
exclusion criteria, and for whom there were no protocol violations or deviations that 
affect assessments of efficacy.   All subjects exposed will be included in the safety 
analysis.  
The decision to exclude any subject or observation will be recorded, and the reasons 
for their exclusion will be documented and signed by those responsible for the 
exclusion.  This documentation will be stored with other trial documentation.   
12. Statistical Analyses 
Statistical analyses will be conducted in the Office of Biostatistics at UTMB by 
Kristofer Jennings, PhD, Assistant Professor in the Division of Biostatistics, 
Department of Preventive Medicine and Community Health at UTMB.   
12.1 Purposes 
The main purpose of the statistical analyses is to test the null hypothesis that 
observed differences between the two treatment groups could have been produced 
solely by chance – the alternative being that differences were due to the difference in 
treatment (i.e. Panhematin™ vs. placebo) – and to estimate the differences between 
measurements for the two treatment groups.  The primary outcome will be change in 
pain score.  In addition, secondary outcomes will be assessed, including use of 
opiods for pain, other symptoms, use of rescue treatment, length of hospital stay and 
time to next attack.  Biochemical parameters, such as urine and serum levels of 
PBG, will be analyzed also, because it is recognized that hemin is almost always 
associated with biochemical improvement.  However, it is known that these 
biochemical changes do not necessarily predict clinical improvement.  
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12.2 Variables for statistical analyses 
12.2.1 Efficacy variables 
The primary efficacy endpoints is:  
 Change in NRS pain score at 12 hours 
Secondary efficacy endpoints are:  
 Change in NRS pain score at later time points 
 Use of opioid for pain 
o Use of morphine or other opioid in each 24 hour period 
o Time to last administration of opioid  
 Other symptoms 
o Scores for nausea, vomiting and other symptoms will be recorded on a 
0-to-10 scale over each 24 hour period 
o Use of medication for nausea, vomiting or other symptoms in each 24 
hour period 
o Time to last administration of medication for such symptoms 
 Rescue treatment with open label Panhematin™ 
o Rescue treatment given or not given 
o Time to rescue treatment 
 Length of hospital stay 
 Time to occurrence of next attack 
The main clinical efficacy variable, which is also the basis for sample size projection, 
is the change from baseline to 12 hours after commencement of treatment in NRS 
score for pain intensity.  Secondary comparisons will include differences from 
baseline at 24, 48, 72 and 96 hours and the sum of pain intensity differences (SPID).  
Baseline is the pre-treatment score just before starting therapy.  Values recorded 
after starting rescue Panhematin™ will not be part of the analysis comparing blinded 
study drug and placebo.  But if rescue treatment occurs before 12 hours, the last 
pain score before rescue treatment and at least 6 hours after starting treatment will 
be used in the analysis.  The analysis will be based on intent to treat, excluding post-
rescue scores.   
Secondary efficacy pain-related variables include pain scores at later time intervals, 
total daily dose of morphine, time to last administration of morphine, time to rescue 
treatment with open label hemin, time to discharge from the hospital and time to the 
next attack.   
Opioids may decrease pain intensity for up to four hours and therefore have a 
lowering effect on NRS scores during that time.  Therefore, NRS scores are 
recorded immediately prior to each administration of morphine throughout the trial. 
But it may not always be possible to avoid giving opioids for a four hour period 
before a NRS score is recorded.  We will examine two methods for dealing with 
these occurrences.  1) NRS scores for pain recorded within 4 hours after 
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administration of an opioid will be excluded from the analyses.  2) Scores within 4 
hours after an opioid will be imputed based on an earlier NRS score recorded within 
the previous 4 hours and not preceded by opioid administration within the preceding 
4 hours.  This second method will be used only if imputed scores are distributed 
evenly between the two treatment groups.   
Differences in scores at 12, 24, 48, 72 and 96 hours will be analyzed statistically as 
described below.  Also, the sum of pain intensity differences (SPID) will be derived 
and subjected to statistical analysis, as the time weighted pain intensity differences: 
SPID = 

6
1
k
(NRS0 – NRSk)(Tk-Tk-1), 
where NRSk and Tk are the NRS scores and times respectively for k= 0, 12, 24, 48, 
72 and 96 hours after treatment.   
