Safety and Efficacy of Panhematin™ for Prevention of Acute Attacks of Porphyria
Phase: PHASE2
Conditions: Acute Intermittent Porphyria, Hereditary Coproporphyria, Variegate Porphyria
Sponsor: The University of Texas Medical Branch, Galveston

 
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Protocol: Panhematin™ Prevention Study 
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Clinical Study Protocol 
 
 
 
 
Safety and Efficacy of Panhematin™ for  
Prevention of Acute Attacks of Porphyria 
 
 
 
 
 
 
 
 
 
Trial phase: II 
 
 
 

 
University of Texas Medical Branch  
Porphyria Laboratory and Center 
Protocol: Panhematin™ Prevention Study 
Date: June 18, 2019 
Version: 7 
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Table of Contents  
1. 
Introduction ....................................................................................................... 5 
1.1 
Description of acute porphyrias and current treatment ................................. 5 
1.2 
Description of the drug under study ............................................................... 12 
1.3 
Rationale for this clinical trial .......................................................................... 13 
2. 
Objectives ........................................................................................................ 14 
2.1 
Endpoints. .......................................................................................................... 15 
3. 
Trial Design ...................................................................................................... 15 
3.1 
Type of Trial ....................................................................................................... 15 
3.2 
Rationale for the trial design ............................................................................ 17 
3.3 
Treatment of Subjects and Rationale for Treatment ..................................... 17 
4. 
Trial Population ............................................................................................... 18 
4.1 
Number of patient and sites ............................................................................. 18 
4.2 
Recruitment of Subjects ................................................................................... 19 
4.3 
Inclusion Criteria ............................................................................................... 19 
4.4 
Exclusion Criteria .............................................................................................. 22 
4.5 
Withdrawal Criteria ............................................................................................ 22 
4.6 
Subject Replacement ........................................................................................ 23 
5. 
Study materials ............................................................................................... 23 
5.1 
Study drug reconstitution and administration............................................... 23 
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 .............................................................................................................. 26 
5.6 
Treatment of acute attacks during the study ................................................. 27 
5.7 
Randomization ................................................................................................... 27 

 
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6. 
Methods and Assessments ........................................................................... 28 
6.1 
Visit Procedures ................................................................................................ 28 
6.1.1 
Visit 1 – Screening and Enrollment .................................................................................... 28 
6.1.2 
Visit 2: ..................................................................................................................................... 29 
6.1.3 
Visit 3, 4, etc. ......................................................................................................................... 30 
6.2 
Assessments for Efficacy................................................................................. 30 
6.2.1 
Clinical improvement ............................................................................................................ 30 
6.2.2 
Biochemical measures of improvement ............................................................................. 30 
6.3 
Safety Assessment............................................................................................ 30 
6.3.1 
Symptoms .............................................................................................................................. 30 
6.3.2 
Physical Examination ........................................................................................................... 30 
6.3.3 
Blood counts and chemistries ............................................................................................. 31 
6.3.4 
Urinalysis ................................................................................................................................ 31 
6.3.5 
Pregnancy test ...................................................................................................................... 31 
6.3.6 
Adverse Events ..................................................................................................................... 31 
7. 
Adverse Events ............................................................................................... 31 
7.1 
Definitions (ICH) ................................................................................................ 31 
8. 
Case Report Forms ......................................................................................... 32 
8.1 
Rules for Completing CRFs ............................................................................. 32 
8.2 
Corrections to CRFs.......................................................................................... 33 
8.3 
CRF Review and Data Entry ............................................................................. 33 
9. 
Monitoring Procedures .................................................................................. 33 
10. 
Data Management ....................................................................................... 34 
11. 
Evaluability of Subjects for Analysis ....................................................... 35 
12. 
Statistical Analyses .................................................................................... 35 
12.1 
Purposes ............................................................................................................ 35 
12.2 
Variables for statistical analyses .................................................................... 35 
12.2.1 
Efficacy variables ............................................................................................................. 35 
12.2.2 
Safety variables ................................................................................................................ 36 
12.3 
Statistical Methods ............................................................................................ 36 

 
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12.4 
Sample size determination ............................................................................... 36 
12.5 
Interim analyses ................................................................................................ 37 
13. 
Ethical considerations ................................................................................ 37 
13.1 
Assessment of Risks ........................................................................................ 37 
13.2 
Assessment of benefits .................................................................................... 40 
13.3 
Research consent .............................................................................................. 40 
13.4 
Institutional Review Boards ............................................................................. 40 
13.5 
Regulatory Authorities ...................................................................................... 41 
14. 
Premature Termination of the Trial ........................................................... 41 
15. 
Deviations from the Protocol..................................................................... 41 
16. 
Essential Documents .................................................................................. 41 
17. 
Reports and Publication ............................................................................. 42 
18. 
Retention of Clinical Trial Documents ..................................................... 42 
19. 
Indemnity Statement ................................................................................... 42 
20. 
Quality Control and Quality Assurance ................................................... 42 
21. 
References cited.......................................................................................... 42 
 
 

 
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1. Introduction 
The trial will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP)1 and applicable regulatory requirements.  The single site for this study is 
the University of Texas Medical Branch (UTMB) in Galveston, Texas.  Conducting 
the study at additional sites is not planned at this time.   
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 in adults and most commonly in 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 400 mutations described in different families.  Most known 
mutations cause the enzyme to be ~50% of normal in all tissues from birth, as 
  
1 Abbreviations used (in alphabetical order): AE, adverse event; ALA, 5-aminolevulinic acid; ADP, 
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; CPOX, coproporphyrinogen oxidase; CRF, case report form; CYPs, cytochrome P450 
enzymes; DMCC, Data Management and 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; ICTSA, Institutional Clinical and Translational Science Award; IRB, Institutional 
Review Board; NRS, numeric rating score, PBG, porphobilinogen; PBGD, porphobilinogen 
deaminase; PPOX, protoporphyrinogen oxidase; 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.   

 
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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 (CPOX) and 
protoporphyrinogen oxidase (PPOX), 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 1,6-8.  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 PPOX 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 1,9.   
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) 1,6,10.   
Many patients do well after one or a few attacks.  However, some develop 
frequently recurring attacks and more lasting symptoms, including depression and 
pain 11. Acute porphyria patients, and especially those with high excretion of 
urinary ALA and PBG are at increased risk for developing hepatocellular 
carcinoma and renal disease, especially after 40-50 years of age 12,13.   
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 

 
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porphyrin precursors and porphyrins in urine, plasma and feces.  A diagnosis 
should be confirmed by DNA studies, which is now standard of care.  The 
identified mutation can then be sought in relatives to detect those at risk for the 
disease 9.   
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.  Moreover, coproporphyrinogen and protoporphyrinogen 
that accumulate in HCP and VP may inhibit hepatic PBGD 14.  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 9.   
The inherited partial deficiencies of PBGD, CPOX or PPOX 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 15.  Hepatic induction of ALAS1 and CYPs 
is controlled by similar nuclear receptor-mediated mechanisms 1,16,17.   
The pathogenesis of the neurological symptoms and signs of the acute porphyrias 
is poorly understood 1,4,18.  A neurotoxic effect of ALA or one or more other 
intermediates or by-products 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) 10.  Reports that liver transplantation cures AIP supports the view 
that the liver produces a neurotoxic effect in this disease 19-21.  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.   

