A Preliminary Study of the Efficacy and Safety of Carbamazepine in Severe Liver Disease Due to Alpha-1 Antitrypsin Deficiency
Phase: PHASE2
Conditions: Alpha-1-antitrypsin Deficiency, Liver Cirrhosis
Sponsor: Washington University School of Medicine

 
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ATD CBZ Study v. 14  February 19, 2016 
 
Cover Page 
 
Study Title: A Preliminary Study of the Efficacy and Safety of Carbamazepine in Severe Liver Disease 
Due to Alpha-1 Antitrypsin Deficiency   
 
 
NCT Number: NCT01379469 
 
 
Document Date: February 19, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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to Alpha-1 Antitrypsin Deficiency   
 
 
 
 
 
 
 
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ATD CBZ Study v. 14  February 19, 2016 
 
A Preliminary Study of the Efficacy and Safety of Carbamazepine in Severe Liver Disease Due to  
Alpha-1-Antitrypsin Deficiency  
 
Date:  February 19, 2016 
 
Sponsor-Investigator: 
 
David H Perlmutter, MD 
Department of Pediatrics 
University of Pittsburgh School of Medicine 
Children’s Hospital of Pittsburgh 
 
Sub-Investigators: 
 
Robert H. Squires, Jr., MD 
Ira Bergman, MD., PhD 
Kapil Chopra, MD 
Shahid Malik, MD 
George Michalopoulos, MD 
Alejandro Hoberman, MD 
Andrew Chu MD 
Steve H. Belle PhD 
Anthony Fabio PhD 
Sharon Lawlor MBA 
Philip Orons, MD 
Michael Dunn, MD 
Mitchell Tublin, MD 
Alessandro Furlan, MD 
Nikhil Amesur, MD 
 
Study Coordinators: 
 
Adam Kufen, RN, BS, CCRC 
Division of Gastroenterology 
Children’s Hospital of Pittsburgh of UPMC 
412-692-6558 
 
Kathleen Calabro, RN, BSN 
Division of Gastroenterology 
Children’s Hospital of Pittsburgh of UPMC 
412-692-6092 
 
Study Monitor:               
Mark E. Lowe, MD, PhD 
                                      
Division of Gastroenterology 
 
 
              
Children’s Hospital of Pittsburgh of UPMC 
 
 
 
 
 
 
 
 
 
Jeffery Rudolph, MD 
 
 
 
 
 
Division of Gastroenterology 

 
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ATD CBZ Study v. 14  February 19, 2016 
 
 
 
              
Children’s Hospital of Pittsburgh of UPMC 
 
 
 
 
 
 
 
 
Study Monitor Assistant:  
Kathy Bukauskas, RN 
Division of Gastroenterology 
Children’s Hospital of Pittsburgh of UPMC 
 
Amy Bookser, RN  
Division of Gastroenterology 
Children’s Hospital of Pittsburgh of UPMC 
 
 

 
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BACKGROUND AND RATIONALE 
 
INTRODUCTION 
 
Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children.  It also 
causes chronic liver inflammation and hepatocellular carcinoma in adults.  It is the most frequent genetic 
liver disease necessitating liver transplantation.  It is an autosomal co-dominant disorder affecting ~1 in 
2000 live births in most populations (1).  A point mutation alters the folding of an abundant hepatic 
secretory glycoprotein and renders it prone to polymerization/aggregation so that aggregated mutant protein 
accumulates in the endoplasmic reticulum (ER) of liver cells (2).  Several lines of evidence indicate that 
liver injury is caused by a gain-of-toxic function mechanism.  The most notable of these is the liver injury 
found in mice transgenic for the mutant human ATZ gene even though the endogenous anti-proteases of 
these mice are intact.  Studies in cell line and transgenic mouse models of AT deficiency have shown that 
several pathways are responsible for degrading mutant ATZ when it accumulates in the ER, including the 
proteasomal and autophagic pathways.  Furthermore, accumulation of mutant ATZ in the ER specifically 
activates the autophagic response (3).  
 
The severity of the liver disease varies dramatically among AT-deficient homozygotes (1).   The disease 
may present with prolonged jaundice in the newborn period and go onto slowly progressive liver 
dysfunction or may first present later in childhood, during adolescence or adulthood with portal 
hypertension, cirrhosis and/or hepatocellular carcinoma.  In a few cases liver failure occurs in the first year 
of life.  In many infants the jaundice will clear and later transaminases will normalize and further liver 
dysfunction never develops.  In some cases liver injury may never be detected.  Indeed, in the most 
important study of this disease Sveger screened all newborns in Sweden from 1972-1974 (4.5).  He 
identified 127 with homozygous PIZZ AT deficiency and has followed that cohort over the last 30+ years.  
Although many had jaundice or elevated transaminases in infancy, only 8% have had clinically significant 
liver disease.  The majority of these individuals have no clinical evidence of liver disease in their fourth 
decade of life.  Liver biopsies were not done in this cohort and so it is not possible to tell how many of the 
patients have subclinical liver damage.  It is well established that chronic hepatitis, cirrhosis and/or 
hepatocellular carcinoma can be detected incidentally in the liver in AT-deficient individuals at autopsy 
(6.7). It has not been possible to discern which infants who are diagnosed with AT deficiency because of 
prolonged jaundice or elevated transaminases will go onto severe progressive hepatic dysfunction. 
 
The diagnosis of this deficiency is based on low serum levels of AT and altered migration of the mutant 
protein in isoelectric focusing gel electrophoresis, called the PI type.  Although it is not pathognomonic, 
proteinaceous globules dilating the ER of liver cells and stained with periodic acid-Schiff after diastase 
treatment are a characteristic hepatic histological finding. 
 
The only treatment currently available for severe progressive hepatic dysfunction due to AT deficiency is 
liver transplantation.  Prior to transplantation, standard therapies (e.g. endoscopic band ligation and 
diuretics) for complications of portal hypertension are employed.      
 

 
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LIVER DISEASE IN AT DEFICIENCY 
 
Liver involvement in AT deficiency is often first noticed at the age of 1 to 2 months because of persistent 
jaundice (1). Conjugated bilirubin levels in the blood and serum transaminase levels are mildly to 
moderately elevated. The liver may be enlarged.  Infants may also be initially evaluated for AT deficiency 
because of an episode of gastrointestinal bleeding, bleeding from the umbilical stump, or bruising. A small 
number of affected infants have hepatosplenomegaly, ascites, and liver synthetic dysfunction in early 
infancy.  
 
An even smaller number have severe fulminant hepatic failure in infancy. A few cases are recognized 
initially because of a cholestatic clinical syndrome characterized by pruritus and hypercholesterolemia. The 
clinical features among these infants resemble those of extrahepatic biliary atresia, but histologic 
examination shows a paucity of intrahepatic bile ducts (1). 
 
Liver disease associated with AT deficiency may be discovered in late childhood or early adolescence, 
when the patient is seen with abdominal distension due to hepatosplenomegaly or ascites or with upper 
intestinal bleeding caused by esophageal variceal hemorrhage (1). In some of these cases, there is a history 
of unexplained prolonged obstructive jaundice during the neonatal period. In others, there is no evidence 
of any previous liver injury, even when the neonatal history is carefully reviewed. 
 
AT deficiency should be considered in the differential diagnosis for any adult who has chronic hepatitis, 
cirrhosis, portal hypertension, or hepatocellular carcinoma of unknown origin. An autopsy study in Sweden 
showed a higher risk of cirrhosis among adults with AT deficiency than was previously suspected and 
indicated that AT deficiency has a strong association with primary liver cancer (1). This study raised the 
possibility that the risk of clinical liver disease is as high as 25% among AT-deficient men in the fifth and 
sixth decades of life.  Numerous studies have indicated that AT deficiency is a more common cause of 
hepatic cirrhosis and hepatocellular carcinoma in adults than previously recognized. 
 
When a patient with the typical symptoms and/or signs of liver disease is evaluated, this diagnosis is 
determined by low serum levels of AT (10-15% of normal levels) and a distinct migration of the serum AT 
protein in isoelectric focusing gel electrophoresis (Pi type Z).  In addition to progressive fibrosis, the 
histological hallmark of the disease are intrahepatocytic deposits which stain with PAS after diastase 
treatment and immunostain for AT, representing the polymerized and aggregated mutant ATZ retained in 
the endoplasmic reticulum (1).     
 
In the absence of a reliable test for liver function, surrogate markers of cellular injury, synthetic function, 
and liver fibrosis are combined with clinical measure (e.g., ascites, encephalopathy, splenomegaly, varicies, 
and hypersplenism) to mark severity of disease.  Results from these assessments are dynamic and are 
impacted by conditions other than worsening liver disease (e.g., sepsis, bleeding, renal insufficiency) yet 
they can also precipitate acute deterioration of liver function.  Two commonly used classifications of 
disease severity include the Child-Turcotte-Pugh (CTP) score and the Model for End-stage Liver Disease 
(MELD). The components of the modified CTP score include encephalopathy, ascites, bilirubin, albumin, 
and prothrombin time or, more recently, the international normalization ratio (INR)(8).   Cut-off values and 
clinical assessments are weighted for severity from 1 (least) to 3 (worse) and the sum of the component 
points determines the CTP score: A (5-6 points), B (7-9 points), and C (10-15 points).  The components of 
the MELD score, used in patients 12 years of age and older, include the total bilirubin, serum creatinine, 

 
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and INR.  The MELD score was developed to assess prognosis for patients undergoing a transjugular 
portosystemic intrahepatic shunt and represents a continuous variable from 6-40 (9). It has been adapted 
for use in determining the listing status for liver transplantation.  While both CTP and MELD have their 
limitations, they are used to reflect disease severity in patients with chronic liver disease.   
 
