411' (cid:9)
`188
`
`133 70 Ur'.
`
`A JOURNAL DEVOTED TO CLINICAL AND BASIC STUDIES OF THE DIGESTIVE TRACT AND LIVER
`
`ALIMENTARY TRACT
`903 Healing and Relapse of Severe Peptic Esophagitis After
`Treatment With Omeprazole
`DJ, HETZEL, J. DENT, W.D. REED, F.M. NARIELVALA,
`M. MACKINNON, J.H. MCCAW' HY, B. MI'T'CHELL,
`B.R. BEVERIDGE, B.H. LAURENCE, G.G. GIBSON, A.K. GRANT,
`D.J.C. SHEARMAN, R. WHITEHEAD, AND P.J. BUCKLE
`913 Effect of Terbutaline, a /32-Adrenoreceptor Agonist, on
`Gastric Acid Secretion and Serum Gastrin Concentra-
`tions in Humans
`R.C. THIRLBY, C.T. RICHARDSON, P, CHEW, AND M. FELDMAN
`920 Soy Protein Meals Stimulate Less Gastric Acid Secretion.
`and Gastrin. Release Than Beef Meals
`K.E. MCARTHUR, J.H. WALSH, AND C.T. RICHARDSON
`927 Opposite Effects of ic-Opioid Agonists on Gastric Empty-
`ing of Liquids and Solids in Dogs
`M. CUE, J. FIORAMONTI, C. HONDE, X. PASCAUD, J.L. JuNtEN,
`AND L. BUENO
`932 Indomethecin-Induced Gastric Antral Ulcers in Hamsters
`K.P. KOLBASA, C. LANCASTER, A.S. OLAFSSON,
`S.K. GILBERTSON, AND A. ROBERT
`945 Effects of Endogenous. and Exogenous Prostaglandins on
`Glycoprotein Synthesis and Secretion in Isolated Rabbit.
`Gastric Mucosa
`U. SEioLER, K. KNAI LA, R. KOWNA I ZKI, AND K-F. SEWING
`952 Isolation of Endopeptidase-24.11 (EC 3,4.24.11, "En-
`kephalinase") From the Pig Stomach
`N.W. BUNNE AJ. TIIIINLR, J. Ha Y.SZhO, R KOBAYASHI, AND
`J.H. WALSH
`958 Calcitonin Gene-Related Peptides I and II and Calcitonin:
`Distinct Effects on Gastric Acid Secretion in Humans
`C. Mx:LINGER, W. BORN, P. HILDEBRAND, J,W. ENSINCK,
`F. BURKHARDT, J.A. Fiscut R, AND K. GYR
`966 Calcitonin Gene-Related Peptide: Enteric and Cardiovas-
`cular Effects in the Dog
`P.G. REASBECK, S.M. BURNS, AND A. SHULKES
`972 Giardia lamblia in Patients Undergoing Endoscopy: Lack
`of Evidence for a Role in Nonulcer Dyspepsia
`M.F. CARR Jr., J, MA, AND P.H.R. GREEN
`975 Effect of Disodium Azodisalicylate on Electrolyte Trans-
`port in Rabbit Ileum and Colon In Vitro
`R. PAMIJKCCI, S.B. HANAULR, AND E.B. CHANC
`982 Breath Hydrogen Testing in Bacterial. Overgrowth of the
`Small Intestine
`P. KERLIN AND L. WONC
`909 Assessment of Inflammatory Bowel Disease Activity by
`Technetium 99m Phagocyte Scanning
`W.E. PULLMAN, P.J. SULLIVAN, P.J. BARR/VIA', J. LISING,
`J.A. BOOTH, AND W.F. DOE
`997 Internal Anal Sphincter in Neurogenic Fecal
`Incontinence
`D.Z. LUBOWSKI, R.J. NICHOLLS, D.E. BURLEIGH, AND M. SWASH
`1003 Primary Culture of the Enteric Nervous System From
`Neonatal Hamster Intestine
`L.Y. KORMAN, E.S. NYLEN, T.M. FINAN, Rd. LINNOILA, AND
`K.L. BECKER
`
`1011 Proenkephalin A-Derived Peptides in the Human Gut
`G-L. FERRI, A. WATKINSON, AND G.J. DOCKRAY
`
`LIVER, PANCREAS, AND BILIARY TRACT
`1018 Evolution and Regression of Pancreatic Calcification in
`Chronic Pancreatitis. A Prospective Long-Term Study of
`107 Patients
`R.W. AMMANN, R. WENCH, R. OT1'0, H. BUEHLER,
`A.U. FREIBURCHAUS, AND W. SIECENTHALER
`1029 Maintenance of Hepatic Bile Acid Secretion. Rate During
`Overnight Fasting by Bedtime Bile Acid Administration
`A. LANZINI, D. FACCHINET11, AND T.C. NoRmrtELD