 
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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) 9.  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 needed for diagnosis of HCP and 
VP, and especially to differentiate these disorders from AIP 6,9,22,23. Urinary 
porphyrin levels generally remain substantially elevated in HCP and VP, even after 
ALA and PBG become normal, and are usually predominantly coproporphyrin III.   
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) 24,25.  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 IX in VP 6,9,22,23.   
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 9.  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 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.  Measuring creatinine allows evaluation for dilution.  Further testing on 

 
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the same spot urine sample, and on plasma, feces and erythrocytes (obtained 
prior to initiating treatment) differentiates AIP, HCP and VP 9.   
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 9.   
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 26.  
Mass spectrometry methods are also available.  A kit for rapid detection of 
increased PBG levels in urine was recommended 9,27, but unfortunately is no 
longer available.  Laboratories that measure urine PBG should be willing to 
expedite testing when requested.   
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 soon 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.  Ideally, major medical facilities should 
provide for in-house determination of urinary PBG levels within hours of obtaining 
the sample, because life-threatening progression of the disease may occur with a 
delay of several days in testing.  The single-void urine sample that is tested should 
then be refrigerated or frozen without additives and shielded from light for 
subsequent quantitative ALA, PBG, and total porphyrin determinations (which can 
detect ADP, and 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 9.   
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 

 
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therapy.  Marked increases in urinary and fecal total porphyrin levels and the 
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 9,25,28.   
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 excretion of 
coproporphyrin 9,29.   
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) 9.  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 
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 30,31; 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 32.  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 9.   
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 

 
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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 9.   
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 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 (referred to generically as hemin) is regarded 
as the most effective treatment for acute attacks of porphyria 1,9.  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)2 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 evident benefit in numerous individual cases and case series, rather 
than randomized, controlled studies 33-43.  One small blinded study of heme 
arginate, in which treatment was delayed for 2 days, showed biochemical but not 
clinical efficacy 44.  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 38.   
  
2 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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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 45-49.  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 10,43,50,51.  This helps preserve peripheral venous access in 
patients who require repeated courses of hematin.  Heme arginate is more stable 
in solution 52, but is also often reconstituted with albumin 53.  Less common 
reported side effects of hemin have included fever, aching, malaise, hemolysis, 
anaphylaxis, and circulatory collapse 54,55.  Excessive doses of hematin can cause 
acute renal tubular damage associated with excretion of heme in urine 56.  
Clearance of drugs that are metabolized by hepatic CYPs is reduced in some 
patients with acute porphyrias 57 and rapidly restored after intravenous hemin 58-60.   
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 9.  Moreover, clinical response to hemin may be 
delayed or incomplete when there is advanced neurologic damage, as may occur 
when treatment is started late 38.  Subacute or chronic symptoms, which may 
reflect persistent neurological damage after repeated or prolonged attacks, are 
unlikely to respond 35,61.  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) 9,38,62, 
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 63,64.   
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), a reduction in mortality was noted after the introduction of 
treatment with human hemin in 1971, but the difference was not statistically 
significant 11.  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 65.   
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 350 mg hemin, 240 mg sodium carbonate and 355 mg of sorbitol. 
The pH may have been adjusted with hydrochloric acid; the product contains no 
preservatives.   

 
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When mixed as directed with sterile water for injection, USP, each 48 mL provides 
the equivalent of approximately 336 mg hematin (7 mg/mL).  When reconstituted 
with 147 mL of 25% human serum albumin instead of sterile water, which is an off-
label recommendation, the hemin concentration is 2.4 mg/mL. 50 
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 43,50,51.  Phlebitis and coagulopathy 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 65.  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.”   
The low quality of the evidence applies to use of hemin for treatment of acute 
attacks of porphyria and also to its use for prevention of such attacks.  A separate 
double blind placebo controlled study protocol aims to improve the quality of the 
evidence for use on Panhematin™ for treating acute attacks.  This protocol 
addresses its use for prevention of frequently recurring attacks of porphyria.  This 
study is important because there is evidence that Panhematin™ is used quite 
frequently to prevent recurrent attacks of porphyria in the U.S.64 and there have 
been few studies to guide or justify its use for this indication 9,66.  Product labeling 
supports its use for prevention of recurrent attacks in women.  This is based on a 
single case report 66, and it is generally believed that frequently recurring cyclic 
attacks are best treated with a hormonal intervention such as a GnRH analogue 67.  
Therefore, the most promising and appropriate preventive use for hemin would 
likely be for frequently recurring noncyclic attacks.   
This study, as well as the study in acute attacks, 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) Current expert opinion is that at least 
for acute attacks, hemin treatment should be started promptly, without an initial 
trial of glucose 9.  Product labeling recommends treatment with Panhematin™ only 
after a trial of glucose for several days is not successful.  Glucose loading is 
sometimes effective for treating mild acute attacks 9, but is seldom effective for 
preventing recurrent attacks, and often leads to unwanted weight gain.  This study 
will likely provide evidence to support initial treatment with Panhematin™ for 
prevention of frequently occurring attacks.  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 

 
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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 for prevention of recurrent attacks of AIP, HCP or VP in men and in 
women with frequently recurring attacks 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 50 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 dose of 4 mg/kg rather than the 1-4 mg/kg daily 
recommended in product labeling.   
2. Objectives 
Patients available for this trial will already be on a prophylactic hemin regimen, and 
as part of the study will be offered the usual number of periodic prophylactic hemin 
(or placebo) infusions, which for most patients will be a single weekly infusion.  
Patients will be offered blinded infusions that correspond to the number of 
infusions they usually receive within approximately one week for prophylactic 
treatment.   
Primary Objectives:  
 To evaluate in 20 patients who are on a Panhematin™ prophylactic 
regimen whether a blinded dose of Panhematin™ is more effective than 
placebo in preventing an attack within the next 1-4 weeks.   
 To evaluate in these 20 patients whether hemin is as safe and well 
tolerated as placebo when administered in a blinded fashion.  Safety 
parameters will include the frequency and severity of phlebitis, nausea, 
vomiting and coagulation abnormalities.   
Secondary Objectives:  
 To evaluate the biochemical effects of Panhematin™ in patients treated 
with Panhematin™ to prevent attacks of acute porphyria by measuring 
urinary 5-aminolevulinic acid and porphobilinogen and serum 
porphobilinogen.  This will determine whether biochemical measurements 
are predictive of efficacy in preventing an attack.   
Exploratory Objectives:  
 To evaluate effects of clinical features, such as sex, age and the factors 
that precipitate attacks of porphyria on response to preventive 
administration of Panhematin™.   
 To evaluate effects of genetic features, including the nature or the PBGD, 
CPOX or PPOX mutation on response to preventive Panhematin™ 
 To evaluate the use of Panhematin™ reconstituted with 25% human 
albumin in patients treated to prevent acute attacks of porphyria  