Hepatic venous pressure gradient (HVPG) measurements have been integrated into routine clinical practice 
in the assessment of adults with cirrhosis (10, 11) During this procedure transvenous liver biopsies 
(typically 2 to 4 samples from different segments of the liver) can be obtained thus providing additional 
clinical and research information from the same procedure.  The procedure can be performed with local 
anesthesia but usually is done with sedation or low levels of general anesthesia (12, 13).  In the study by 
Manolakopoulos, HVPG dropped significantly in 19 subjects after a 12-month course of lamivudine therapy 
for chronic hepatitis B (14.4 + 3.9 vs 12.4 + 3.3 mmHg, p =0.007) (12).  In the study by Roberts, of the 10 
subjects with chronic hepatitis C with a sustained viral response to pegylated interferon and ribavirin, there 
was a significant drop in HVPG (9.0 + 4.0 vs 6.9 + 3.4 mmHg, p =.05) (13).This procedure provides an 
outstanding global assessment of the degree of fibrosis by assessing overall resistance to portal flow via the 
calculated portal pressure.  The global nature of the measurement avoids problems related to sampling 
errors from non-homogeneous patterns of fibrosis.     
 
AUTOPHAGY 
 
Because liver damage is caused by intracellular accumulation of the mutant ATZ, the pathways by which 
this mutant protein is degraded within liver cells have been the subject of a number of investigations.  
Indeed, one of the major hypotheses about this disease is that pathways for intracellular degradation of 
mutant ATZ play a role in protecting some deficient individuals from liver disease or in decreasing the 
severity of the liver disease phenotype (2).  The studies in this area have shown that at least 2 major cellular 
disposal pathways are involved, the proteasome and autophagy (3).  Autophagy is a tightly regulated 
process by which cells consume unwanted cytoplasmic macromolecular constituents and recycle nutrients 
for cellular remodeling.  During autophagy, a double membrane known as the isolation membrane wraps 
around portions of the cytoplasm to form a double-membrane vesicle, the autophagosome.  The engulfed 
cargo, including organelles and damaged proteins, is degraded upon autophagosome fusion with late 
endosomes or lysosomes. Autophagy appears to be particularly important for disposal of polymerized 
and/or aggregated mutant ATZ and the pathway is specifically activated when ATZ accumulates in the 
endoplasmic reticulum of liver cells (3). 
    
CARBAMAZEPINE AMELIORATES LIVER INJURY IN MOUSE MODELS OF AT DEFICIENCY 
BY ENHANCING INTRACELLULAR DISPOSAL OF MUTANT ATZ 
 
Because autophagy plays an important role in intracellular disposal of ATZ, particularly aggregated ATZ 
that accumulates when there are high levels of expression, we recently tested the possibility that drugs 
which enhance autophagy could reduce the hepatic load of ATZ and reduce hepatic fibrosis in mouse 
models of AT deficiency.  From a list of FDA-approved drugs that have been shown to enhance autophagic 
disposal of aggregation-prone polyQ proteins, we selected carbamazepine (CBZ) because it has a long 

 
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history of safe use in children with seizures.  We found that administration of CBZ to PiZ mice by orogastric 
gavage for 2 weeks resulted in a marked decrease in hepatic ATZ load, as measured by number and size of 
AT-containing intrahepatocytic globules in liver sections and by hepatic ATZ levels on immunoblots (14).  
Furthermore, there was a significant reduction in hepatic fibrosis, as measured by Sirius red staining and 
by quantification of hepatic hydroxyproline concentration.  Studies in cell line models of AT deficiency 
indicate that CBZ mediates increased intracellular degradation of ATZ by several mechanisms including 
autophagy.  Taken together, these results provide a basis for testing the possibility that CBZ will reduce the 
hepatic load of ATZ and hepatic fibrosis in patients with AT deficiency. 
 
CARBAMAZEPINE (CBZ) 
 
Clinical uses 
CBZ is a drug that has been used for many years as an anticonvulsant and mood stabilizer.   Its chemical 
name is 5H-dibenz [b, f] azepine-5-carboxamide and its structural formula is shown below.  The FDA-
approved product insert that includes detailed chemical data, active and inactive ingredients and labeling 
information is included with this protocol as Attachment 1. 
 
CBZ is effective in preventing partial (focal) seizures, especially complex partial (psychomotor) seizures 
and generalized tonic-clonic (grand mal) seizures (15).  It is also used for treatment of chronic neurogenic 
pain and in hemifacial spasm.  CBZ also has psychotropic actions and has been used in affective disorders. 
It has had beneficial effects in depression and mania, both alone and together with lithium.  CBZ also has 
beneficial effects in the dyscontrol syndrome, a disorder characterized by episodes of aggressive outbursts.  
 
The mechanism of action of CBZ on neurons is thought to be similar to that of lithium and valproic acid 
and to involve depletion of cellular inositol (16).  Interestingly, this is thought to be the mechanism by 
which these 3 drugs enhance autophagic activity (17).   
 
Chemistry and Metabolism  
CBZ is a tricyclic compound related to iminostilbene.  It is a hydroscopic, neutral, lipophilic chemical that 
is soluble in organic solvents but has low solubility in water.  Its limited aqueous solubility has made 
formulation difficult.  Furthermore it tends to form insoluble crystals when its hydration increases in humid 
conditions. CBZ is eliminated predominantly by hepatic conjugation and hydroxylation.  A stable epoxide 
accumulates in serum.  This epoxide has activities that are similar to those of CBZ but lower in potency.  
The epoxide is eliminated in the urine after hydrolysis of the epoxide.  CBZ is also inactivated by 
conjugation and hydroxylation.  A minor metabolic pathway involves aromatic hydroxylation of the lateral 
rings.  CBZ is known to induce hepatic drug-metabolizing enzymes CYP2C and CYP3A as well as UDP-
glucuronosyltransferase (18). 

 
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Pharmacokinetics  
CBZ 
has 
linear 
and 
predictable 
elimination kinetics.  The 
relationship 
between dose and concentration in the blood is predictable within individuals but not within groups and 
this is why measurement of blood levels is important in determining the appropriate dose in any single 
subject.  CBZ induces its own metabolism.  This autoinduction causes the elimination rate to increase when 
doses of CBZ are initiated or modified.  This process takes several weeks to evolve so that the half-life of 
the drug decreases by ~50% within several weeks.  CBZ elimination rate also declines with age.   
 
CBZ is absorbed slowly after oral administration with peak concentrations reached within 4-8 hours.  This 
is mostly due to the time it takes for dissolution of CBZ tablets.  The bioavailability is estimated at 75-85% 
and variably affected by food intake (19).  CBZ is distributed throughout the body and ~75% is bound to 
albumin.  It passes the blood-brain barrier, placenta and penetrates breast milk.   
 
Safety 
CBZ is a very safe drug with minimal side effects noted after extensive use (15).  Side effects have led to 
reduction of dosage in only 3% of patients receiving the drug and to discontinuation of the drug in another 
3%.  Dose dependent side effects include drowsiness, sedation, vertigo and opthalmoplegia.  These tend to 
occur early in treatment and dissipate with chronic treatment in an overwhelming number of cases.  Use of 
a dose escalation schedule also reduces the incidence of these side effects.  Hyponatremia has been noted, 
especially in elderly patients.  It is usually mild and asymptomatic.  It may lower plasma concentrations of 
thyroid binding globulin, bound and unbound T4 and T3 but clinical hypothyroidism is rare.  CBZ treatment 
may be associated with elevated serum transaminase levels in 5-10% of cases.  In the vast majority of these 
cases CBZ can be continued without dose reduction.  On rare occasions when evidence for hepatic 
dysfunction develops, CBZ must be discontinued.   
 
Severe idiosyncratic reactions are rare.  Hematological toxicity with aplastic anemia, agranulocytosis and 
or thrombocytopenia has been estimated to occur in less than 1 in 50,000 individuals treated with CBZ.  A 
dose-dependent reduction in neutrophil count occurs in 10-20% of patients.  However, the neutrophil count 
rarely goes below 1,200 per mm3 and CBZ administration has not been associated with an increase in 
infections. Allergic rash occurs in 4 to 10% of patients and is the most common reason for intolerance to 
CBZ.  Allergic reactions with fever, renal and hepatic toxicity are very rare.   
 

 
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They usually occur in the first month of treatment.  These generalized hypersensitivity reactions are almost 
always self-limited with discontinuation of drug.  Serious, sometimes fatal reactions, including toxic 
epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported; with a risk of these 
events estimated to be 1-6 per 10,000 new users.  The risk is higher for individuals of Han Chinese ancestry 
with the genetic marker HLA-B*1502 (20, 21) and individuals of European ancestry with HLA-A*3101 
(22).  The liver histology can look like a chemical hepatitis, sometimes with granulomas.  In recent work, 
screening for HLA-B*1502 in Taiwan significantly reduced the incidence of Stevens-Johnson 
syndrome/toxic epidermal necrolysis in people taking CBZ (23).  Presence of HLA-A*3101 was found to 
increase the incidence of CBZ hypersensitivity syndrome and also the mild maculopapular exanthema 
associated with CBZ treatment (22)  Idiosyncratic neurological reactions including tics, asterixis and 
dystonia are rare.  Moreover these reactions often occur in patients with neurobehavioral diagnosis and so 
are difficult to completely attribute to CBZ. 
 
CBZ treatment has been associated with AV block.  Other cardiovascular events that have been reported 
include congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, 
aggravation of coronary artery disease, thrombophlebitis, and thromboembolism.  Other side effects that 
have been reported in limited numbers include urinary frequency and urinary retention.  
 
A recent study reported an increase in suicide caused by CBZ, particularly in patients who are on this 
medication for indications other than epilepsy (24).  However, these patients were probably receiving CBZ 
for indications such as refractory depression, refractory neurogenic pain or agitation associated with severe 
dementia that can be independently highly associated with suicide.  This study did not have the appropriate 
control groups for these indications.  Furthermore, an extensive series of studies do not show an increase 
in suicide in patients taking CBZ for epilepsy or any of these other clinical indications (25-29).  
Nevertheless, the FDA continues to include this drug as a cause of suicidal ideation.  We will evaluate and 
monitor subjects for suicide potential as described below and exclude or remove them from the trial based 
on previously established guidelines. 
 