`1036 Prospective Trial of Penicillamine in Primary Sclerosing
`Cholangitis
`N.F. LARUSSO, R.H. WIESNER, J. Luowic, R.L. MACCARTY,
`S.J. BEAVER, AND A.R. ZINSMEISTER
`1043 Decreased Loss of Liver Adenosine Triphosphate During
`Hypothermic Preservation in Rats Pretreated With
`Glucose
`J.D. PALOMBO, Y. HIRSCHBERG, J.J. POMPOSELLI,
`G.L. BLACKBURN, S.H. ZEISEL, AND B.R. BISTRIAN
`1050 Effect of Nifedipine on Sphincter of Oddi Motor Activity
`M. GUELRUD, S. MENDOZA, G. Rossri LR, L. RAMIREZ, AND
`J. BARKIN
`
`1056 Alcohollike Liver Disease in Nonalcoholics
`A.M. DIEHL, Z. GOODMAN, AND K.G, IsuAR
`1063 Effect of Cessation of Alcohol Use on the Course of Pan-
`creatic Dysfunction in Alcoholic Pancreatitis
`L. GULLO, L BARBARA, AND G. LAeo
`1069 Biliary Motility Associated With Gallbladder Storage and
`Duodenal Delivery of Canine Hepatic Biliary Output
`R.B. SCOTT' AND S.C. DIAMANT
`1081 Intrarenal Thromboxane A2 Generation Reduces the Fu
`rosemide-Induced Sodium and Water Diuresis in Cirrho-
`sis With Ascites
`M. PINZANI, G. LAFTI, E. Ivic Ac (cid:9)
`AND P. GENTILINI
`1088 Pharmacologic Perturbation of Rat Liver Lysosomes: Ef-
`fects on Release of Lysosomal Enzymes and of Lipids Into
`Bile
`R.B. SEWELL, S.A. GM:41,11FM., A.R, ZINsmuls•IER, AM)
`N.F. LARusso
`1099 Effects and Mechanisms of Action of Motilin on the Cat
`Sphincter of Oddi
`J. BEIIAR AND P. BLANC ANI
`
`G. LA VILLA, F. CON/IINE1.1.1,
`
`CASE REPORTS
`1106 Massive Plasma Cell Infiltration of the Digestive Tract
`J.F. COLOMBEL, 1.C. Pe
`J.P. VAERNIAN, A. GALIAN,
`D.L. DELACROIX, J. NEMETH, F. DUPREY, M. HALPHEN,
`P. GODEAU, AND C. DIVE
`1114 Isolated Intestinal Myopathy Resembling Progressive
`Systemic Sclerosis in a Child
`J. JAYACHANDAR, J.L. FRANK, AND M.M. JONAS
`Sandoz v. AbbVie
`Sandoz Ex. 1079
`
`Ex. 1079 - Page 1
`
`(cid:9)
`

`

`General Information
`GASTROENTEROLOGY: GASTAB 95(4) 903-1166 (1988)
`ISSN 0016-5085
`0 1988 by the American Gastroenterological Association
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`Ex. 1079 - Page 2
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`GASTROENTEROLOGY 1988;95:1036-42
`
`Prospective Trial of Penicillamine in
`Primary Sclerosing Cholangitis
`
`NICHOLAS F. LARUSSO, RUSSELL H. WIESNER, JURGEN LUDWIG,
`ROBERT L. MAcCARTY, SANDRA J. BEAVER,
`and ALAN R. ZINSMEISTER
`Departments of Medicine, Pathology, Radiology, Statistics, and Epidemiology, Mayo Clinic and
`Mayo Foundation, and the Mayo Medical School, Rochester, Minnesota
`
`We evaluated the therapeutic efficacy of penicil-
`'amine in primary sclerosing cholangitis. In a ran-
`domized, prospective, double-blind trial, 39 pa-
`tients received penicillamine (250 mg t.i.d.) and 31
`received a placebo. The two groups were highly
`comparable at entry with regard to clinical, bio-
`chemical, radiologic, and hepatic histologic fea-
`tures. Although a predictable cupruresis and a
`decrease in levels of hepatic copper were achieved
`in patients taking penicillamine, there was no ben-
`eficial effect on disease progression within 36 mo or
`on overall survival. Progressive symptoms, deterio