 
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2.1 Endpoints. 
The primary efficacy endpoint is whether a Panhematin™ is more successful 
than placebo in preventing a porphyria attack within the next 1-4 weeks when 
given as the patient’s usual periodic prophylactic regimen given within 
approximately one week.  Symptoms during past acute attacks should have 
included severe abdominal pain requiring a narcotic analgesic.  An acute porphyric 
attack is defined by the presence of abdominal pain and one or more other 
characteristic manifestations such as tachycardia (heart rate 100 per minute or 
greater), nausea, vomiting, constipation, extremity pain, acute hypertension, low-
grade fever, objective evidence of peripheral neuropathy, ileus, dehydration, mild 
leukocytosis, or hyponatremia.  The manifestations of the recurrent attacks should 
have been similar to each other in nature (although not necessarily in degree or 
severity).  The presence or absence of all such symptoms will be recorded on the 
CRFs by study personnel who are blinded to the treatment that was given.   
The primary safety parameters will include the frequency and severity of 
phlebitis, nausea, vomiting and coagulation abnormalities.  An additional series of 
safety measures will include other symptoms, physical findings and laboratory 
measurements.   
Secondary efficacy endpoints will include urinary 5-aminolevulinic acid and 
porphobilinogen and serum porphobilinogen and comparisons of changes in these 
levels with prophylactic treatment with hemin and placebo.   
Exploratory objectives.  We will explore the effects of clinical features, such as 
sex, age, the factors that precipitate attacks of porphyria, and the nature of the 
PBGD, CPOX or PPOX mutation on response to Panhematin™ prophylaxis.  We 
will also gain experience on the use of Panhematin™ reconstituted with 25% 
human albumin in patients treated to prevent acute attacks of porphyria.  
3. Trial Design 
3.1 Type of Trial 
The trial is a double-blind, randomized, placebo-controlled, parallel group trial 
investigating the efficacy and safety of Panhematin™ for preventing acute attacks 
in at least 20 patients with well-documented acute porphyria (AIP, HCP or VP).  
These patients will (1.) have had frequent attacks in the past, with symptoms such 
as abdominal, back and/or limb pain and diagnosed after exclusion of other 
causes, and (2.) be on hemin prophylaxis for prevention of frequent attacks.  
Although clear guidelines have not been developed, it is expected that patients will 
have had 6 or more attacks in one year before starting hemin prophylaxis.  This 
would be considered justification for a preventive regimen of hemin on clinical 
grounds.  Most patients on hemin prophylaxis are given a single dose once 
weekly.  However, other prophylactic regimens are effective in some patients, 
such as twice weekly infusions or a series of 3-4 infusions at monthly intervals.  
Giving only one blinded infusion may not be meaningful for a patient for whom 
more than a single infusion is needed to prevent attacks.  Therefore, patients will 

 
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be offered the number of blinded infusions they usually are given within 
approximately one week for prophylaxis.  All infusions for each patient will be 
either Panhematin™ or placebo.  An interim analysis will be carried out after 
completion of ~10 patients to assess progress and possibly adjust the sample 
size.  The trial consists of the following: 
 A screening visit to determine eligibility and obtain informed consent 
 A treatment visit for administration of one or more double blind prophylactic 
doses of Panhematin™ or placebo, corresponding to each patient’s usual 
prophylactic regimen.  Depending on the regimen, this visit may be completed 
in one day or after the number of days corresponding to their usual prophylactic 
regimen over approximately one week.   
 Follow up visit at 1, 2, 3, and 4 weeks to assess response to the infusion of 
Panhematin™ or placebo.  These visits will be in person or by telephone.   
 Additional visits may be scheduled if needed, for example for treatment of 
symptoms.   
 Follow-up visits 3 and 6 months after the end of treatment either in person or by 
telephone 
Patients will have laboratory documentation of one of the acute porphyrias.  
Molecular documentation is also expected, although rarely a causative mutation 
cannot be detected.  Upon entry into the study they will be given in a blinded 
fashion one or more preventive dose of either Panhematin™ (4 mg/kg) or placebo.  
The number of infusions will correspond to the number of prophylactic doses of 
hemin they customarily receive over approximately one week.  A recurrent attack 
within the next 1, 2, 3 and 4 weeks will represent treatment failures.  Because at 
study entry most patients are expected to be on weekly prophylactic hemin 
treatment, and hemin is a short-acting drug, emphasis in the analysis will be on 
attacks occurring within 1 week after study treatment.   
Any attacks that occur during the study will be treated according to standard of 
care, which may include Panhematin™, either at the study site or at the patient’s 
usual treatment location.   
It is intended that 20 patients will complete treatment with a single blinded dose 
and at least 4 weeks of follow up.  A completed patient is one who meets all 
entrance criteria, has no exclusion criteria and completes the single dosing and at 
least one week of follow up, or is withdrawn because of an adverse event.   
The site for this study is the University of Texas Medical Branch (UTMB) at 
Galveston.  The UTMB Porphyria Laboratory will carry out laboratory 
determinations related to porphyria as needed for this study.  DNA studies to 
identify the familial mutation are now standard of care and will not be done as part 
of the study.   

 
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3.2 Rationale for the trial design 
A randomized, double-blind, placebo controlled study design is important for 
evaluation of clinical efficacy of a treatment or preventive regimen for acute 
porphyrias because the symptoms of these disorders (e.g. pain) are highly 
variable and subjective.  Physical signs other than pulse and blood pressure are 
also at least somewhat subjective.  A single dose of blinded treatment, or the 
number of doses corresponding to patients’ usual prophylactic treatment over 
approximately one week, was adopted because a blinded study of an extended 
course of preventive treatment would require repeated treatment visits to the study 
site, which is difficult unless a patient lives close to the site.  Also, most patients on 
hemin prophylaxis have been on a preventive regimen for an extended period, and 
are not available to be studied when prophylactic Panhematin™ is initiated.  On 
the other hand, many more patients are available who can travel even long 
distances to UTMB for a study that focusses on prophylactic dosing for less than 
approximately one week.    
A single dose or multiple doses of study drug within approximately one week does 
not fully test the effectiveness of a continued regimen of hemin prophylaxis.  
However, if Panhematin™ prophylaxis is effective in preventing attacks, a 
difference should be seen between the Panhematin™ and placebo groups in the 
effectiveness in preventing an attack over the next 4 weeks.  However, some 
patients may not remain constantly susceptible to attacks, and at times might not 
have an attack after a single dose of placebo.  Therefore, efficacy data will be 
collected for 4 weeks or until the next time the patient is treated with 
Panhematin™ (either for an acute attack or for prophylaxis), whichever is longer.  
Given the uncertainty of the follow up interval that will be most informative, and 
other related uncertainties, an interim analysis will be done after the first ~10 
patients to see if an adjustment in sample size or other protocol modification may 
be needed.   
Both groups will receive either a single dose, which can presently be considered 
the standard dose of Panhematin™ for a prophylactic regimen, or the 
individualized prophylactic regimen that has been judged clinically to be effective 
in an individual patient when given during approximately one week.  Any recurrent 
acute attacks that occur during the study will be treated as part of the study (i.e. 
with glucose or Panhematin™).  Observations made during treatment of individual 
patients will be made available to their doctors at the end of the study and may 
contribute to their future management.   
Potential study participants will be identified through the Porphyrias Consortium 
and its Longitudinal Study or referred by the American Porphyria Foundation as 
well as physicians countrywide.    
3.3 Treatment of Subjects and Rationale for Treatment 
Panhematin™ 4 mg/kg will be reconstituted with 25% human albumin 50 and 
infused over a 1 hour period.  The amount of albumin is based on achieving a 1:1 
molecular ratio for hemin and albumin 43,50.  Product labeling suggests that 