CBZ can cause damage to the fetus when administered to women during pregnancy.  Congenital anomalies, 
especially spina bifida, have been reported.  It is considered class D for low but increased risk during 
pregnancy by FDA.   
 
Use of CBZ in Children and Adolescents 
CBZ has been used safely in children and adolescents for many years.  In most cases, CBZ is used to 
manage chronic seizure disorders.  Side effects are similar to what is described in adults.  There are no 
pediatric-specific adverse events or precautions. 
 
Interaction with other medications 
CBZ induces hepatic microsomal enzymes which can alter CBZ metabolism as well as other medications 
that include: other anticonvulsants (phenytonin, phenobarbital, primidone, and valproic acid), barbiturates, 
clozapine, corticosteroids, cyclosporine, dacarbazine, doxycycline, estrogens and oral contraceptives, 
fleodipine, haloperidol, levothyroxine, quinidine, tricyclic antidepressants, warfarin, xanthines (e.g., 

 
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caffeine, theophylline).  Drugs that can inhibit metabolism of CBZ and increase plasma concentrations 
include: cimetidine, clarithromycin, diltiazem, erythromycin, troleandomycin, verapamil, and 
metronidazole.  Monamine oxidate inhibitors cannot be used concurrently with CBZ.  Increased CNS 
depressant effects can occur with CBZ plus lixapine, maprotiline, molindone, phenothiazines, pimozide or 
thioxanthenes. 
 
NON-EPILEPTIC USES OF CBZ 
 
CBZ appears to have benefits as adjunctive treatment in major depressive disorders, including bipolar 
disorder (24). Mostly it is used to treat irritability or agitation in patients who are already on conventional 
antidepressants.  CBZ is used for aggression and impulsive behavior.  In one study it was superior to placebo 
in reducing self-aggressive activity of women with borderline personality disorder but in other studies it 
was not different from placebo (25).  CBZ treatment improved mood and overall functioning in short-term 
trials for patients with agitation/aggression associated with Alzheimer’s disease.   
Although several studies suggest that CBZ is more effective than benzodiazepines in treating alcohol 
withdrawal symptoms, the evidence for use of CBZ for this indication is not compelling (26).  CBZ is the 
first line treatment for trigeminal and glossopharyngeal neuralgia (27).  
 
USE OF CBZ IN PATIENTS WITH LIVER DISEASE 
 
CBZ has been in clinical use for over 40 years, yet clinical studies relating to the use of CBZ in patients 
with known liver disease are not available (28).   In fact, the presence of chronic liver disease has been an 
exclusion criteria for drug studies, including CBZ (29). As chronic elevation of serum aminotransferase 
levels is present in  up to 8% of adults (30), the importance of targeting patients with chronic liver disease 
to assess safety and efficacy of medications in this population is now recognized (31).  
 
Pathophysiologic changes associated with chronic liver disease and cirrhosis can impact drug absorption, 
metabolism, bioavailability, and elimination.  Portal hypertensive gastropathy, delayed gastric emptying 
(32), and altered intestinal permeability (33) can alter the expected absorption kinetics of an orally 
administrated medication.  An increased volume of distribution may increase drug elimination half-life 
(34).  Hepatic extraction of the absorbed medication as well as elimination through conjugation, 
hydroxylation and biliary excretion will be highly individualized depending upon the severity of the liver 
disease (35).  Renal function can also be impaired (36).   
 
 
CBZ has a low hepatic extraction (<30%) and low protein binding (75%)[18, 35].  With this 
pharmacodynamic profile, peak CBZ levels would be expected to be similar to patients without liver 
disease, but elimination of CBZ may be slowed (37).  Cholestasis can impair the activity of CYP2C which 
would also decrease hepatic clearance of CBZ (38).  Therefore, the maintenance dose may be lower than 
expected in subjects with liver disease as compared to those without liver disease.  While careful attention 
to CBZ serum levels will minimize dose-dependent adverse effects, idiosyncratic reactions may not be 

 
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avoidable with dose reduction.  We find no evidence that patients with compensated cirrhosis are at any 
greater risk of developing an idiosyncratic reaction than patients without liver disease. 
 
OBJECTIVES 
1. Determine whether CBZ treatment reduces hepatic ATZ load in AT-deficient patients with severe 
liver disease 
2. Determine whether CBZ treatment reduces hepatic fibrosis in AT-deficient patients with severe 
liver disease 
3. Determine whether CBZ treatment  reduces portal pressure in AT-deficient patients with severe 
liver disease as assessed by serial hepatic venous pressure gradient measurements 
4. Determine whether CBZ treatment is safe and tolerated by patients with severe liver disease caused 
by AT deficiency 
5. Determine whether CBZ treatment leads to stabilization in disease severity as measured by the 
MELD scores 
 
STUDY DESIGN (See also Study Flow Chart in Attachment 2) 
This is a Phase II prospective study of the use of CBZ in adolescents and adults with AT deficiency and 
compensated cirrhosis.  It is a randomized, double-blinded, placebo-controlled study in which 20 subjects 
will receive drug and 10 subjects will receive placebo.  Eligible patients will take CBZ or placebo for 12 
months.  Transvenous catheterization of the hepatic vein for measurement of hepatic venous pressure 
gradient will be carried out before and after the treatment period.  Liver biopsies will be carried out through 
the transvenous catheterization at the same time to obtain liver tissue for measurement of hepatic ATZ load 
and hepatic fibrosis.  These studies are often done as a part of standard of care for adults with cirrhosis.  
Clinical and biochemical follow-up will be undertaken to assess safety and tolerability of CBZ in these 
patients.  After 12 months of therapy, HVPG and transvenous biopsies will be repeated permitting a formal 
assessment of effects on ATZ load (by PAS staining, immunostaining, and immunoblot analysis) and 
fibrosis (by quantitative Sirius red staining and by examination of changes in HVPG).This approach has 
been effectively utilized to demonstrate efficacy of antiviral therapy in both Hepatitis C and Hepatitis B in 
reducing portal pressure. 
 
The primary efficacy outcome will be to determine the effect of CBZ on hepatic ATZ load.  This will be 
based on the number of hepatocytes with PAS+/diastase-resistant globules.  Secondary measures will 
include the area of a liver section occupied by these globules.  If there is enough tissue available for 
immunoblot analysis we will also use the steady state level of ATZ as a measure of hepatic ATZ load.  For 
the secondary efficacy outcomes we will determine the effect of CBZ treatment on hepatic fibrosis on the 
basis of Sirius red staining and hydroxyproline concentration and whether CBZ treatment changes portal 
pressure as determined by HVPG.  We will also determine if CBZ treatment reduces the MELD score by 
monitoring it at the beginning and end of the 12-month treatment period, including measuring at 7 follow-
up visits while on active medication or placebo.  The differences in the change in MELD score for subjects 
on active medication will be compared to that in subjects on placebo.  Safety and tolerability will be 
investigated by close observation and routine laboratory testing of the 30 subjects. 
 
 

 
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STUDY POPULATION 
 
Potential subjects for the study will be identified from the clinical practices of the pediatric and adult 
hepatology programs in the UPMC system and via outside referrals.  The typical potentially eligible subject 
will have AT deficiency (ZZ and SZ phenotypes and low serum level) and clinical evidence of cirrhosis 
complicated by portal hypertension (e.g. splenomegaly or thrombocytopenia [platelet count <150,000 or a 
complication of portal hypertension (e.g. varices or ascites)].  HVPG measurement will be used as a 
screening procedure to determine if the potential study subject has documented significant portal 
hypertension (HVPG greater than or equal to 10 mm Hg or as indicated in inclusion criteria below). The 
research program will be advertised in relevant specialty journals and through the Alpha-1 Association.  
Interested individuals would need to be seen in the aforementioned clinical programs.  Eligible subjects 
will be approached by one of the study investigators so that the study can be explained and 
inclusion/exclusion criteria can be reviewed.  
 
SCREENING 
 
Following a signed assent/consent, patients with AT deficiency will undergo a screening assessment to 
determine their eligibility for the interventional study.   
Entry criteria for the screening assessment include:  
1. Age > 14 years to ≤to 80 years of age. 
2. AT deficiency confirmed by ZZ or SZ phenotype and serum level < 83 mg/dl (in subjects who are 
receiving AT replacement therapy at the time of enrollment, AT deficiency will be confirmed by 
ZZ or SZ phenotype and serum levels <83 mg/dl at the time of initial diagnosis and/or prior to the 
initiation of AT replacement therapy). 
3. Clinical evidence of portal hypertension 
a. History of endoscopically confirmed esophageal or gastric varicies, or 
b. Hypersplenism, or 
c. Splenomegally and  
a. Platelet count <150,000 
b. History of sonographic or  
c. Clinically evident ascites requiring on-going diuretic therapy 
 
Exclusion criteria for the screening assessment include: 
1. Child Pugh Score > 12 
2. Serum total bilirubin > 5 mg/dl 
3. INR > 2.2 
4. Hepatic encephalopathy uncontrolled with outpatient medical therapy 
5. Serum creatinine > 1.5 mg/dl 
6. History of bone marrow depression (independent of hypersplenism associated with cirrhosis), 
hypersensitivity to carbamazepine or any of the tricyclic compounds such as amitriptyline, 
desipramine, imipramine, protiptyline or nortriptyline. 
7. Evidence of a known secondary process leading to active liver disease, and for which there is 
compelling evidence, including but not limited to Hepatitis B, Hepatitis C, alcohol related liver 
disease, Wilson disease, sclerosing cholangitis, primary biliary cirrhosis  
8. Alcohol intake > 30 gm/day (average from total intake over a week) 

 
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9. Evidence or history of hepatobiliary malignancy, e.g. hepatocellular carcinoma 
10. Pregnancy, lactation  
11. Severe cardiac or pulmonary disease felt to be a contraindication to CBZ therapy 
12. History of suicide attempt 
13. Potential for suicide behavior based on pre-treatment screening tools (PHQ-9 score greater than or 
equal to 10)  
14. WBC <1,500 
15. Platelets <25,000 
16. Inability to take oral medication 
17. Status post Transjugular Intrahepatic Portosystemic Shunt (TIPS) or scheduled to undergo 
procedure during trial participation 
 
 
Screening visits: 
At the screening visits a complete history and physical examination will be performed.  Screening blood 
tests will be obtained to assess liver function and to verify the Child Pugh status.  A pregnancy test will be 
done.  AT phenotyping and absence of the genetic markers HLA-A*3101 and HLA-B*1502 will be 
confirmed.  Potential subjects will be screened with the Personal Health Questionnaire-9 (PHQ-9).  The 
PHQ-9 has been used successfully to screen adolescents over 13 years of age and adults (39).  Subjects will 
be excluded if scoring 10 or higher on PHQ-9. An abdominal sonogram with Doppler will be performed to 
assess patency and directional flow of the portal and hepatic veins. Once these studies are confirmed as 
being consistent with the eligibility criteria arrangements will be made for the pre-treatment HVPG 
measurement (see below).  The hepatic venous pressure gradient measurement and liver biopsy are done 
together as a single procedure using the transvenous route.  Intravenous conscious sedation is used to carry 
out the procedure.  Subjects will receive fresh frozen plasma if the INR >1.6 and platelet transfusion if the 
platelet count is <50,000 prior to the procedure to prevent bleeding as per usual clinical practice.  Subjects 
will be carefully monitored during the procedure and in the recovery room after the procedure.  
 