Secondary efficacy and exploratory endpoints also include biochemical effects of 
treatment, time to hospital discharge and to next attack, and the effects of genetic 
and clinical features on treatment response.   
The following biochemical endpoints will be analyzed:  
 Serum (or plasma) ALA, PBG and porphyrins  
 Urinary total porphyrins, including fractionation of individual porphyrins by 
HPLC 
 Plasma porphyrins, including fractionation of individual porphyrins by 
HPLC (if elevated initially) 
 Fecal porphyrins, including fractionation of individual porphyrins by HPLC 
(if elevated initially) 
The area under the ‘reduction in PBG relative to baseline’ versus time curve (AUC 
PBG reduction) will be determined by the linear trapezoid rule for each 24 hour period 
during treatment.   
The relative plasma PBG reduction (% reduction relative to baseline, R) at time t is 
calculated as one hundred multiplied by one minus the plasma PBG at time t (PBGt) 
over the plasma PBG at time zero (immediately before dosing): 
R = 100 * (1 – (PBGt/PBG0)) (%), R 1. 
Note that R may be negative if PBG exceeds the baseline level. 
A few sporadically missing values will be disregarded and replaced by linear 
interpolation for application of the trapezoid rule.  Any other options considered for 
handling missing values will be finalized before unveiling the treatment allocation.  
Changes in ALA and porphyrins will be analyzed in the same way as for PBG.   
12.2.2 Safety variables 
As noted earlier, safety endpoints will include:  
 Symptoms 
 Finding on physical examination including vital signs 
 Routine clinical testing daily including 
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o Complete blood counts 
o Metabolic and liver panels 
o Coagulation panel (platelets, prothrombin time and partial 
thromboplastin time) 
 Unexpected adverse events 
These will be subjected to descriptive analyses and differences between the 
treatment groups analyzed for significance as described below.   
12.3 Statistical Methods 
All tests for significance will be two sided at the 5% significance level and 
accordingly 95% confidence intervals will be determined.   
The main clinical efficacy variable, change in pain from baseline after 
commencement of treatment will be analyzed by analysis of covariance with 
treatment as a factor and baseline value as a covariate.  Data for the post 
randomization exclusions will be listed and the possible impact assessed.   
Length of hospitalization and total dose of opioids received will be analyzed by exact 
two sample Wilcoxon tests. The use of rescue treatment with hemin within each 
treatment group will be analyzed by  Fisher’s exact test, and the time to use of 
human hemin, the time to last administration of opioids and the time to new attack 
will be analyzed by exact log rank test.  The analysis of time to next attack will be 
done separately in the groups of subjects with attacks related or not related to the 
menstrual cycle. 
Efficacy analyses for changes in biochemical parameters (AUC PBG reduction , etc.) will 
be an exact two sample Wilcoxon test and associated Hodges-Lehmann confidence 
interval for difference in medians.  Changes from baseline to end of treatment will be 
analyzed by analyses of covariance with baseline value as a covariate.   
Supplementary analyses of the role of clinical features, such as attack relationship to 
the menstrual cycle will be performed.  
Pain intensity difference based on NRS for current pain will be analyzed by repeated 
measures analysis of variance.   
Analyses of signs and symptoms will be descriptive. 
Safety variables such as physical and laboratory findings will be analyzed 
descriptively, using shift tables – screening versus end of treatment or by repeated 
measures analysis of variance.   
Adverse events will be coded and analyzed descriptively.   
12.4 Sample size determination 
The primary outcome measure in this study will be the difference in NRS pain score.  
The power to detect a treatment-related difference in pain and other measurements 
increases with the magnitude of the difference in, for example, pain intensity before 
and after treatment.   