 
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Panhematin™, after reconstitution with sterile water, be infused within 15 minutes.  
After reconstitution with albumin, an infusion time of 1 hour is based on guidelines 
for infusion of the amount of human albumin used for reconstitution.  The longer 
infusion time of 1 hour is acceptable given the enhanced stability of hemin in the 
presence of albumin, and based on experience of investigators in the Porphyrias 
Consortium 9.   
Glucose infusions will be permitted during the study for treatment of acute attacks. 
Its use will be recorded but will not be specified by the study.  For treatment of 
acute attacks, Panhematin™ product labeling suggests an initial trial of glucose at 
a dose of 400 grams daily, whereas a dose of 300 grams daily as 10% glucose is 
generally accepted 9,68-70 and a higher dose given as 10% glucose may 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 71.  There are no 
guidelines or published experience for glucose loading for prevention of attacks, 
but based on expert experience the impression is that it is not very effective and 
may lead to unwanted weight gain.   
Symptomatic treatment, including opioids, needed to control pain and other 
symptoms during an attack that occurs during the study will be recorded.  Use of 
medications needed to control chronic symptoms, including pain, will also be 
recorded.      
4. Trial Population 
4.1 Number of patient and sites 
Patients to be randomized: 
20 
Patients to be evaluated and screened:  40  
Approximately 2 patients will need to be evaluated for every patient found suitable 
for study and randomization.  Patients who do not complete the study will need to 
be replaced.    
This study will be conducted at UTMB.  Although it will not be a project of the 
Porphyrias Consortium, which has been funded in part by a U54 grant from the 
National Institutes of Health (NIH) beginning in 2009, the other sites in the 
Consortium are aware of this protocol and will refer patients that seem appropriate 
for evaluation.  The Porphyrias Consortium is one of 23 NIH-funded consortia that 
comprise the Rare Disease Clinical Research Network (RDCRN).  Funds for the 
Porphyrias Consortium U54 grant is provided by the National Institute for 
Diabetes, Digestive and Kidney Diseases (NIDDK) and the NIH Office of Rare 
Diseases Research.  At present, the Consortium consists of 6 sites funded by the 
NIH grant, and 2 satellite sites that receive some support from the American 
Porphyria Foundation.   
The American Porphyria Foundation (APF) is an active patient support group and 
is a supporting partner in the Porphyrias Consortium.  The U54 grant supports 

 
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infrastructure for clinical research on porphyrias but not the costs of major clinical 
trials.  Funding by the FDA Office of Orphan Product Development beginning in 
September 2014 supports costs for this study and an acute treatment study, which 
is also a Porphyrias Consortium single-site study conducted at UTMB.  Recordati 
Rare Diseases, the manufacturer of Panhematin, provides some additional grant 
support for both studies and supplies study drug at no cost.   
4.2 Recruitment of Subjects 
The investigators will contact patients known to them who are likely to be eligible 
for the trial by phone.  Many of these patients will already be in contact with the 
Porphyrias Consortium.  Additional patients will be referred by the American 
Porphyria Foundation (APF), which has been an important referral source for 
previous porphyria studies.  Those patients not previously known to the study 
team at UTMB, the APF and the Porphyrias Consortium 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.  A 
Screening Log will be kept of all subjects who are contacted by phone.   
4.3 Inclusion Criteria 
1. Male or female aged 18 years 
2. Willing to provide written informed consent  
3. A diagnosis of AIP, HCP or VP confirmed by the following criteria, which are 
based on the criteria for enrollment in the Longitudinal Study of the Porphyrias 
Consortium.  For each type of porphyria, the inclusion criteria are based on 1) 
clinical features, 2) biochemical findings, as documented by laboratory reports 
(or copies) of porphyria-specific testing, and 3) molecular studies to identify a 
mutation in a porphyria-related gene.  Equivocal biochemical measurements 
may require confirmatory testing.  DNA testing is now considered standard of 
care and will not need to be done as part of this study.  DNA testing for acute 
porphyrias is available through participation in the Porphyrias Consortium’s 
Longitudinal Study (IRB#10-183), and is done by the CAP-approved laboratory 
at Mt. Sinai, which is the molecular laboratory resource for the Consortium.  
Such testing is also offered by major referral laboratories such as Mayo and 
GeneDx, and is currently offered at no cost by inVitae as part of a porphyria 
testing program supported by Alnylam Pharmaceuticals.  An identified mutation 
is not essential for enrollment, since it is known that a mutation cannot be found 
in a small fraction (<5%) of biochemically proven cases of porphyria.   
Diagnostic inclusion criteria:  
Acute intermittent porphyria (AIP): 
1. 
Clinical features – a history of consistent clinical features such as 
acute attacks of abdominal, back and/or limb pain 

 
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2. 
Biochemical findings: 
a. A marked increase in urinary or serum PBG before treatment with 
Panhematin™.   
i. Urinary PBG >8 mg/24 hours or g of creatinine, or >2 fold 
increase (relative to upper limit of normal (ULN) of 4 mg/24 
hours or mg/g creatinine) 
ii. Serum PBG >0.2 ug/dL, or >2 fold increase (relative to ULN of 
0.1 ug/dL) 
iii. Marked increases are expected at initial diagnosis and before 
treatment with Panhematin™.  But increases may be less 
marked in patients already on prophylactic treatment with 
Panhematin™.   
b. Normal or only slight increases in plasma and fecal porphyrins.   
i. Plasma porphyrins <4.5 ug/dL, or <5-fold increase (relative to 
ULN of 0.9 ug/dL); fluorescence scanning at neutral pH 
should show no peak or a small peak at ~620 nm.  Note: AIP 
patients with severe renal disease are an exception and may 
have substantial increases in plasma porphyrins.   
ii. Total fecal porphyrins <400 ug/g dry weight or <2-fold 
increase (relative to ULN of 200 ug/d dry weight 
c. Erythrocyte HMBS/PBGD activity - deficient in ~90% of cases 
i. Activity should be below the lower limit of normal, or <60% of 
the normal mean for the laboratory; this enzyme activity may 
be falsely low due to improper sample handling or 
physiologically increased when erythrocyte turnover is 
increased.   
3.  Molecular findings known:  
a. Disease-causing mutation in HMBS (also known as PBGD) in 
>95% of cases.   
b. Biochemical criteria will suffice if no mutation can be identified.   
4. Previous acute attacks of porphyria, consisting of symptoms such as abdominal, 
back and/or limb pain, diagnosed by the investigator as caused by porphyria after 
exclusion of other causes, and currently on a prophylactic regimen of 
Panhematin™.   
 
Hereditary coproporphyria (HCP): 
1.  Clinical features – a history of consistent clinical features such as acute 
attacks of abdominal, back and/or limb pain 

 
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2.  Biochemical findings: 
a. A marked increase in urinary or serum PBG and/or in urinary 
coproporphyrin III before treatment with Panhematin™. 
i. 
For urinary and serum PBG, same as for AIP (see above) 
ii. 
For urinary total porphyrins: >450 nmol/24 hours or g of 
creatinine, or more than 1.5-fold increase (relative to ULN 
of 300 nmol/24 hours or g of creatinine 
b. Normal or only slight increases in plasma porphyrins.   
i. 
Plasma porphyrins <5 ug/dL, or <5-fold increase (relative 
to ULN of 0.9 ug/dL); fluorescence scanning at neutral pH 
should show no peak or a small peak at ~620 nm.  Note: 
this criterion applies to HCP patients without skin lesions.  
Skin lesions are rare in this disease, but if present are 
often accompanied by substantial increases in plasma 
porphyrins.  An exception will be made for this criterion in 
such cases.   
c. A substantial increase in fecal porphyrins, with a predominance of 
coproporphyrin III.   
i. 
Total fecal porphyrins >400 ug/g dry weight or >2-fold 
increase (relative to ULN of 200 ug/g dry weight, with a 
predominance of coproporphyrin III and a coproporphyrin 
III/I ratio >1.5 
3.   Molecular findings known:  
a. Disease-causing mutation in CPOX in >95% of cases.   
b. Biochemical criteria will suffice if no mutation can be identified.   
4. Previous acute attacks of porphyria, consisting of symptoms such as 
abdominal, back and/or limb pain, diagnosed by the investigator as caused by 
porphyria after exclusion of other causes, and currently on a prophylactic 
regimen of Panhematin™.   
 
Variegate porphyria (VP): 
1.  Clinical features – a history of consistent clinical features such as acute 
attacks of abdominal, back and/or limb pain 
2.  Biochemical findings: 
a. A marked increase in urinary or serum PBG and/or in urinary 
coproporphyrin III (same criteria as for HCP) before treatment with 
Panhematin™. 