Screening Hepatic venous pressure gradient: 
HVPG measurements will be obtained at the screening visits and at the 12-month follow up visit to 
determine the effect of the treatment.  After anesthesia a venous introducer is placed in the right femoral 
vein or internal jugular vein by the Seldinger technique.  Under fluoroscopy a 7-F balloon-tipped catheter 
(Boston Scientific Medi-Tech, Natick, MA) is guided into one of the major veins that drain blood from the 
liver into the inferior vena cava.  An FDA-approved radiopaque contrast agent is infused into the catheter 
to be assured that it is located within the main right hepatic vein.  The free hepatic vein pressure (FHVP) is 
then measured by recording for 60 seconds. This is done two to three times to assure that the mean pressure 
is reproducible.  The balloon is then inflated and gently wedged so that it totally occludes the hepatic vein 
for the wedged hepatic vein pressure (WHVP).  Once the pressure reading stabilizes the tracing is recorded 
for 60 seconds. This is repeated three times to assure that the mean pressure is reproducible.  At the end of 
the measurement, contrast is injected while the balloon is inflated to check for total occlusion.  The HVPG 
is then determined by calculating the difference between the WHVP and FHVP.   
 
 

 
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Screening Liver biopsy: 
Liver biopsy provides detailed additional information regarding fibrosis and accumulation of abnormal AT 
in liver cells and ATZ globules.   
The advantage of the current protocol, which includes HVPG measurement, is the ability to obtain 2 to 4 
transvenous biopsies at the same procedure with no incremental increase in risk to the subjects (40-42).  
The results of the liver biopsy will in no way determine whether the subject is eligible for the trial.  
However, it is necessary to carry it out at the same time as the screening HVPG measurement because 
otherwise the subject would have to undergo 2 separate procedures (including anesthesia and transvenous 
catheter insertion) in the screening phase of the study 
 
TREATMENT TRIAL 
 
Patients who have completed the screening phase and meet the following inclusion and exclusion criteria 
will be eligible for the proposed interventional study. For the convenience of the study subjects, if it is 
verified per protocol that they do meet full inclusion criteria, the subject may be enrolled to the study and 
initiate therapy on the same day.   
 
Those who completed the screening phase and are found not to be eligible will be given the option to be 
reevaluated in the future to determine eligibility for future studies of CBZ or other potential therapeutic 
agents. Patients will be eligible for the proposed CBZ trial and will be approached for informed consent to 
participate in the full clinical trial if following inclusion and exclusion criteria are met.  They will be 
provided with the Carbamazepine medication guide before they give informed consent. 
 
Inclusion criteria: 
1. Met criteria for entry into the treatment trial from screening protocol 
2. Age > 14 years to ≤80 years of age 
3. AT deficiency confirmed by ZZ or SZ phenotype and serum level < 83 mg/dl (in subjects who are 
receiving AT replacement therapy at the time of enrollment, AT deficiency will be confirmed by 
ZZ or SZ phenotype and serum levels <83 mg/dl at the time of initial diagnosis and/or prior to the 
initiation of AT replacement therapy). 
4. Subjects must have HVPG greater than or equal to 10 mm Hg unless collateral intrahepatic vessels 
are visualized via fluoroscopy, in which case the subject must meet all other criteria to participate 
in the trial.  
 
Exclusion criteria; 
1. Child Pugh Score > 12 
2. Serum total bilirubin > 5 mg/dl 
3. INR > 2.2 
4. Hepatic encephalopathy uncontrolled with outpatient medical therapy 
5. Serum creatinine > 1.5 mg/dl 
6. History of bone marrow depression (independent of hypersplenism associated with cirrhosis), 
hypersensitivity to carbamazepine or any of the tricyclic compounds such as amitriptyline, 
desipramine, imipramine, protiptyline or nortriptyline. 

 
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7. Evidence of a known secondary process leading to active liver disease including but not limited to 
Hepatitis B, Hepatitis C, alcohol related liver disease, Wilson disease, sclerosing cholangitis, 
primary biliary cirrhosis  
8. Alcohol intake > 30 gm/day (average from total intake over a week) 
9. Evidence or history of hepatobiliary malignancy, e.g. hepatocellular carcinoma 
10. Pregnancy, lactation  
11. Severe cardiac or pulmonary disease felt to be a contraindication to CBZ therapy 
12. HLA-B*1502 positive 
13. HLA-A*3101 positive 
14. History of suicide attempt 
15. Potential for suicide behavior based on pre-treatment screening tools (PHQ-9 score greater than or 
equal to 10)  
16. WBC <1,500 
17. Platelets <25,000 
18. Inability to take oral medication 
19. Status post Transjugular Intrahepatic Portosystemic Shunt (TIPS) or scheduled to undergo during 
trial participation 
 
STUDY DRUG AND DRUG MANAGEMENT: 
 
Rationale for Placebo Control: 
The placebo group is designed to provide control for the effects of sample error and variability.  This 
variability could affect liver biopsy as well as HVPG measurements and the placebo control is particularly 
important because of the relatively small number of subjects in the trial.  In addition, the placebo control 
may provide insight into the tolerability of CBZ by providing natural history data for complications of AT 
deficiency-associated cirrhosis.  Placebo will be prepared by the UPMC Investigational Drug Service (IDS) 
in capsules that are identical to those of the active compound CBZ. 
 
Randomization: 
Once it is determined the patient is eligible for the clinical trial, the patient will be randomized to receive a 
study medication that will be CBZ, the active medication, or a placebo that will appear similar to but not 
contain the active medication.  Patients will be randomized 2:1 (CBZ: Placebo) with two patients receiving 
CBZ for every one patient receiving placebo.  Patients will be further stratified by ongoing treatment with 
non-selective beta-blockers used for portal hypertension (e.g. propranolol, nadolol or carvedilol).  If the 
patient is receiving any dose of nonselective beta-blocker prior to study entry, this may decrease portal 
hypertension which in turn should be associated with decreased HVPG.  We want to ensure that both 
treatment and placebo arms have an equal number of patients receiving nonselective beta-blocker and do 
not plan to alter this therapy during this investigation.   
 
The Investigational Drug Service will provide subjects with study medication sufficient to last until the 
next visit + 5 days extra. The UPMC Investigational Drug Service (IDS) will use Medi-dose cups for 
dispensing CBZ/placebo capsules, depositing one dose of medication/placebo (two capsules) in each Medi-
dose cup. UPMC Investigational Drug Service (IDS) will seal and then label the Medi-dose cup with the 
subject’s ID number and the dose of medication (or placebo). IDS will be responsible for delivering the 

 
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Medi-dose cups to subject’s home address via UPS overnight shipping, and storing the remaining of the 
Medi-dose cups. 
 
A Study Monitor (see below) will be the only members of the investigative team that is not blinded because 
the Study Monitor will be responsible for adjustments in CBZ dosage based on drug levels.  The Study 
Monitor will consult with the sponsor-investigator and/or physician sub-investigators to determine exactly 
how to adjust the dosage but these consultations will be carried out without revealing the identity of the 
patient.   
 
Administration and Drug Accountability: 
CBZ/placebo will be administered at a maximum dose of 1200 mg/day orally for 12 months for subjects 
over 15 years of age and at a maximum dose of 1000 mg/day for subjects less than 15 years of age.  This 
will involve twice daily dosing with a combination of 100 mg-extended release tablets.  Extended release 
tablets are better tolerated, have a narrow fluctuation in drug concentration, and fewer central nervous 
system complications than immediate-release formulations (43).  To reduce the likelihood of 
hypersensitivity reactions the subjects will be started on 400 mg/day in 2 doses and the dose will be 
increased weekly by 200 mg per day until reaching a dose of 1200 mg/day (or 1000 mg/day in subjects less 
than 15 years of age).  A subject’s dose escalation may be adjusted if deemed appropriate by the sponsor-
investigator or principal investigator but it will not exceed a weekly 200 mg per day increase.  Drug levels 
will be monitored beginning at the 4 week visit, then at each study visit to ensure that the therapeutic 
concentration of 4-12 ug/ml is reached but not exceeded and then maintained. CBZ will be administered 
orally twice a day using extended release tablets.  The Study Monitor will review the results of the blood 
level measurements following each visit and use that information for adjustment of the dose of CBZ to 
maintain the therapeutic drug level.  The Study Monitor will not be a member of the investigative team 
involved with direct patient management.  The Study Monitor will not be blinded.  To maintain the blinding 
that is essential to the study design, the Study Monitor will not communicate the actual blood level result 
to the subject, the subject’s physician or to the sponsor-investigator team.   
 