A minimum clinically relevant difference between the means of NRS pain scores on 
a 0-10 scale is judged to be 1.5 (64).  A sample size of 20 in each group will have 
80% power to detect a difference in means of 1.5 assuming that the common 
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standard deviation is 1.65 using a two group t-test with a 0.050 two-sided 
significance level. 
12.5 Interim analyses 
An interim analysis is planned after the first 15-20 subjects, since there are a number 
of uncertainties related to variance in treatment outcomes and the potential effects of 
factors such as opioid administration and rescue treatment on outcome measures.  
An interim analysis is appropriate in a phase 2 study such as this that has an 
intentionally flexible study design.   
It is anticipated that there will be large differences in pain and other efficacy 
parameters in this study, but differences in NRS pain scores may be reduced by 
opioids needed for symptom control.  Rescue treatment may also reduce the power 
of the observations.  Only one adequately powered double-blind placebo-controlled 
study of treatment of acute attacks of porphyria (with recombinant human PBGD) 
has been done previously, and that study did not show a positive treatment effect 
(unpublished); variance in outcomes from that study have not been made available 
(7).  Therefore, an interim analysis will be important in this study to consider 
adjustment in sample size and possibly even treatment outcomes.   
The sample size needed to have 80% power to reject the null hypothesis of no effect 
by the appropriate test at the 5% significance level will be determined based on this 
minimum clinically relevant difference.  If the estimated sample size is smaller than 
30 the trial will stop after 30 patients have completed; if it is 30-40, the trial will 
continue to 40 patients; if it exceeds 40 the trial will continue until this sample size 
has been reached, if that is feasible.  If it is not feasible to reach a target sample 
size, or if it is not even feasible to find enough patients to have 80% power for 
establishing either biochemical or clinical efficacy, the trial will continue and stop 
when 40 patients have completed.   
A statistician will unblind the data for this analysis sufficiently to separate the two 
treatment groups, but blinding will be preserved for all others.  An interim analysis is 
planned after completion of 15-20 subjects, to determine a reasonable estimate of 
the variance, as stated above in 12.4. 
13. Ethical considerations 
The study will be conducted in accordance with accepted standards for human 
studies, including the Declaration of Helsinki. The study will be approved by the IRB 
at each participating center, and changes made in study documents as needed to 
achieve these approvals.   
13.1 Assessment of Risks 
Patients enrolled in this study have clinical indications for treatment with 
Panhematin™.  Therefore, the risks from this study will not be substantially different 
from standard treatment, which would likely include Panhematin™.   
The following are reported or possible risks related to the products and procedures in 
this study.  How these risks will be minimized is noted.   
Risks related to the randomized study design and other study procedures:  
 Progression of symptoms due to initial randomization to placebo and 
treatment at least initially with glucose rather than Panhematin™.   
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This risk will be minimized, because all patients are provided with intravenous 
glucose treatment, which may be sufficient treatment in some cases, and the 
study design allows for rescue treatment with Panhematin™.  Patients will be 
treated early in an attack, so any delay in rescue treatment will not be prolonged.  
Moreover, some patients who might benefit from Panhematin™ which they might 
not have been given as part of standard care, and others who respond to glucose 
will not be at risk from side effects of Panhematin™.   
 Blood drawn in this study could contribute to iron deficiency.  The volume of 
blood drawn will depend on the length of treatment with Panhematin™ or 
placebo.  We expect that the great majority of patients will be treated for 4 
days.  The volume drawn will total <160 mL if the patient is treated for 4 days, 
or <260 mL if treatment is required for 10 days.  
This may be somewhat more than would have been drawn during standard 
treatment, but safety assessments may provide for earlier detection and 
correction of complications, such as electrolyte imbalances.  Iron status will be 
assessed by serum iron, iron-binding capacity and ferritin measurements and 
corrected with iron supplements if clinically indicated.   
Risks of Panhematin™: 
This includes reported effects of other human hemin preparations.   
 Reversible renal shutdown was observed in a case where an excessive 
hematin dose (12.2 mg/kg) was administered in a single infusion. Oliguria and 
increased nitrogen retention occurred although the patient remained 
asymptomatic (50).   