 
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b. Increases in plasma porphyrins and a fluorescence emission peak at 
~626 nm.   
i. 
Plasma porphyrins >2.7 ug/dL, or >3-fold increase (relative 
to ULN of 0.9 ug/dL) 
ii. 
Fluorescence scanning at neutral pH showing a peak at 
~626 nm.   
c. 
Substantial increase in fecal porphyrins, with a predominance 
of coproporphyrin III and protoporphyrin IX.   
i. 
Total fecal porphyrins >400 ug/g dry weight or >2-fold 
increase (relative to ULN of 200 ug/d dry weight, with a 
predominance of coproporphyrin III and protoporphyrin 
3.   Molecular findings known:  
a. Disease-causing mutation in PPOX in >95% of cases.   
b. Biochemical criteria will suffice if no mutation can be identified.   
5. Previous acute attacks of porphyria, consisting of symptoms such as 
abdominal, back and/or limb pain, diagnosed by the investigator as caused by 
porphyria after exclusion of other causes, and currently on a prophylactic 
regimen of Panhematin™.   
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 
All inclusion and exclusion criteria must be satisfied for inclusion of a patient in the 
efficacy analysis.   
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.   

 
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Patients who require treatment of acute attacks with open label Panhematin™ are 
not withdrawn from the study.   
Patients withdrawn will be offered standard of care treatment, which may include 
Panhematin™, at the study site or through their own physician.   
4.6 Subject Replacement 
Subjects who are enrolled initially and then found not to meet inclusion criterion 
will be replaced in order to provide 20 patients eligible for randomization and trial 
completion. 
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 Rare Diseases in a vial containing 
either 350 mg of product, and reconstituted with 147 mL of 25% human serum 
albumin 43,50.  Standard directions for dose preparation using either vial are in 
place in the UTMB Pharmacy and are reflected here.   
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 313 mg 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.  
Procedure for reconstitution of Panhematin™ 50.   
The following materials are needed:  
1. One 350-mg vial of 
Panhematin™.   
2. One 150-mL or 
larger sterile empty 
glass bottle for 
infusion; a second 
bottle is needed for 
processing the 
350-mg vial of 
Panhematin.   
3. Three 50-mL vials 
of 25% albumin (only 147 mL will be used) 
4. One 5-micron filter needle  
5. One vent needle.   
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 313 mg Panhematin™ should be 
used per single dose. 

 
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To prepare Panhematin™ for infusion.  (Note that the 350-mg vial requires 147 mL 
of 25% albumin.  Because only 132 mL of 25% albumin will fit in the vial, this 
amount is used initially, followed by the additional 15 ml of 25% albumin):   
1. Reconstitute the 350-mg vial of Panhematin™ initially 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).   
3. Withdraw the full contents of the vial into a syringe.   
4. Inject the full contents (350 mg hemin reconstituted with 132 mL 25% 
albumin) into a 150-mL empty sterile bottle.   
5. After the full contents is transferred to a sterile glass bottle (as described in 
step 4 above) add an additional 15 mL of 25% albumin to the original vial, 
swirl as in step 2 and transfer this using a syringe to the same 150-mL 
bottle, which will now contain 350 mg hemin reconstituted with 147 mL of 
25% albumin. 
6. After reconstitution of the entire contents of the vial (350 mg hemin) with 
147 mL of 25% albumin, the concentration of hemin in the glass bottle is 2.4 
mg/mL. The volume required to deliver the desired dose (usually 4 mg/kg of 
body weight) should be calculated based on the patient’s body weight, but 
not to exceed 313 mg.  See Table for example volumes for some example 
body weights. 
7. Withdraw the calculated required dose for the patient into a syringe by 
using a 5-micron filter needle. 
8. Inject the dose into a 150-mL empty sterile bottle. 
9. Label the bottle.   
10. Place the bottle in an amber bag to protect the mixture from light.  Also 
place a vented spike adapter in the bag.  To preserve blinding, do not label 
the amber bag.  (Customarily, a yellow Medication Administrations 
Recording blood products label (for both albumin and Panhematin™) would 
be attached to the amber bag.)  Then place the amber bag inside a STAT-
labeled bag. 
11. Hand-deliver the bag to the clinical unit immediately.  The infusion should 
be started within 1 hour or less of preparation.  The infusion is administered 
by an unblinded nurse and other blinding procedures are followed (as 
described in sections 5.2 and 5.5).  The heme–albumin complexes may be 

 
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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 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 43,50.  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.   
The study drug is administered at a dose of 4 mg/kg body weight.  The infusion is 
given over 60-90 minutes 50, 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 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 non-transparent container, so is not visible to study personnel or 
the patient.  One research nurse will have responsibility for the infusion and will 
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 drug or placebo will be administered through an already 
established intravenous access.  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.  The unblinded nurse will not otherwise be involved in the patient’s 
care or in collecting data. At completion of the one-hour infusion, the unblinded 

 
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nurse will remove the IV set and other materials to another location for disposal.  
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.  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 given within ±2 days of the 
time a prophylactic dose or series of doses would have been administered.  
Panhematin™ is FDA approved at the dosage level used in this study.   
It is recommended in product labelling that Panhematin™ be given once or twice 
daily.  Therefore, in this study a dose of Panhematin™ will not be given within 12 
hours of a previous preventive dose of active study drug.  If an attack occurs within 
12 hours of the study dose of Panhematin™ or placebo, open label treatment with 
Panhematin™ will be delayed until 12 hours after the last study dose of 
Panhematin™ or placebo.  If it considered clinically necessary to start open label 
Panhematin™ for treatment of the attack in less than 12 hours, the first therapeutic 
dose for the attack will be blinded, and will be Panhematin™ if the patient was 
randomized to placebo, and will be placebo if the patient was randomized to 
Panhematin™.  Whether active drug or placebo is given in this instance will be 
determined by the Pharmacy, where 1-2 individuals will not be blinded.   
5.4 Glucose administration 
Glucose loading will be permitted for treatment of acute attacks during the study at 
the discretion of the patient’s physician.  No particular amount or regimen will be 
required during participation in this study, although a recommendation may be 
made to treat intravenously with glucose 300 grams daily, which is considered the 
standard dosage for glucose loading 9,10,68-70,72.  This amount is usually delivered 
as 3 liters of 10% glucose infused daily for 4 days or longer.  Although larger daily 
amounts are sometimes recommended, this results in larger volumes of 
intravenous fluid and increased risk for fluid overload and hyponatremia.   
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, 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.  As described above (Section 
5.2), pharmacy personnel (1-2 individuals) and one study nurse who will 
administer the drug will not be blinded.  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 possible.  Any difficulties that might 
compromise blinding will be recorded.   