The Study Monitor may increase or reduce the dose of CBZ based upon the drug level, but will not increase 
the dose of the study drug above 1200 mg/day (or 1000 mg/day in subjects less than 15 years of age). We 
will only be using trough blood levels.  Subjects will have to return for repeat testing if it is discovered that 
a determination was not done at the trough. The Study Monitor may also elect to repeat the trough blood 
level determination if needed to have 2 determinations before deciding on a dose adjustment. The 
formulation of the extended release CBZ tablets approved for commercial marketing will be supplied by 
Novartis and dispensed by the UPMC IDS.  Patient-subjects will not be charged for CBZ or placebo. 
 
Study Monitor 
The Study Monitor will be a physician who is familiar with the side effects of CBZ.  The Study Monitor 
will receive and review each CBZ blood level determination.   Other members of the research team will 
monitor the clinical status and physical examination of the patients and will receive the results of the 
monitoring laboratory values (with the exception of CBZ levels).    The Study Monitor will not 
communicate the actual blood level of the study medication to the patient, family, or the research team 

 
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involved with day to day management of patient-subjects participating in the clinical study.  However, the 
Study Monitor will release the identity of the subject’s study group to the Sponsor-investigator or physician 
sub-investigators if that information is needed for the patient’s safety.  The Study Monitor will recommend 
adjustment of the CBZ dosing based upon the blood level of CBZ.   
 
On-treatment assessments: 
During therapy, study subjects will be seen on a regular basis to assess their clinical status and to obtain 
standard biochemical measures of liver and renal function, cell counts, etc.  Visits will also include a full 
history and physical examination.  Specific assessments and queries will be made for any signs or symptoms 
of liver disease.  Child-Pugh (CP) score and MELD score will be calculated at each study visit.  Other than 
blood collection during study visits, no additional invasive testing is proposed until the week 52b visit when 
a repeat liver biopsy and HVPG will be obtained.  The procedure for the liver biopsy and HVPG will be 
identical to the procedure used in the screening visit.  Data will be collected from procedures undertaken 
as part of clinical follow up (e.g. endoscopy reports, imaging studies, etc.).   
 
If the study subject undergoes liver transplantation during the study period, samples will be obtained at the 
time of surgery to provide follow up data.  If a subject dies during the study period and the family consents 
to an autopsy, samples of liver tissue will be obtained at autopsy to provide follow up data.  In these cases, 
follow up HVPG measurements will not be available. 
 
Potential for suicide attempts will be monitored with the Columbia Suicide Severity Rating Scale (C-SSRS) 
at study visits the week of enrollment through week 52a.  It is a semi-structured, clinician-administered 
instrument to track severity of both suicidal behavior and ideation.  This measure is reliable and valid and 
has been used in previous clinical trials (44, 45). Patients will be withdrawn from the trial if the C-SSRS 
identifies suicidal ideation or behavior and then the patient will then be referred for mental health evaluation 
and treatment. 
 
Study visits will be scheduled at weeks 4 (+/- 1 week), 8 (+/- 2 weeks), 18 (+/- 2 weeks), 36 (+/- 2 weeks), 
and 52a (+ 3 weeks)  for a history and physical examination, assessment for depression and suicide 
behavior, biochemistry measures, and measurement of the blood level of the CBZ.  Blood will also be 
collected at the time of enrollment and at week 52 visit for Fibrotest analysis. All female subjects of child-
bearing age will undergo a urine pregnancy test on visit S2, enrollment, and at each follow up visit during 
the trial. The effect of CBZ treatment will also be assessed by a novel investigative test, a hepatic biomarker 
assay using samples that are obtained pre- and post-treatment as well as once during treatment. Study 
subjects may undergo MRI using Elastography within the first six months of study enrollment and at week 
52 visit.  
 
Additional visits may be scheduled, at the discretion of the Investigator, to ensure the safety and well-being 
of subjects.  These will include a history, assessment for depression and suicide behavior, biochemistry 
measures, and measurement of the blood level of the CBZ.  A physical exam may also be performed at the 
discretion of the investigator.  Full list of assessments can be found on the schedule of events flow sheet. 
 

 
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Assessment of adherence: 
Adherence will be assessed at each of the follow up visits by pill counts and patient medication diaries.   
Medications will only be available from the Investigational Drug Service (IDS), thus an accurate assessment 
of medication dispensed will be available. Subjects will be instructed to return unused medications at each 
visit.  By pill count, medication adherence will be assessed.  Adherence will be defined as intake of > 80% 
of the prescribed CBZ or placebo – persistent nonadherence to the study regimen may lead to 
discontinuation of the study for those subjects.  For patients receiving CBZ, adherence will also be assessed 
by measuring trough CBZ levels at each visit.  It is expected that the levels will be between 4 and 12 µg/ml.  
Standard deviations of sequential levels will also be used as a measure of adherence (46). 
 
End of treatment assessment (week 52 visit  + 1 wk): 
 
Hepatic venous pressure gradient – see above 
 
Liver biopsy – see above 
 
Concomitant Medications:   
CBZ may interact with other anticonvulsants, including half-life shortening when given with phenobarbital, 
phenytoin and primidone and half-life prolongation with valproate.  Several drugs inhibit the elimination 
of CBZ and therefore elevate its serum levels, including erythromycin, isoniazid, triacetyloleandomycin, 
destropropoxyphene, viloxazine, nicotinamide, verapamil and diltiazem.  CBZ itself can affect the serum 
concentrations of other drugs, including valproate, ethosuximide, doxycycline, clonazepam, haloperidol, 
phenytoin and warfarin.   
 
These drug interactions may necessitate changes in dose of CBZ or other drugs but do not prohibit the use 
of CBZ or other drugs while administering CBZ.  These changes will be directed by the Sponsor-
Investigator or sub-investigators.    
 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
 
Subjects will be closely monitored for the major side effects of CBZ, including allergic reaction, sedation, 
and bone marrow depression as well as for hepatotoxicity that could worsen the liver disease.  This will 
include history, clinical examination and laboratory testing.  Monitoring will be carried out at each study 
visit.  In general it will not be necessary to reduce the dose of CBZ or discontinue CBZ unless there is an 
obvious allergic reaction, progressive hematological toxicity that includes aplastic anemia, neutropenia 
and/or thrombocytopenia, progressive hepatic toxicity with rising transaminases, decreasing albumin levels 
or prolongation of the prothrombin time, unremitting sedative effect, or CBZ levels in the toxic range.   
 
In the event that a subject temporarily discontinues drug for any reason OR an investigator determines the 
a subject should temporarily hold study drug due to a clinical reason, we will reinitiate therapy based upon 
the following parameters; 
 

 
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-If study drug has been stopped for less than or equal to 5 days the subject will resume taking the 
previous dose.  
-If study drug has been stopped for more than 5 days but less than or equal to two weeks, the subject 
will resume half of the previously assigned dose (if half the previous dose is unavailable, the next available 
formulation close to but less than half the previous dose is acceptable) for one week and return to the full 
previous dose 7 days later. 
-If study drug has been stopped for more than 2 weeks, the sponsor-investigator along with 
principal investigator will determine both the dose with which the subject restarts and the appropriate dose 
escalation schedule.  
 
Carbamazepine (study drug) or placebo dose alteration: 
The dose of the study drug will be altered based upon the schedule below.  Only the study monitor will 
know the serum trough level and only the study monitor will make dose adjustments for changes in the 
blood level.  The Sponsor-Investigator and/or sub-investigators will be responsible for making adjustments 
in the dose of Study Medication based upon the clinical and biochemical results outlined below.  If these 
individuals determine that the dose of study drug needs to be adjusted, the request will be made to the Study 
Monitor who will in turn contact the IDS to carry out the change in dose.  When a dose alteration is made 
based on findings other than the trough blood level, comparable dose reductions will not occur in patients 
receiving placebo.   
 
1. Serum trough level > 12 µg/ml (to be performed ONLY by the study monitor) See algorithm. 
 
2. (Serum trough level < 4 µg/ml (to be performed ONLY by the study monitor)(study monitor may 
elect to order a repeat trough level before making a change in dosage) 
a. No change in protocol unless prior dose reduction.  
CBZ result
Greater than 12 ug/ml
Repeat drug level
Still elevated
Decrease CBZ dose by 
200 mg and repeat CBZ 
trough within 7 days. 
Repeat algorithm as 
needed.
Therapeutic –no 
changes required
WNL (4-12 ug/ml)
Dose increase per 
protocol or dose 
remains at max dose

 
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b. If a prior dose reduction has been made by the study monitor based upon clinical or 
biochemical abnormality, the dose of the study medication will not be increased unless 
there is resolution of the clinical or biochemical finding. Increase in dose cannot be made 
if subject is already on dose of 1200 mg/day or, if less than 15 years of age, on a dose of 
1000 mg/day 
c. Continue “b” until trough level is in the therapeutic range 
2. WBC <1,000 
a. Decrease dose by 50% 
3. Neutrophil count <500 
a. Decrease dose by 50% 
4. Platelets < 20,000 
a. Decrease dose by 50% 
5. ALT > 500 IU/dl 
a. Decrease dose by 50% 
6. INR > 1.8 not corrected by 5 mg of vitamin K 
a. Decrease dose by 50%  
 
Guidelines for subsequent Study drug dose adjustments 
 
Indications to discontinue CBZ 
1. Child-Pugh score > 12 
2. Hepatic encephalopathy uncontrolled with outpatient medical therapy 
3. Total bilirubin > 7 mg/dL 
4. Evidence of anticonvulsant hypersensitivity syndrome 
a. Fever > 38.5 and  
b. Lymphadenopathy, and  
c. Erythematous, maculopapular, pruritic, or exfoliating rash 
5. WBC <1,000 despite 2 weeks of Carbamazepine dose reduction, may resume therapy at 50% of 
starting dose when WBC > 3,000 
6. Neutrophil count <500 despite 2 weeks of Carbamazepine dose reduction, may resume therapy at 
50% of starting dose when ANC > 1,500 
7. Platelet count <20,000 despite 2 weeks of Carbamazepine dose reduction, may resume therapy at 
50% of starting dose when plt > 40,000 
8. Hgb <8.5 mg/dl 
9. INR > 2.5 not corrected by 5 mg of Vitamin K 
10. ALT > 750 IU/L 
a. May resume previous dose when ALT < 500 
11. Pregnancy 
12. Liver transplantation 
13. Signs or symptoms of TEN or SJS. 
14. Breast feeding.  
15. Allergic reaction of Grade 3 or Grade 4. 
16. Evidence for behavior or ideation predisposing to suicide (increase in C-SSRS score of 1 from 
previous test score). 
 