No worsening of renal function has been seen with administration of 
recommended dosages of hematin (50, 65).   
 Phlebitis at the site of intravenous infusion is common, which can lead to loss 
of venous access in patients who require repeated treatment.   
This is felt to be due to degradation products of hematin, and use of human 
albumin rather than sterile water for reconstitution of the lyophilized product (37, 
44) is expected to reduce the risk of this complication in this study.  
 A transient anticoagulant effect manifested by prolonged PT and PTT and 
thrombocytopenia is also common, which in one case may have contributed 
to gastrointestinal bleeding (66).   
This transient coagulopathy is thought to be due to degradation products of 
hematin, which are formed before infusion if the product is reconstituted with 
sterile water.  This side effect, which is not usually sufficient to cause bleeding by 
itself, can be prevented by stabilizing hematin with human albumin.  Therefore, it 
seems unlikely that hematin reconstituted with albumin will worsen a pre-existing 
coagulopathy, although to our knowledge this has not been studied.  Preexisting 
coagulation abnormalities or concurrent anticoagulant therapy will not be reasons 
for exclusion if the investigators and medical team agree that treatment with 
hemin is indicated clinically and the potential benefits of treatment outweigh the 
risks.   
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 Fever, aching and malaise are sometimes seen (48, 49).  Some patients have 
noted headache or migraine.   
These side effects are transient, and may be related to hematin degradation 
products, although this is not established.   
 Very uncommonly reported side effects of hemin (hematin or heme arginate) 
have included hemolysis, anaphylaxis, and circulatory collapse (48, 49).  
Patients will be closely monitored for these rare side effects and for any other 
unanticipated effects.   
 Panhematin™ is made from human blood, and theoretically may contain 
infectious agents, such as disease-causing viruses, the Creutzfeldt-Jakob 
disease (CJD) agent, and unknown infectious agents. This risk has been 
reduced by screening blood donors for prior exposure to certain viruses, by 
testing for the presence of certain current virus infections, and by inactivating 
certain viruses.  
No pre- or postmarketing reports have associated such illnesses with 
administration of Panhematin™.   
 Iron overload can occur after repeated administration of hemin.  Amounts of 
hemin administered in this acute study are insufficient to cause iron overload, 
but might worsen pre-existing iron loading from previous courses of hemin 
treatment.  Serum ferritin will be measured in all patients to assess iron 
status, and if found to have iron overload they will be advised regarding 
management by repeated phlebotomies after recovery from the attack.    
Risks of placebo:  
There are no known risks from administration of a small volume of 0.9% saline. 
Risks for randomization to treatment with placebo rather than Panhematin™ are 
discussed above.   
Risks of glucose infusions:   
 Elevated blood glucose 
This represents a risk in patients with preexisting diabetes mellitus, and will be 
avoided by initial screening for elevated blood glucose or a history of diabetes. In 
patients with diabetes, blood glucose will be monitored and treated with insulin as 
clinically indicated.   
 Hyponatremia, seizures and fluid overload 
Hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion 
(SIADH) are common complications of acute porphyric attacks, and may lead to 
seizures if not recognized and treated.  Serum electrolytes will be monitored daily 
during treatment.  If hyponatremia is present initially, this will be treated according 
to clinical indications, which may include saline infusions and/or fluid restriction.  
The amounts of 10% glucose administered will be reduced if clinically indicated.  
Development or worsening of hyponatremia despite these measures is 
indications for rescue with Panhematin™.   
Risks from infusion of albumin.   
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 Rare allergic reactions.   
 Albumin is made from human plasma, and theoretically may contain infectious 
agents, as described for Panhematin™.   
 Albumin may expand the blood volume and could worsen the condition of 
patients with heart failure, significant chronic anemia or advanced kidney 
disease.   
 Some patients have complained of malaise or headache lasting for several 
hours after infusion of albumin with Panhematin™, but it is not clear that this 
is caused by albumin.   