`ration in serial hepatic laboratory values, or his-
`tologic progression on sequential liver biopsy spec-
`imens were similar in both groups, occurring in
`>80% of the entire study population. The develop-
`ment of major side effects led to the permanent
`discontinuation of penicillamine in 21% of the pa-
`tients taking the drug. We conclude that the use of
`penicillamine in primary sclerosing cholangitis is
`not associated with a beneficial effect on disease
`progression or survival, and has considerable tox-
`icity. The study also suggests that primary scleros-
`ing cholangitis is a progressive disease in many
`patients.
`
`p
`rimary sclerosing cholangitis (PSC), a chronic
`hepatobiliary disease of unknown etiology, is
`characterized by diffuse inflammation and fibrosis of
`the intrahepatic and extrahepatic bile ducts leading
`to cholestasis, hepatic copper overload, biliary cir-
`rhosis, and premature death from liver failure (1).
`The cause is unknown; damage to small and large
`bile ducts may be due to immune mechanisms.
`Increased hepatic copper concentrations in this con-
`dition probably are the result of diminished hepato-
`biliary copper excretion (2,3). Currently, no effective
`
`medical therapy:for PSC is available. Moreover, no
`controlled therapeutic trials have been performed.
`Because of the cupruretic, antifibrogenic, and hu-
`munosuppressive effects of penicillamine (a-penicil-
`lamine) (4-6), as well as the initial promising results
`of this agent in the treatment of primary biliary
`cirrhosis (PBC), a cholestatic disease with many
`similarities to PSC (7), we initiated in 1980 a ran-
`domized' double-blind trial of penicillamine voHus
`placebo. After treating 70 patients for a minimum of
`36 mo, we found no beneficial effect of penicillamine
`on the progression of PSC. Also, use of this drug was
`associated with a high incidence of serious but
`reversible sitle effects.
`
`Patients and Methods
`Patient Selection
`All patients with PSC who had been evaluated at
`the Mayo Clinic were considered for entry into the study.
`Diagnosis of PSC was based on the following criteria (1):
`established liver disease of >6-mo duration; a serum lsvel
`of alkaline phosphatase more than twice the upper limit of
`normal; a cholangiogram demonstrating diffuse (>25%)
`narrowing, irregularity, dilatation, and tortuosity of the
`extrahepatic biliary ductal system with or without in-
`volvement of the intrahepatic ductal system; and a preen-
`try liver biopsy specimen compatible with the diagnosis of
`PSC and showing cholangitis or portal hepatitis (stage 1),
`periportal fibrosis or periportal hepatitis (stage II), septa)
`fibrosis, bridging necrosis, or both (stage III), or biliary
`cirrhosis (stage IV) (8), Patients were excluded from entry
`for the following reasons: previous biliary tract surgery
`(excluding simple cholecystectomy) or documented
`choledocholithiasis (not cholelithiasis) before the diagno-
`sis of PSC, radiographic changes (e.g., focal constriction
`
`Abbreviations used in this paper: PBC, primary biliary cir'
`rhosis; PSC, primary sclerosing cholangitis.