 
 

 
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SCREENING AND MANAGEMENT FOR SPECIFIC ADVERSE EVENTS 
 
Patients entering the study will have evidence of chronic liver disease from AT deficiency.  At entry into 
the study, patients may have one or more of the following: elevated serum aminotransferase levels, 
jaundice, elevated total and direct bilirubin, medically treated ascites, esophageal and/or gastric and/or 
hemorrhoidal varicies, biochemical evidence of hypersplenism with a white blood count (WBC) and 
platelet count (PLT) below the normal range, and a prolonged prothrombin time (PT) or International 
Normalized Ratio (INR).  Adverse events will be assessed using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0.  Baseline laboratory values for patients entering the study will likely 
be above the normal range in the case of ALT, AST, total bilirubin, and INR and below the normal range 
for hemoglobin, WBC, platelets and neutrophils count.   Therefore, changes in laboratory values after 
initiation of the study drug will need to be assessed within the context of the patient’s baseline laboratory 
tests. We will not be reporting every variation in subject lab results as an adverse event. Small deltas from 
within normal limits to just outside the normal range are not clinically significant in the care of patients and 
should not be used to define AEs. The investigative team will use standards that define a minimum delta 
that determines when a change becomes an AE, either as a discrete value change or a percentage change. 
These can be used in combination with claims of clinical significance by the site investigator. 
 
An increase of CP score to > 12, development of Grade III-IV encephalopathy, or total bilirubin > 7 mg/dl 
will be considered a treatment failure and therapy will be discontinued.  Therapy will not be restarted in 
these subjects even if there is an improvement in clinical status.     
 
Alterations in liver function: 
Markers of liver injury and dysfunction that will be monitored include: PT, INR, AST, ALT, GGTP, total 
and direct bilirubin, WBC, platelet count, hemoglobin, absolute neutrophils count, and lymphocyte count.  
These tests will be monitored regularly during the course of treatment, with more frequent measurements 
occurring in the first four months of treatment.  It is anticipated that there will be fluctuations in liver 
biochemistries (especially ALT, AST, GGTP and alkaline phosphatase) as part of the expected clinical 
course of AT deficiency.  It is anticipated that study subjects will have some element of hypersplenism and 
associated cell line reductions.  
 
Dermatologic reactions: 
Patients will be counseled regarding dermatologic signs that should be reported to a study investigator or 
study coordinator immediately, these include redness of the skin, blister formation, pealing, itching or oral 
ulceration.  If these signs or symptoms occur, the study medication would be discontinued immediately and 
the patient would be seen within 24 hours.  If the skin lesions are felt to be consistent with Stevens-Johnson 
syndrome (SJS) or Toxic Epidermal Necrolysis (TEN), then appropriate treatment will be initiated and the 
study medication will be permanently discontinued.  The risk of developing SJS or TEN will be decreased 
as patients who carry the HLA-B*1502 and/or HLA-A*3101 gene will be excluded from the study. In 
addition, other less serious dermatologic changes will be assessed at each visit.  The presence of mild 
dermatologic changes such as photosensitivity, non-specific erythema, or mild pruritus, can be observed 
without dose modification.   
 

 
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Nervous system  
Mild symptoms of dizziness, drowsiness, confusion or headache have been described with CBZ.  Beginning 
with a low dose with an incremental increase in medication on a weekly basis has been shown to reduce 
these side effects.  It is possible these symptoms may be more pronounced when CBZ is given to patients 
with chronic liver disease.  Patients will be monitored carefully for evidence of these symptoms.   
 
Metabolism: 
Hyponatremia can occur in patients with chronic liver disease and chronic diuretic use in the management 
of ascites.  Therefore, its presence may reflect the natural course of liver disease.  On rare occasion, 
inappropriate antidiuretic hormone (ADH) secretion has been associated with CBZ.  Serum electrolytes 
will be monitored regularly as well as a “first void” urinalysis to assess specific gravity (see appended Study 
Flow Chart).   Alterations or thyroid function studies have been reported with CBZ treatment, but they have 
not been associated with clinical evidence of hypothyroidism.  T4 and TSH will be monitored periodically 
(see Study Flow Chart in Appendix 2). 
 
 
Suicide 
An increase in suicide in patients taking CBZ has been reported in one study (24) but numerous other 
studies provide strong evidence against this potential risk (25-29).  Nevertheless we will monitor for 
suicidal tendencies very assiduously and patients will be withdrawn based on well-established guidelines 
(see above). 
 
Pregnancy 
Transplacental passage of CBZ to the fetus is rapid and associated with congenital malformations, including 
spina bifida, cardiovascular malformations, and developmental disorders.   
Patients will be asked to practice effective birth control while they are taking CBZ in this study.  However, 
given the long duration of therapy and the number of female subjects in the child-bearing age, the following 
precautions will be taken: 
1. All female subjects of child-bearing age will undergo urine pregnancy test on enrollment, prior to 
starting therapy, and monthly during the trial.  
2. All female subjects of child-bearing age will need to use a barrier method of contraception as CBZ 
has the potential to interfere with oral contraceptives 
3. All female subjects of child-bearing age will be counseled monthly during the treatment portion of 
the trial on barrier methods of birth control.  
4. If a subject is found to be pregnant, CBZ will be immediately discontinued and permanently 
stopped and the subject will be referred to an obstetrician for advice and consultation 
5. The study will collect data on the outcomes of any pregnancies that occur in women who conceived 
while taking the study medication. 
6. The study will collect data on the outcome of liver disease for those women whose medication was 
immediately discontinued. 
 
Breast feeding 

 
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CBZ and its metabolites are transferred to breast milk and can result in transient cholestatic hepatitis[45].  
The estimated dose given to a breast feeding infant is 2-5 mg/kg/day.  Breast feeding will not be allowed 
while the mother is receiving CBZ. 
 
 
 
Adverse events 
 
Definition 
An adverse event (AEs) is any adverse change from the patient’s baseline (pre-treatment) condition, 
including intercurrent illness which occurs during the course of the trial, after the consent form has been 
signed, whether the event is considered related to treatment or not.    
 
A serious adverse event (SAE) is an untoward medical occurrence that results in any of the following:  
Death, or an event that is either life-threatening (risk of death at the time of the event) requires in-patient 
hospitalization or prolongation of existing hospitalization, or results in persistent or significant 
disability/incapacity or congenital abnormality or birth defect.  Important medical events that do not result 
in one of the events listed above may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed above.   
 
A SAE which is unexpected and is drug related (even remotely) will require expedited reporting to the FDA 
and the University of Pittsburgh IRB in accordance with respective timeline requirements.  The following 
events are disease outcomes and will not be considered to be serious adverse events as they can occur in 
the usual course of patients with AT deficiency. 
 
1. Development of hepatocellular carcinoma 
2. Complications associated with chronic liver disease which include, but not limited to 
a. Worsening ascites 
b. Bleeding from esophageal, gastric, or hemorrhoidal varicies 
c. Worsening hypersplenism (hard to differentiate from bone marrow toxicity) 
d. Hepatic encephalopathy 
e. Hepatopulmonary syndrome 
f. Portopulmonary hypertension 
3. Extra-hepatic conditions related to alpha-1 antitrypsin deficiency which include, but not limited to 
a. Chronic obstructive pulmonary disease 
b. Hypoxia 
 
Data collection procedures for adverse events 
 
Patients will be interviewed regarding medical conditions, medication changes, and symptoms that have 
occurred at each study visit.  An AE form will be completed if any adverse event is reported. 

 
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ATD CBZ Study v. 14  February 19, 2016 
 
  If a study coordinator or investigator learns of any hospitalizations or other adverse events between study 
visits, an AE form will be completed.  All AEs and SAEs from time of study entry (consent) up to the end 
of follow-up will be reported to the Sponsor-Investigator.  A SAE form will be completed for all adverse 
events rated as serious.  Patients will be followed for all ongoing unresolved adverse events until they are 
either resolved, or in the opinion of the Sponsor-Investigator or treating sub-investigator, the patient is 
medically stable.   
 
The Sponsor-Investigator will assess the relationship of each adverse event to the use of study drug, based 
on available information, using the following as guidelines: 
1. Unlikely related: No temporal association, or the cause of the event has been identified; or the drug 
cannot be implicated. 
2. Possible related: Temporal association is present, but other etiologies are likely to be the cause; 
however, involvement of the drug cannot be excluded. 
3. Probably related: Temporal association is present; other etiologies are possible, but unlikely. 
 
Reporting procedures 
All SAEs that are unexpected and related to study drug will be reported to the Sponsor-Investigator within 
72 hours by telephone.  This reporting includes serious adverse events that occur from the time the patient 
has signed the clinical trial consent.  The Sponsor-Investigator will promptly review all SAEs and will 
notify the reviewing IRB and FDA within requisite time frames if an event is considered to be unexpected 
and possibly or definitely related to the study drug (e.g., serious, unexpected adverse events related to the 
investigational drug to the agency within 15 days of the Sponsor becoming aware of such; deaths and life-
threatening reactions reported to the agency within 7 days of the Sponsor’s awareness).  The Sponsor-
Investigator will notify all sub-investigators of unexpected SAEs related to the CBZ.  Status reports on all 
adverse events will be generated under the direction of the Sponsor-Investigator and sent to the DSMB 
every month and will include the relationship of the AE to trial medication, the severity of the event and if 
the event is resolved or ongoing.  All AEs will be reported annually to the FDA and reviewing IRB, as 
required 
 
Statistical considerations 
 
Analysis 
 
Objective 1. Determine whether CBZ treatment reduces hepatic ATZ load in AT-deficient patients with 
severe liver disease. 
 