Risks of loss of confidentiality of sensitive medical information.  Safeguards to 
reduce this risk include using unique codes rather than patient identifiers and other 
procedures to comply with the requirements of the Health Insurance Portability and 
Accountability Act (HIPAA).   
Certificate of Confidentiality 
 
To help protect participant privacy, a Letter of Confidentiality has been obtained from 
the National Institutes of Health (NIH).  With this Certificate, the researchers cannot 
be forced to disclose information that may identify a study participant, even by a 
court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings.  The researchers will use the Certificate to resist 
any demands for information that would identify a participant, except as explained 
below. 
 
The Certificate cannot be used to resist a demand for information from personnel of 
the United States Government that is used for auditing or evaluation of Federally 
funded projects or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA). 
 
Even with the Certificate of Confidentiality, the investigators continue to have ethical 
and legal obligations to report child abuse or neglect and to prevent an individual 
from carrying out any threats to do serious harm to themselves or others.  If keeping 
information private would immediately put the study participant or someone else in 
danger, the investigators would release information to protect the participant or 
another person. 
 
Department of Health and Human Services (DHHS) personnel may request 
identifying information for purposes of performing audits, carrying out investigations 
of DHHS grant recipients, or evaluating DHHS funded research projects. 
13.2 Assessment of benefits 
Patients may derive no immediate benefits from this study, since both treatments are 
available as standard of care.  However, demonstration that Panhematin™ is safe 
and effective in a well designed controlled study will benefit many patients with acute 
porphyrias, and especially those with frequent attacks.  The study may lead to 
greater recognition and acceptance of this treatment and eventually lead to 
broadening of the FDA-approved treatment indications.  The study will likely lead to 
NIH Approved 12-02-15

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more general acceptance of the use of albumin for reconstitution, which will increase 
safety of the product when used in clinical practice.  For these reasons, overall 
benefits are considered to outweigh the risks.   
13.3 Research consent 
Written informed consent will be obtained from each participant before any study-
specific procedures or assessments are done and after the aims, methods, 
anticipated benefits, and potential hazards are explained.  The participant’s 
willingness to participate in the study will be documented in writing in a consent form, 
which will be signed by the participant with the date of that signature indicated.  The 
investigator will keep the original consent forms and signed copies will be given to 
the participants.  It will also be explained to the participants that they are free to 
refuse entry into the study and free to withdraw from the study at any time without 
prejudice to future treatment.  Written and/or oral information about the study in a 
language understandable by the participant will be given to all participants. 
13.4 Institutional Review Boards 
Prior to commencement of the trial, the protocol, any protocol amendments, the 
research consent form and any other written information to be provided for the 
subject must be submitted to and approved by the IRB.  Other documents, such as 
investigators’ CVs or Biosketches will also be submitted to the IRB, as required.  
Since resources of a Clinical and Translational Science Award (CTSA) will be used 
at some sites, all documents should be jointly submitted for approval to the CTSA as 
well as the IRB, as appropriate.  Written final approval must be obtained from IRB 
and all other institutional requirements met before starting the study.   
During the trial, the Investigator must promptly report new information that affects the 
risk/benefit ratio to the IRB and, if required, the CTSA including unexpected SAEs 
where a causal relationship cannot be ruled out, amendments to the protocol, 
notification of administrative changes, any protocol deviations implemented to 
eliminate immediate hazards to the subjects, new information that may adversely 
affect the safety of the subjects or the conduct of the trial, annually written 
summaries of the trial status and other documents as required by the IRB.   
Amendments to the protocol or consent form must not be implemented before 
approval by the IRB, unless urgently necessary to eliminate hazards to the subjects.  
The Investigator must maintain an accurate and complete record of all submissions 
made to the IRB.   
13.5 Regulatory Authorities 
An application for an investigator IND has been obtained from the US Food and Drug 
Administration (FDA) for this study by the Coordinating Center (IND#13,929), and 
the protocol, amendments, reports on SAEs, annual reports and other documents 
will be provided as required by the FDA.  The Coordinating Center will submit to the 
FDA all required documents related to the participation of each site, and copies will 
be provided to each site for submission to local IRBs.   