 
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5.6 Treatment of acute attacks during the study 
Attacks during the study that occur at the study site will be treated at the study site 
with the usual hemin regimen of 4 mg/kg body weight daily for 4 days, or longer if 
clinically indicated, as part of the study.  Attacks that occur after the patient leaves 
the study site and returns home will be treated in the manner considered optimal 
by the patient’s physicians.  Such treatment will be recorded but not prescribed by 
the protocol.  Study site physicians will be available to provide advice on 
management, as appropriate.  This will not be considered formally as rescue 
treatment since it is not prescribed in the study protocol.  It will be recommended 
that Panhematin™ be reconstitution with human albumin, as described above, 
since this is now considered optimal 9.  Blinding of the study treatment will be 
maintained during unblinded treatment of any acute attacks, unless doing so 
would compromise patient safety.   
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 9.  When two doses are given, an interval of at least 6-8 hours is 
customary.  During this study, a need to give two doses of Panhematin™ within a 
period of 12 hours will occur only if an acute attack develops and needs to be 
treated within 12 hours of the previous study dose of Panhematin™ or placebo.   
As noted above, if open label treatment with Panhematin™ is required less than 
12 hours after a blinded infusion, the first infusion for treating the acute attack will 
also be blinded, and the first infusion will be Panhematin™ if the patient was 
randomized to placebo, and will be placebo if the patient was randomized to 
Panhematin™.  This will avoid unblinding of the randomly assigned study 
treatment.   
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 
regarded as expected treatments rather than rescue treatments and are not a 
prescribed part of this study.   
5.7 Randomization 
Treatment in this double-blind, symmetrically randomized, parallel group trial study 
will be assigned by the study statistician, who will inform the Pharmacy of the 
assignment.  Randomization will be in blocks of 4, and occur after the inclusion 
and exclusion criteria are satisfied.  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.  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.   

 
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6. Methods and Assessments 
This study will be carried out in an outpatient setting, with an option for inpatient 
visits if needed, and will consist of screening and enrollment visits (designated 
Visit 1), followed by a treatment visit for blinded hemin or placebo administration 
(Visit 2), and post-treatment visits: weekly for the first month, then at3 and  at 6 
months.  Visits 1 and 2 may be combined to occur on the same day.   
6.1 Visit Procedures 
Visits are designated as shown below to facilitate scheduling of procedures and 
recording of study-related data.  All study visits will be numbered as a single 
consecutive series.  Variations outside specific windows will be recorded as a 
protocol deviations.   
Visit 1 
Screening and enrollment.  (If screening and enrollment 
require more than one visit, they will be designated 1a, b, 
etc.) 
Visit 2 
Administration of Panhematin™ or placebo.  (This visit might 
be on the same day as Visit 1.)  If additional days are 
needed at the study site, such as for additional doses of 
study drug for prevention, or for treatment of an attack of 
porphyria, these will be designated 2a, b, etc.   
Visit 3,4,5,6, 
7 & 8 
These will occur in person or by phone at weekly intervals 
for the first month to determine efficacy, and 3 and 6 months 
after completion of blinded treatment to record long terms 
effects of the study treatment and subsequent course and 
clinical treatment of the disease 
6.1.1 Visit 1 – Screening and Enrollment 
Patients will be fully informed about the purposes and procedures of the study, 
orally and in writing, and asked to sign an informed consent form approved by the 
IRB, which describes study procedures and the risks and potential benefits of the 
study.  Patients will be screened for eligibility and enrolled at Visit 1.  Any 
additional studies needed to determine eligibility will be done at that time.   
Procedures: 
After enrollment 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. 
2. Demographic Information, to include: 
- Date of Birth 
- Sex 
- Race and ethnicity 

 
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3. History, to include:  
- Year of first porphyria attack 
- Number of attacks during the past 6 months 
- 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 the most recent attack 
- Previous treatment with Panhematin™ 
4. Concomitant illnesses 
5. History of allergy 
6. Concomitant medications 
7. Use of opioid agonists during the previous 6 months 
8. Physical Examination, including:  
a. Body height and weight 
b. Vital Signs 
9. Electrocardiogram, if clinically indicated 
10. Recording of porphyria-related signs and symptoms 
11. Blood samples will be drawn for testing, to include erythrocyte PBGD activity, 
serum or plasma PBG and porphyrins, complete blood counts, and metabolic 
and hepatic panels 
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).  
This is now considered standard of care diagnostic testing for porphyrias, and 
is widely available.  A separate consent form for this testing will be provided 
only if required by the testing laboratory.   
15. Urine pregnancy tests (for females of childbearing potential only). 
6.1.2 Visit 2:  
Procedures: 
The following will be performed and recorded in the CRF (at time of treatment): 
1. Concomitant medications, and any changes not recorded previously 
2. Vital Signs 
3. Recording of porphyria-related signs and symptoms 
4. Urine, blood and fecal samples for ALA, PBG and porphyrins (pretreatment) 
5. Recording of adverse events 

 
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6. Administration of a dose of study treatment (Panhematin™ or placebo) 
6.1.3 Visit 3, 4, etc.   
Procedures: 
Recording of clinical information and obtaining samples, as appropriate clinically.  
Observation and treatment of any attacks or symptoms of porphyria.   
6.2 Assessments for Efficacy 
6.2.1 Clinical improvement 
Attack prevention will be assessed especially over the 4 weeks following study 
drug administration.  The expectation is that efficacy in preventing an attack is 
most likely within the first week, or within the time interval between usual 
prophylactic dosing.   
6.2.1.1 Number of attacks and porphyria-related signs and symptoms 
At the post-treatment visits the patients will be queried about symptoms 
attributable to porphyria, treatment that was given for such symptoms and any 
doctor for hospital visits or admissions since the previous visit.  Symptoms 
recorded will include pain, nausea, vomiting, constipation and specified 
neurological and psychiatric symptoms.  This information will be recorded on the 
CRFs.   
6.2.1.2 Other clinical information 
Use of Panhematin™, glucose loading and potent opioid agonists since the last 
visit including the generic and trade names, dose, route of administration and time 
of each dose will be recorded.  
6.2.2 Biochemical measures of improvement 
Biochemical measures, to include urinary ALA, PBG and porphyrins, plasma PBG 
and porphyrins and fecal porphyrins will be measured at each visit, but will be 
optional for the follow up visits at 1, 2, 3, and 4 weeks and 3 and 6 months.  
Analyses will be performed at the Porphyria Laboratory of the University of Texas 
Medical Branch.   
6.3 Safety Assessment 
6.3.1 Symptoms 
Any new symptoms not related to porphyria will be recorded during the treatment 
period.   
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 at each visit, but will be optional 
for the follow up visits.  Height will be recorded only at Visit 1.   

 
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6.3.3 Blood counts and chemistries 
Blood samples will be drawn for complete blood counts and metabolic, hepatic and 
coagulation panels at each visit, but will be optional for follow up visits.  Analyses 
will be performed either by the hospital 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 UTMB, 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 UTMB at Visit 1.  Since pregnancy is not a reason for avoiding 
treatment with Panhematin™, a positive pregnancy test will not exclude a patient 
from entering or continuing the study.  Pregnancy will be recorded as a 
concomitant condition.   
6.3.6 Adverse Events 
Adverse Events will be recorded at each visit.   
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 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 a 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.   

 
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Serious Adverse Event (SAE): 
A SAE is defined and distinguished from a non-serious AE as follows:  
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 
* 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 
severe. 
8. Case Report Forms 
Case Report Forms (CRFs) will be prepared at UTMB for this study.   
8.1 Rules for Completing CRFs 
CRFs may be completed by investigators, coordinators and study nurses.  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. 