The primary analysis will test for differences between the treated and placebo groups in the change from 
baseline to follow-up in the number of hepatocytes with PAS+/diastase-resistant globules using an unpaired 
t-test (or nonparametric equivalent if appropriate). Given the small sample size, we do not assume that 
randomization will balance treated and placebo groups at baseline with respect to outcome variables. 
Therefore, we will compare changes over the course of the treatment rather than differences at the end of 
the treatment. Secondary analyses will look at the area of a liver section occupied by these globules and the 

 
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steady state level of ATZ by immunoblot again using an unpaired t-test (or nonparametric equivalents if 
appropriate) of the differences between the treated and placebo groups in changes from baseline to follow-
up. 
 
Given that the sample is small, randomization may not balance the groups with respect to important 
covariates, though our ability to detect statistically significant differences is likewise limited to relatively 
large effect sizes.  Furthermore, the number of variables that could be adjusted for in a regression model is 
also limited by the sample size, as is our ability to do subgroup analyses.  However, as exploratory analyses, 
we will compare the distributions of important confounders between treated and placebo groups and fit 
multiple linear regression models that include independent variables, in addition to treatment group and 
baseline values of outcome measures, with variables whose distributions are markedly imbalanced between 
treatment groups.  
 
Objective 2. Determine whether CBZ treatment reduces hepatic fibrosis in AT-deficient patients with 
severe liver disease. 
 
Analysis will proceed as in objective 1; however, the outcome will be hepatic fibrosis. The primary analysis 
will compare treatment group differences in baseline to follow-up changes in hepatic hydroxyproline 
concentration using an unpaired t-test (or nonparametric equivalent if appropriate). Secondary outcome 
measures will include Sirius red staining of the liver. Exploratory analyses using multiple regression models 
will proceed as described above.  
 
Objective 3. Determine whether CBZ treatment reduces portal pressure in AT-deficient patients with severe 
liver disease as assessed by serial hepatic venous pressure gradient measurements. 
 
Analysis will proceed as in objective 1; however, the outcome will be portal pressure. The analysis will 
compare treatment group differences in baseline to follow-up changes in hepatic wedge pressure gradient 
as the outcome. An unpaired t-test (or nonparametric equivalent if appropriate) will be the primary analysis 
and we will conduct exploratory multiple regression analyses to adjust for the possibility of covariate 
imbalances as described above.  
 
In subjects with intrahepatic collateral vessels (visualized radiologically) together with HVPG less than 10 
at baseline, we will assess the outcomes in all categories other than objective 3 
 
It is possible that we will not see a difference in hepatic ATZ load or fibrosis because of variability and 
heterogeneity within the liver but that the drug will produce a stabilization or improvement in overall 
clinical status. Therefore, as an exploratory analysis we will assess whether CBZ treatment will lead to 
stabilization or improvement in disease severity as measured by the MELD score. The analysis will 
compare treatment group differences in baseline to follow-up changes.  
Analysis will proceed as above; however, the outcome will be the MELD score. Unpaired t-tests (or 
nonparametric equivalent if appropriate) will be the primary analysis and we will conduct exploratory 
multiple regression analyses to adjust for the possibility of covariate imbalances.  

 
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Power calculations 
 
Resources limited the sample size, so we performed power calculations with an effect size estimated from 
prior work on the primary outcome for this study – the number of hepatocytes with PAS+/diastase-resistant 
globules.  
 
The only available data come from studies we have carried out in mice. We found statistically significant 
differences between 18 treated and 11 placebo mice in the number of globule-containing hepatocytes after 
CBZ treatment. At the end of the study there were an average of 1088 (sd=260) globule-containing 
hepatocytes among control and 323 (sd=179) globule-containing hepatocytes among treated mice (14). 
Assuming that the average number of globule-containing hepatocytes at baseline was the same in the two 
groups of mice, then the group difference at follow-up (765 globule-containing hepatocytes) reflects the 
group difference in changes.  Assuming equal standard deviation (sd) in the two groups, the effect size was 
3.5. Then, for the proposed sample size (20 treated:10 controls) and a two-sided type I error of 5% there 
would be 80% power even if the effect is 1.1, about 1/3 of what was found in mice. This translates to being 
able to detect a drop in the treated group of 765 globule-containing hepatocytes compared to a drop in the 
controls of 514 (rather than 0).   
 
For the second objective of fibrosis the only relevant data come from hepatic hydroxyproline concentrations 
in mice after CBZ treatment. There were statistically significant differences between the treated and placebo 
groups in hepatic hydroxyproline concentrations after CBZ treatment with values of 2.27 (sd=1.02) in 24 
control mice and 1.21 (sd=0.70) in 25 CBZ-treated mice (14).  Assuming that the hepatic hydroxyproline 
concentrations at baseline were the same in the two groups of mice, then the group difference at follow-up 
(1.06) reflects the group difference in changes. Assuming equal standard deviation (sd) in the two groups, 
the effect size was 1.2. Then, for the proposed sample size (20 treated:10 controls) and a two-sided type I 
error of 5% there would be 80% power even if the effect is 1.1, about 1/10 of what was found in mice. This 
translates to being able to detect a drop in the treated group of 1.06 compared to a drop in the controls of 
0.106 (rather than 0).   
 
For the third objective of portal pressure, power calculations utilized information from 3 studies in which 
statistically significant and clinically relevant changes in HVPG were demonstrated in small numbers of 
individuals treated with antiviral drugs. A drop of ~2 mm Hg, or 20%, was found in response to drug 
treatment (26-28). With 20 patients treated with drug and 10 treated with placebo, there would be 80% 
power, assuming an average drop in portal pressure of 3.4 or more mm Hg in the treated group compared 
with no change in the placebo group, with a standard deviation of 3 mm Hg for the measurements. 
 
To increase recruitment, subjects in which an HPVG cannot be measured but have collateral intrahepatic 
vessels visualized via fluoroscopy, may be enrolled if they meet all other criteria. We expect the 
possibility of a loss of 20% of the patients for the primary aim due to no HVPG measurement. We expect 
the loss to be balanced in the intervention and placebo group. With 16 intervention/8 placebo as a sample 
size, we would have power to find an effect size of 1.2 demonstrating that we have adequate power.  

 
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Statistical Support, Data Management and Quality Control 
The study administrator will prepare data collection forms and manuals of operations and will monitor 
study adherence to the trial protocol. 
 
Safety analysis of this limited group of study subjects will be descriptive and will indicate tolerability of 
carbamazepine by individuals with compensated cirrhosis.  Descriptive statistics of laboratory parameters 
at the end of therapy and at the time point of largest deviation from normal will be compiled.   
The prevalence of other potential toxicities (e.g. dermatologic reactions) will also be compiled.  Limited 
comparisons to the control group will be performed, although the study is not powered to identify relatively 
rare toxicities.    
 
Approach to safety/tolerability 
Clinical adverse events or laboratory value abnormalities requiring treatment reduction or discontinuation 
will be recorded.  Particular attention will be placed upon potential serious adverse events known or 
believed to be related to CBZ that are fatal, potentially life threatening, significantly or permanently 
disabling, or require hospitalization. 
 
Safety analysis 
Adverse events.  Summaries of adverse events (number adverse events, number and percentage of subjects 
with adverse events, rates per person-months) will be provided.  Events will be summarized based on the 
date of onset for the event.  A treatment emergent adverse event will be defined as an adverse event that 
begins on or after the date of first dose of study drug.  Events that occur prior to the first dose of study 
medication or after the last dose of study medication will be summarized separately. 
 
Summaries of the following are planned: 
1. All adverse events recorded between screening and first dose of study medication. 
2. All treatment emergent adverse events. 
3. All emergent and related adverse events. 
4. All treatment emergent hepatic adverse events. 
5. All treatment emergent hematologic adverse events. 
6. All adverse events that caused permanent discontinuation of study drug. 
7. All adverse events that caused temporary interruption of study drug. 
8. All serious adverse events and.  
9. All serious and related adverse events. 
 
Annual safety analysis will be reported to DSMB. 
Laboratory abnormalities. 
Laboratory results will be presented as both actual value as well as a function of normal range.  Selected 
data (using conventional units) will be summarized by the change from baseline in laboratory test.  If 
baseline data are missing, then any graded abnormality is considered treatment emergent. 
Interim analysis. 

 
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Interim analysis of safety data will be performed after all subjects have completed 24 weeks of therapy.  
Interim analysis of adverse events will be made quarterly throughout the study.   
Additional analyses will be performed at the request of the DSMB, if there are any concerns raised by 
adverse events or serious adverse events reported.   
 
 
EFFORTS TO ENSURE ADHERENCE TO THE PROTOCOL 
 
Every effort will be made to ensure adherence by patients, their family and study personnel.  This includes 
inclusion of all eligible patients, accession of initial data in a timely fashion and prompt institution of CBZ 
treatment.  Data sheets will be used to record every step in the protocol including enrollment, collection of 
initial clinical and lab data, data transmission and initiation of CBZ treatment.  Patients will be seen at 4 
weeks (+/- 1 week) following initiation of study product and then again at 8 weeks (+/-2 weeks), 18  weeks 
(+/- 2 weeks), 36 weeks (+/-2 weeks) and finally at the week 52 visit( +3 weeks), which will include the 
repeat HVPG measurement and liver biopsy. 
These visits will involve history, physical exam, pill counts and lab tests to monitor each of the clinical and 
biochemical parameters mentioned above (refer to Study Flow Chart in Appendix 2).  In addition serum 
levels of CBZ will be measured at each follow- up visit.  All data will be recorded on the patient flow log. 
 