`© 1988 by the American Gastroenterological Associaticn
`0016-5085/88/$3.50
`
`Ex. 1079 - Page 3
`
`

`

`October 1988 (cid:9)
`
`PENICILLAIvIINE IN PSC 1037
`
`with proximal duct dilatation) strongly suggestive of
`cholangiocarcinoma, alcohol abuse, or a malignancy other
`than skin cancer. Of the 197 patients referred to us from
`June 1, 1980, to May 31, 1983, for consideration for entry
`into the trial, 70 (36%) were enrolled and 56 (28%) did not
`fulfill entry criteria and were excluded; 71 patients (36%)
`fulfilled entry criteria but chose not to participate. The
`most common reasons for not entering the trial were
`reluctance to travel to the Mayo Clinic for annual evalua-
`tion, including liver biopsy, economic concerns regarding
`return visits, and apprehension regarding possible drug
`side effects.
`Of these 71 patients with PSC who chose not to enter the
`study, an initial liver biopsy specimen was available for
`review in 54 (76%). The 54 nonstudy patients with liver
`biopsies were compared with the 70 study patients based
`on entry data. Using study versus nonstudy as the depen-
`dent variable, a logistic regression analysis (9) examined
`the association of various entry variables, with study par-
`ticipation. There was an association with histologic, stage
`of disease (77% of study patients vs. 59% of nonstudy
`patients had stage III or IV disease), but no other variables
`were associated with entry into the study.
`
`Study Organization and Randomization
`Each patient was provided with a detailed descrip:
`tion of the nature and goals of the study and signed a
`written consent form. A complete medical history was
`obtained and a physical examination performed on each
`patient at entry. Baseline laboratory tests included a com-
`plete blood count, urinalysis, and measurements of serum
`alkaline phosphatase, aspartate aminotransfer-
`ase, albumin, y-globulin, cholesterol, ceruloplasmin and
`copper, antimitochondrial antibody, hepatitis B surface
`antigen, prothrombin time, immunoglobulins A, G, and M,
`and a 24-h urinary excretion of copper. A barium-swallow
`examination or upper endoscopy, or both, was performed
`to determine whether esophageal varices were present. At
`entry, 56 (80%) patients had endoscopic retrograde chol-
`angiography performed at the Mayo Clinic using a stan-
`dardized procedure. In the remaining 14 (20%) patients,
`cholangiograms performed elsewhere during the 6 months
`before entry were available for review. All patients at entry
`had either a colonoscopic examination (n = 26) or both a
`protoscopic examination and a double-contrast barium
`enema (n = 44). All patients were instructed at entry in a
`low copper diet by a dietitian.
`A preentry liver biopsy specimen was obtained and
`processed as described (10). For the measurement of he-
`patic copper, atomic absorption spectrophotometry was
`used.
`Patient cohorts were stratified based on the presence or
`absence of cirrhosis on liver biopsy or varices on radio-
`rraphic or endoscopic examination of the tipper gastroin-
`testinal tract. Patients were randomly assigned to drug or
`placebo groups. Randomization was weighted in favor of
`the drug group in anticipation of possible drug toxicity
`requiring severance from the study. Penicillamine and
`placebo (furnished to us through the courtesy of Merck
`Sharp & Dohme, West Point, Pa.) were dispensed in
`identical yellow capsules by one pharmacist.
`
`Treatment Regimen and Follow-up
`Patients were reexamined 6 mo and 1 yr after entry
`and at yearly intervals therafter. Liver biopsies and endo-
`scopic retrograde cholangiograms were repeated at 12-mo
`intervals• or as clinically indicated. All biopsy specimens
`were interpreted by one pathologist (J.L.) and all cholangi-
`ograms by one radiologist (R.L.M.) without knowledge of
`the clinical history or treatment group. The initial dose
`was 1 capsule of penicillamine (250 mg) or placebo each
`day for 4 wk. The dose was increased by 1 capsule per day
`every 4 wk until a maintenance dose of 3 capsules per day
`was achieved.