 
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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. 
8.3 CRF Review and Data Entry 
The original CRFs are reviewed by the investigator and study coordinator during 
the study and after completion of each subject.  CRFs are finalized after no further 
corrections or amendments to the content are expected.  After CRFs are verified 
and finalized, data will be compiled for analysis by the study biostatistician.  CRFs 
will be archived at a secure archiving location at UTMB.   
9. Monitoring Procedures 
Safety Monitoring Plan 
The risk level for this study is judged to be low, since treatment with Panhematin™ 
is already part of clinical practice and treatment of enrolled patients, 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 Section 13.1 below).  
Because this is not a Phase III clinical trial, a Data and Safety Monitoring Board 
(DSMB) is not required.   
Recruitment, enrollment, retention, adverse events, and study procedures will be 
monitored carefully by the PI and study coordinator(s).  They 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 study meetings that usually occur monthly, and discuss 
any instances of adverse events or unexpected problems encountered regarding 
patient safety or data collection.   
Plan for Adverse Event (AE) Reporting. See Section 7.  The investigators will be 
notified immediately if an AE occurs, and a medical member of the team will 
evaluate the patient and enter a note in the CRFs.  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, and others as required, within 24 h of occurrence or notification. The 
investigators, and the IRB are primarily responsible for determining whether 
modifications to the protocol and consent form are required.  If a determination is 

 
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made that participants are found to be exposed to excessive risks in relation to 
anticipated benefits, the study may be immediately suspended, unless corrective 
changes can be made quickly.  Studies will continue after modifications are made 
that are deemed to result in an acceptable risk/benefit ratio.  Aggregate reports of 
SAEs will be prepared on an annual basis and forwarded to the IRB and others as 
required.   
Plan for Safety Review. Every effort will be undertaken to monitor and minimize 
the risks to subjects.  Prior to obtaining 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.  The PI will be responsible for 
ongoing monitoring of data integrity and patient safety.   
This is an investigator-initiated single site clinical study that is supported by a grant 
from the FDA Office of Orphan Product Development.  Some additional grant 
support as well as study drug are provided by Recordati Rare Diseases.  External 
monitoring will not be required.  Data monitoring will be done, as described above, 
by the investigators and study coordinator.  The following items must be verifiable 
in source documentation: 
- 
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 medications 
- 
Blood pressure, pulse, weight and height  
- 
Reason for exclusion or withdrawal 
The data recorded in the CRF are considered as source data.   
10. Data Management 
The PI and research staff will be responsible for management of data as recorded 
on the CRFs or secure electronic databases.  Data downloaded from the database 
for 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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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 to active drug or placebo 
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 Epidemiology and 
Biostatistics of the 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 true 
differences between measurements for the two treatment groups.  The emphasis 
in the efficacy analysis will be the effects of treatment with Panhematin™ vs. 
placebo in preventing a subsequent attack in the week following a single infusion.  
Attacks occurring at weeks 2, 3 and 4 will also be subject to analysis, since 
recurrent attacks do not always occur at precisely predictable intervals.   
Biochemical parameters, such as urine and serum levels of PBG, will be analyzed 
also, but will not be primary efficacy measures.    
12.2 Variables for statistical analyses 
12.2.1 Efficacy variables 
The primary efficacy endpoint is the prevention of an acute attack during the first 
week following a blinded infusion of either Panhematin™ or placebo, and at other 
weekly intervals up to one month.   
Secondary efficacy and exploratory endpoints include changes in biochemical 
parameters during treatment, and the effects of genetic, clinical and demographic 
features on treatment response.   
The following biochemical endpoints will be analyzed:  
 Urine (or plasma/serum) ALA, PBG 
 Urinary total porphyrins, including fractionation of individual porphyrins 
by HPLC 

 
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 Plasma porphyrins, including fractionation of individual porphyrins by 
HPLC (if elevated initially) 
 Fecal porphyrins, including fractionation of individual porphyrins by 
HPLC (if elevated initially) 
Data related to these secondary endpoints will be subjected to descriptive 
analyses and differences between the treatment groups analyzed for significance 
as described below.   
12.2.2 Safety variables 
As noted earlier, safety endpoints will include:  
 Symptoms 
 Findings on physical examination including vital signs 
 Routine clinical testing daily including 
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, the occurrence or nonoccurrence of an acute 
attack each of the 4 weeks following test infusion, will be analyzed by logistic 
regression with treatment as a factor and drug dose as a covariate.  Data for any 
post randomization exclusions will be listed and the possible impact assessed.   
Use of Panhematin™ and opioids for treatment of porphyria symptoms during the 
4 weeks following treatment will be analyzed by exact two sample Wilcoxon tests 
or by Fisher’s exact test.   
Supplementary analyses of the role of demographic and clinical features will be 
performed.  
Adverse events will be coded and analyzed descriptively.   
12.4 Sample size determination 
The power to detect a treatment-related difference in frequency of attacks and 
other measurements increases with the magnitude of the differences that are 
induced by treatment.  A prior case series with cross over from a pre-existing 

 
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control period to open label use of heme arginate to prevent frequent attacks 
showed a substantial effect in some patients, but little effect in others.  That study 
suggests that a sample size of 20 should be sufficient.  However, the previous 
study may not be useful in assessing sample size for the current study, which is of 
a different design.  Therefore, an interim analysis is planned in this study after the 
first 10 subjects.  The biostatistician will unblind the data for this analysis, but 
blinding will be preserved for all others.   
The sample size needed to have 80% power to reject the null hypothesis of no 
effect using the two-sample comparison of proportions at the 5% significance level 
will be determined based on the initial sample.  For instance, if the probabilities of 
recurrence are 0.8 and 0.2 in the control and treatment groups respectively, the 
power to detect with 20 patients (10 patients per group) is 80%. However, if the 
treatment group chance of recurrence is 0.38, the estimated sample size is 40 (20 
patients per group).  If the estimated sample size is 20 or less the trial will stop 
after 20 patients have completed; if it is up to ~40, consideration will be given to 
increasing the number of completed patients to 40; if it greatly exceeds 40 the trial 
will continue until 20 patients have been completed.  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 clinical efficacy, the trial will continue and stop when 20 
patients have completed.   
12.5 Interim analyses 
An interim analysis is planned after completion of 10 subjects, to determine a 
reasonable estimate of the variance, as stated above in 12.4.  Given the change in 
inclusion criteria, a logistic model will be fit to assess the change in recurrence rate 
by dose.  We do not, however, expect that the dose or regimen effect will be 
statistically significant or have a substantial effect on the outcome. 
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 UTMB, as will changes made in study documents as appropriate.   
13.1 Assessment of Risks 
Patients enrolled in this study will have a history of frequently recurring attacks of 
porphyria and be on preventive treatment with Panhematin™, which is considered 
a clinical indication for use of this drug.  Therefore, the risks from administration of 
a single dose of Panhematin™ will not be substantially different from their 
standard treatment.   
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:  
 Occurrence of an attack due to randomization to placebo rather than 
Panhematin™.   

 
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This risk is small, because patients will be treated for an attack promptly in a 
manner at least as beneficial as their treatment before beginning prophylactic 
treatment.  The risks from treatment of an attack occurring after placebo will 
not be different or greater than for attacks that occur at other times.   
Patients on hemin prophylaxis will at some point need to stop treatment to see 
if it is still needed.  An attack that occurs in this study will be clinically beneficial 
because it provides some useful clinical information, and reinforces the need 
for continued hemin prophylaxis.   
 Blood drawn in this study could contribute to iron deficiency.  The volume 
drawn at each visit will total <30 mL.   
This may be somewhat more than would have been drawn if the patient were 
not enrolled in the study.  Iron status will be assessed by serum ferritin 
measurements and corrected with iron supplements if clinically indicated.   
Risks of Panhematin™: 
This includes reported effects of Panhematin™ and 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 56.   
No worsening of renal function has been seen with administration of 
recommended dosages of hematin 56,73.   
 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 product43,50 
is expected to reduce the risk of this complication in this study.  The great 
majority of patients in this study are expected to have previously implanted 
chest wall ports to facilitate repeated hemin infusions, which also reduces the 
risk of phlebitis.   
 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 74.   
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.  
Patients with preexisting coagulation abnormalities or concurrently on 
anticoagulant therapy will be excluded if the investigator believes the risk is 
unacceptable.   