OVERALL PATIENT MANAGEMENT 
This study will generally not affect patient management, although there will be minor modifications made 
related to the HVPG measurements. Medications known to influence HVPG measurements (e.g. 
nonspecific beta blockers) will be discontinued for 3 days prior to HVPG measurements. Each of the 
subjects is being followed for supportive management of severe liver disease. This will include careful 
monitoring and medical therapy as indicated by the responsible physician team.  At the end of the study 
period a follow-up HVPG measurement will be performed accompanied by transvenous liver biopsy. As 
with the first procedure, medications known to influence HVPG measurements will be discontinued for 3 
days prior to the procedure.  If the subject undergoes liver transplantation during the study period, tissue 
from the native liver will be collected immediately upon its removal for the analyses proposed above.  
Follow up HVPG measurements will not be performed in these patients.   
 
PATIENT WITHDRAWAL 
 
It is the right of the patient, the patient’s parents or legal guardians, or the physicians caring for the patient 
to discontinue study medication at any time during the study. Medical care and transplantation will proceed 
in a manner that is unaffected by study participation. 
 
COMPLETE LIST OF WITHDRAWAL CRITERIA 
 
1. Child-Pugh score >12. 
2. Hepatic encephalopathy uncontrolled with outpatient medical therapy. 
3. Total bilirubin >7 mg/dl. 

 
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4. Evidence of anticonvulsant hypersensitivity syndrome. 
5. Leukocyte count <1,000 despite 2 weeks of CBZ dose reduction. 
6. Neutrophil count <500 despite 2 weeks of CBZ dose reduction. 
7. Platelet count <20,000 despite 2 weeks of CBZ dose reduction. 
8. Hemoglobin <8.5 mg/dl. 
9. INR greater than or equal to 2.5 not corrected by vitamin K 5 mg. 
10. ALT >750 IU/L. 
11. Pregnancy. 
12. Breast feeding. 
13. Evidence for behavior or ideation predisposing to suicide or increase in C-
SSRS score of 1 from previous test score. 
14. Persistent non-adherence to medication study regimen. 
 
DATA RETRIEVAL AND STORAGE 
 
A data repository in the University of Pittsburgh computing facility has been established to accept all 
information about subjects including; demographics, history, physical exam, labs and a tracking/event file.  
The tracking/event file is designed for important events: study entry; study completion; adverse events; 
treatment failures; exits; dropouts; protocol violations; etc.  Security of the deposited data will be 
maintained through the use of unique patient identifier numbers and passwords to enter the repository.  Data 
can be exported from the repository for reporting and statistical analysis. 
 
Data quality and accuracy will be audited annually by comparing what is in the database with the medical 
records of the patients. 
 
The electronic data storage and retrieval system used for the purpose of this clinical investigation has not 
been fully validated for compliance with the FDA regulations at 21 CFR Part 11 taking into account the 
limited size and scope of the investigation. 
 
DATA AND SAFETY MONITORING PLAN 
 
The Data and Safety Monitoring Board (DSMB) will consist of individuals who are independent of the 
institutions and investigators participating in the CBZ study, and who have no financial ties to the 
outcome of the trial.  The ongoing review of the data by this independent committee assures the 
investigators and the study sponsor that the trial can continue without jeopardizing patient safety.  
Individuals on the DSMB will be responsible for monitoring data and safety during the course of this 
study.   
 
The DSMB will review the study protocol, recommend recruitment continuation, monitor all aspects of the 
study (e.g., recruitment, protocol deviations, adverse events, site visit summaries, data quality, attrition, 
descriptive characteristics), and recommend protocol modifications, which may include early study 
termination.  Annual reports will be prepared by the study investigators including tables showing study 
progress overall and including recruitment, protocol deviations, attrition, adverse events, and data quality.  
There will also be a table providing descriptive characteristics of the study sample.  The study investigators 

 
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will maintain a cumulative summary of adverse events overall and stratified by serious/non-serious status to 
be forwarded to the DSMB biannually.  The DSMB will meet at least once per year in person or via internet 
conferencing.  A closed session will be held to review safety, efficacy, and data quality.   Based on the data 
presented, the DSMB will recommend continuation, changes, or termination of the study.  A summary of 
the DSMB findings will be forwarded to all investigators for submission to the IRB. 
 
The DSMB will meet at least annually in person or via internet conferencing to evaluate the following 
issues: 
1. Progress of the study, including assessment of data quality and timeliness. 
2. Subject recruitment, accrual and retention. 
3. Review of outcomes and adverse events to determine whether there has been a change in the risk-
benefit ratio of the study and whether the study should continue as originally planned, should be 
changed or terminated. 
4. Assessment of external factors such as relevant information from the current literature, including 
therapeutic developments and results of related studies, that could have an impact on safety of 
participation in the study or ethics of the study. 
5. Review of study procedures to protect the privacy of the research subjects and confidentiality of 
their research data. 
 
The following information will be reported by the DSMB to the investigators for submission to the IRB at 
regular annual intervals: 
1. The date(s) and frequency of the DSMB meetings. 
2. Summary of cumulative adverse event data including a respective assessment of whether the 
events were caused by the experimental intervention. 
3. Summary of the assessment of relevant information from the current literature that could have an 
impact on safety of participation in the study or ethics of the study. 
4. Summary of the outcome of procedural reviews carried out to ensure subject privacy and 
confidentiality of research data. 
5. Final conclusions regarding changes to the benefit-to-risk ratio of study participation and final 
recommendations related to continuing, changing or terminating the study. 
6. Rationale for any recommended changes in the research study protocol. 
7. The study investigators are committed to comply with IRB policies for reporting of serious and 
unexpected adverse events, disputes between investigators and research subjects, and disputes 
between investigators as articulated in chapters 3.0, 3.4 and 3.5 of the IRB Reference Manual.  
The study investigators are also committed to monitoring of data for accuracy and protection of 
subject confidentiality.  This monitoring will be carried out by the study coordinator.  The study 
coordinator will also audit all regulatory documents.  The investigators and study coordinator will 
conduct quarterly meetings to review study data and confidentiality.  Minutes from these 
meetings will be kept in the study regulatory binder. 
 
INSTITUTIONAL REVIEW BOARD REQUIREMENTS 
 

 
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ATD CBZ Study v. 14  February 19, 2016 
 
The protocol will be approved by the University of Pittsburgh IRB. 
 
INFORMED CONSENT 
 
Written informed consent from the patient, parent or legal guardian is required for any part of this study.  
The consent form will embody the legally required elements of informed consent.  The investigative team 
shall give the patient or his/her representative adequate time to read the form prior to signing.  A copy shall 
be given to the person signing the form.  The patient, parent or legal guardian can withdraw from the study 
at any time and this decision will not influence the treatment otherwise offered.  The NIH guidelines on 
inclusion of females and minorities as subjects in clinical research will be followed. 
 
CONTRACTUAL ARRANGEMENTS 
None yet. 
 
REIMBURSEMENT OF SUBJECTS 
If subjects need financial assistance to cover travel expenses for participation in the study, funds will be 
provided in the following amounts: up to $500 if they live within 100 miles of Pittsburgh; up to $3,000 if 
they live 100-500 miles away from Pittsburgh; up to $5,000 if they live 500-1,000 miles away from 
Pittsburgh; up to $7,000 if they live more than 1,000 miles from Pittsburgh, and up to $10,000 if they live 
more than 1,300 miles from Pittsburgh.  When airfare from certain locations exceeds these amounts, we 
may provide an amount of funding that covers the airfare and other travel costs for the subject and an 
accompanying adult (parent(s), spouse, etc.) even if it exceeds the amounts mentioned above. 
 
SUMMARY 
 
A Preliminary Study of the Efficacy and Safety of Carbamazepine in Severe Liver Disease Due to  
Alpha-1-Antitrypsin Deficiency 
 
Aim of project:  The primary objective is to determine if CBZ therapy in patients with severe liver disease 
due to AT deficiency leads to a significant reduction in the hepatic accumulation of ATZ globules 
 
1. Criteria for Inclusion:  Subjects must have clinical or histologic evidence of compensated 
cirrhosis secondary to a diagnosis of homozygous PIZZ or PISZ AT deficiency confirmed by PI 
typing and serum AT levels (in subjects who are receiving AT replacement therapy at the time of 
enrollment, AT deficiency will be confirmed by ZZ or SZ phenotype and serum levels <83 mg/dl 
at the time of initial diagnosis and/or prior to the initiation of AT replacement therapy). Subjects 
must be able to tolerate oral medication.  Age >14 to <or equal to 80 years of age.   Inclusion of 
nonpregnant females and minorities will follow NIH guidelines. 
 
Criteria for Exclusion:  Subjects will not be excluded on the basis of gender, race or ethnic group.  Subjects 
will be excluded if they have a history of bone marrow depression, hypersensitivity to carbamazepine or 
any of the tricyclic compounds such as amitriptyline, desipramine, imipramine, protiptyline or nortriptyline.  

 
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ATD CBZ Study v. 14  February 19, 2016 
 
Subjects will be excluded if they have evidence of an additional potential cause of active liver disease (e.g. 
infectious hepatitis, alcohol related liver disease, Wilson disease, sclerosing cholangitis, primary biliary 
cirrhosis).  Subjects will also be excluded if they have very severe liver disease (Child-Pugh score greater 
than or equal to12; serum bilirubin>5; INR>2.2; hepatic encephalopathy uncontrolled with outpatient 
medical therapy), severe renal disease (serum creatinine >1.5 mg/dl), alcohol intake >30 gms/day, evidence 
of hepatobiliary malignancy, pregnancy/lactation, portal vein or splenic vein thrombosis, severe cardiac or 
pulmonary disease felt to be a contraindication to CBZ therapy, HLA-B*1502-positivity, HLA-A*3101-
positivity, history of suicide attempt, potential for suicide behavior based on pre-treatment screening test, 
severe leucopenia (wbc count<1,500) or thrombocytopenia (platelet count<25,000). 
 
Total Duration of Therapy: 12 months 
 
Forms to Complete: Informed consent signed by patient and or parent/legal guardian; entry data; visit 
follow up data; final report 
 
Endpoints of the study:  
1. Change in hepatic load of ATZ. 
2. Change in degree of hepatic fibrosis. 
3. Change in HVPG. 
4. Ability to tolerate long-term course of CBZ without adverse events. 
 
Reimbursement for study participation: Only financial assistance to cover travel related expenses. 
 
  

 
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