14. Premature Termination of the Trial 
The Coordinating Center may decide to stop the trial or part of the trial at any time. A 
site may decide to withdraw from study participation at any time, and the site and 
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Coordinating Center must agree on procedures to be followed for withdrawal from 
the study.   
If a trial is prematurely terminated or suspended, the Investigator at each site should 
promptly inform the IRB and provide a detailed written explanation. The pertinent 
regulatory authorities should be informed according to national regulations.  The 
Investigator should also promptly inform the subjects and ensure appropriate therapy 
and follow-up.   
The NIH, the 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: 
 Early stopping rules have been met  
 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 DSMB suspends or closes the trial 
 The NIH suspends or closes the trial 
 The FDA suspends or closes the trial 
15. Deviations from the Protocol 
If protocol deviations occur, the Investigator must inform the Coordinating Center 
and the Monitor, and each deviation must be documented, stating the reason and 
date, the action taken, and the impact for the subject and/or the trial.  The 
implications of the deviation must be reviewed and discussed to help determine 
whether the deviation needs to be reported to the IRB and other regulatory bodies.  
The documentation must be kept in the study files of the site Investigator and the 
Coordinating Center.  
16. Essential Documents 
Before the Investigator starts the trial (i.e. obtains research consent from the first 
subject) the following documents must be provided to the Coordinating Center: 
- 
Curriculum vitae of Investigator and sub-investigator(s) (current, dated and 
signed and/or supported by an official regulatory document) 
- 
Signed and dated agreement of the final protocol 
- 
Signed and dated agreement of any amendment(s), if applicable 
- 
Final written approval from the IRB, with clear documentation of the 
documents that the IRB has reviewed, which must include the protocol title 
and protocol version date, any amendments, the research consent form, and 
any other written information to be provided to the subjects during recruitment 
- 
Copies of the IRB approved research consent form and any other written 
information or advertisements to be used for recruitment 
- 
Signed FDA forms documenting that the site Investigator is approved as an 
investigator in this study by the FDA.   
- 
Any other required regulatory approvals and/or notifications. 
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17. Reports and Publication 
The information obtained during this study by the participating group of investigators 
is considered confidential and will be used to prepare a joint Clinical Trial Report, a 
joint publication and possibly joint presentations of the study results at scientific 
meetings.  The investigators at all sites who enrolled patients in the study will be 
offered co-authorship.  The investigators agree that they will not individually submit 
data for publication or for presentation at scientific meetings until a joint publication 
has been accepted for publication, after which each investigator will have the right to 
publish results obtained at that site.   
18. Retention of Clinical Trial Documents 
All study records and source documents must be stored at each site for at least 15 
years or longer, or for the maximum time period permitted by the institution.  The 
Coordinating Center must be informed at study initiation the policy on storage that 
will be followed at each site.  No study-related documents should be destroyed 
before that time without notifying the Coordinating Center in advance.   
19. Indemnity Statement 
This is an investigator-initiated study that will be conducted by academic medical 
centers with support from federal grants.  The participating institutions will not 
provide indemnification for the marketed products used in this study, and local 
institutional policies regarding compensation for research-related injury will apply.   
20. Quality Control and Quality Assurance 
Monitoring functions for this study will be provided by the DMCC of the NIH RDCRN 
as described earlier (see Section 9).  Details will be provided prior to study initiation.   
21. References cited 
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biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: Scriver CR, 
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2. Sassa S. ALAD porphyria. Semin Liver Dis. 1998;18(1):95-101. 
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7. Harper P, Wahlin S. Treatment options in acute porphyria, porphyria cutanea 
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53. Mustajoki P, Himberg JJ, Tokola O, Tenhunen R. Rapid normalization of 
antipyrine oxidation by heme in variegate porphyria. Clin Pharmacol Ther. 
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porphyric attacks (abstract). Acta Haematologica. 1997;98, Supplement 1:120. 
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