 
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 Fever, aching and malaise are sometimes seen 54,55.  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 
54,55.  
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™.   
Risks of placebo:  
There are no known risks from administration of a small volume of 0.9% saline. 
Risks from randomization to treatment with placebo rather than Panhematin™ 
are discussed above.   
Risks from infusion of albumin.   
 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.  Patients with these conditions will not be excluded from this study 
but will be observed closely.  Hemin for prophylaxis is often reconstituted 
with albumin in clinical practice, so there would be little or no increased risk 
compared to their usual ongoing prophylactic treatment with Panhematin™.   
 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).   

 
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13.2 Assessment of benefits 
Patients may derive no immediate benefits from this study, since hemin 
prophylaxis is available as standard of care.  However, demonstration that 
Panhematin™ is safe and effective as a preventive treatment 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 contribute to broadening of the FDA-
approved treatment indications.  The study will likely lead to 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 using a research consent form approved 
by the IRB at UTMB.  The investigators will give subjects the opportunity to ask 
questions before informed consent is given, and at any time thereafter.  Subjects 
will be given a copy of the signed consent form, and any additional written 
instructions and information needed.   
The research consent form must be signed and dated by the person who 
conducted the informed consent procedure.  The informed consent process will 
also be documented in the medical record or other source document.  All 
individuals who obtain informed consent must be approved to do so by the IRB.   
If information that may be relevant to the subject’s willingness to continue 
participating in the trial becomes available, the investigators must inform the 
subject in a timely manner, and if appropriate a revised written informed consent 
prepared and signed.  
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 UTMB IRB.  Other documents, 
such as investigators’ CVs or Biosketches will also be submitted to the IRB, if 
required.  Resources of the Institute for Translational Sciences (ITS) Clinical 
Research Center (CRC) will be used, and any additional review requirements will 
be met.  Written final approval must be obtained from the 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 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.   

 
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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 investigator IND has been submitted to the US Food and Drug Administration 
(FDA) for study of Panhematin™ at UTMB (IND#13,929), and the protocol, 
amendments, reports on SAEs, annual reports and other documents will be 
provided as required by the FDA.  The investigators will submit to the FDA all 
required documents related to ongoing study progress including annual reports 
and study amendments.   
14. Premature Termination of the Trial 
The investigators may decide to stop the trial or part of the trial at any time.  
If the trial is prematurely terminated or suspended, the PI will promptly inform the 
IRB and provide a detailed written explanation. The pertinent regulatory authorities 
will be informed according to national regulations.  The investigators will also 
promptly inform the subjects and ensure appropriate therapy and follow-up.   
15. Deviations from the Protocol 
If protocol deviations occur, these 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.  
16. Essential Documents 
The following must be maintained in study records for all investigators and study 
personnel: 
- 
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, 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 investigators are approved as 
an investigator in this study by the FDA.   

 
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- 
Any other required regulatory approvals and/or notifications. 
17. Reports and Publication 
The information obtained during this study is considered confidential and will be 
used to prepare abstracts, study reports, presentations at scientific meetings and 
publications.  Study subjects will not be individually identified in such presentations 
and reports.   
18. Retention of Clinical Trial Documents 
All study records and source documents must be stored for at least 15 years or 
longer, or for the maximum time period permitted by the institution.  No study-
related documents should be destroyed before that time without notifying the 
investigators in advance.   
19. Indemnity Statement 
This is an investigator-initiated study originating at UTMB that will be conducted by 
an academic medical center with support from federal and industry 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 PI and others on the 
study team, as described earlier (see Section 9).     
21. References cited 
1. 
Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme 
biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: Scriver 
CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, eds. The 
Metabolic and Molecular Basis of Inherited Disease, 8th edition. Vol II, 
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2. 
Sassa S. ALAD porphyria. Semin Liver Dis. 1998;18(1):95-101. 
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Akagi R, Kato N, Inoue R, Anderson KE, Jaffe EK, Sassa S. δ-
Aminolevulinate dehydratase (ALAD) porphyria: The first case in North 
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Deybach J-C. Acute intermittent porphyria (Chapter 86). In: Kadish KM, 
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Badminton MN, Elder GH. Molecular mechanisms of dominant expression 
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Meissner P, Hift RJ, Corrigall A. Variegate porphyria (Chapter 89). In: 
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Whatley SD, Puy H, Morgan RR, et al. Variegate porphyria in Western 
Europe: identification of PPOX gene mutations in 104 families, extent of 

 
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allelic heterogeneity, and absence of correlation between phenotype and 
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Lamoril J, Puy H, Whatley SD, et al. Characterization of mutations in the 
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Andersson C, Bjersing L, Lithner F. The epidemiology of hepatocellular 
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Andant C, Puy H, Bogard C, et al. Hepatocellular carcinoma in patients with 
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Meissner P, Adams P, Kirsch R. Allosteric inhibition of human lymphoblast 
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Anderson KE, Freddara U, Kappas A. Induction of hepatic cytochrome P-
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Peyer AK, Jung D, Beer M, et al. Regulation of human liver delta-
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Podvinec M, Handschin C, Looser R, Meyer UA. Identification of the 
xenosensors regulating human 5-aminolevulinate synthase. Proc Natl Acad 
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Seth AK, Badminton MN, Mirza D, Russell S, Elias E. Liver transplantation 
for porphyria: who, when, and how? Liver Transpl. Sep 2007;13(9):1219-
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21. 
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Combined liver and kidney transplantation in acute intermittent porphyria. 
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Hift RJ, Davidson BP, van der Hooft C, Meissner DM, Meissner PN. Plasma 
fluorescence scanning and fecal porphyrin analysis for the diagnosis of 
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Kuhnel A, Gross U, Jacob K, Doss MO. Studies on coproporphyrin isomers 
in urine and feces in the porphyrias. Clin Chim Acta. 1999;282(1-2):45-58. 
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Longas MO, Poh-Fitzpatrick MB. A tightly bound protein-porphyrin complex 
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Poh-Fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate 
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Deacon AC, Peters TJ. Identification of acute porphyria: evaluation of a 
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erythrocytes and plasma: a rapid diagnostic method in primary and 
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of hepatic heme and repair by hematin infusions in the "inducible" hepatic 
porphyrias. Proc Natl Acad Sci USA. 1977;74(5):2118-2120. 

 
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34. 
Watson CJ, Pierach CA, Bossenmaier I, Cardinal R. Use of hematin in the 
acute attack of the "inducible" hepatic porphyrias. Adv Intern Med. 
1978;23:265-286. 
35. 
Lamon JM, Frykholm BC, Hess RA, Tschudy DP. Hematin therapy for acute 
porphyria. Medicine. 1979;58:252-269. 
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Pierach CA, Bossenmaier I, Cardinal R, Weimer M, Watson CJ. Hematin 
therapy in porphyric attacks. Klin Wochenschr. 1980;58:829-832. 
37. 
Kostrzewska E, Gregor A, Tarczynska-Nosal S. Heme arginate 
(Normosang) in the treatment of attacks of acute hepatic porphyrias. Mater 
Med Pol. Oct-Dec 1991;23(4):259-262. 
38. 
Mustajoki P, Nordmann Y. Early administration of heme arginate for acute 
porphyric attacks. Arch Int Med. 1993;153:2004-2008. 
39. 
Nordmann Y, Deybach JC. [Acute attacks of hepatic porphyria: specific 
treatment with heme arginate]. Ann Med Interne. 1993;144(3):165-167. 
40. 
Kostrzewska E, Gregor A. Acute hepatic porphyrias. Detection, prophylaxis 
and treatment. Mater Med Pol. Jan-Mar 1996;28(1):5-7. 
41. 
McColl KEL, Moore MR, Thompson GG, Goldberg A. Treatment with 
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