`Patients from either group were referred for liver trans-
`plantation if they developed advanced, irreversible end-
`stage liver disease that resulted in either life-threatening
`complications or an unacceptable quality of life.
`
`Toxicity Monitoring
`Determinations of hemoglobin levels, counts of
`leukocytes and platelets, and routine urinalysis were per-
`formed at 2-wk intervals for the first 3 mo of therapy; after
`that, leukocyte and platelet counts were performed every
`6-8 wk. The 24-hr urinary excretion of protein and copper
`was measured at 1 and 3 mo after entry and at 3-mo
`intervals thereafter. Toxicity was categorized as minor or
`major as previously described (10).
`All decisions regarding appropriate management of pos-
`sible drug reactions were made by an intramural study
`monitor who did not otherwise participate in the study.
`
`Management of Associated Inflammatory
`Bowel Disease
`Inflammatory bowel disease was defined by con-
`ventional radiologic, colonoscopic, or histologic criteria.
`At entry, 45 patients had inflammatory bowel disease. In
`general, study patients with inflammatory bowel disease
`did not require aggressive medical or surgical treatment for
`intestinal disease because it was almost always asympto-
`matic or only minimally symptomatic. Patients did not
`require steroid treatment for their inflammatory bowel
`disease during the trial but 21 (48%) patients with associ-
`ated inflammatory bowel disease were treated with azul-
`fidine or azulfidine and imodium (12 on placebo and 9 on
`penicillarnine). All study patients who had not undergone
`colectomy had annual proctoscopic examination with rec-
`tal biopsy plus double-contrast barium enema (49%) or a
`colonoscopy (51%) performed at the Mayo Clinic, regard-
`less of whether a diagnosis of inflammatory bowel disease
`had been made at entry.
`
`Statistical Methods
`Comparison of treatment groups focused on five
`endpoints: (a) overall survival (follow-up censored at liver
`transplant or last follow-up); (b) time to treatment failure
`(failure based on clinical, biochemical, cholangiographic,
`and hepatic histologic indices); (c) changes (entry vs. 1 yr)
`in biochemical variables; (d) progression of hepatic histol-
`ogy; and (e) overall progression as judged by a combina-
`tion of clinical (e.g., development of ascites or encepha-
`
`Ex. 1079 - Page 4
`
`

`

`1038 LARUSSO ET AL.
`
`GASTROENTEROLOGY Vol. 95, No,
`
`Table .1, Characteristics of Study Population at Entry
`
`Variable
`
`Number
`Age
`Mean
`Range
`Sex (% male)
`Symptoms 1% present)
`Prior surgery (%)
`Yes
`Proctocolectomy
`Cholecystectomy
`Bile duct.reconstruction
`Associated diseases (%)
`Chronic ulcerative colitis
`Grohn's disease
`Cholelithiasis
`Complications (%)
`Portal hypertension
`Cholangitis
`Biochemical tests (median)
`Bilirubin (mg/dl)
`Alkaline phosphatase (U/L; normal
`<250)
`SCOT (U/L; normal <30)
`Albumin (g/dl)
`Urine copper (pg/24 h; normal <60 p.g/
`24 h)
`Hepatic copper (normal •<40 p..g/g liver)
`Hepatic histology (%)
`Early
`(Stage I or II)
`Advanced
`(Stage HI or IV)
`Duration of follow-up (yr) (median)
`Patients still alive
`Patients dead
`Number undergoing liver transplanation
`SCOT, serum glutamic-oxaloacetic transaminase.
`
`Entire
`population
`70
`
`42
`17-71
`63
`83
`
`67
`26
`30
`13
`
`66
`
`17
`
`30
`27
`
`1,8
`1097
`
`81
`3.35
`87
`
`212
`
`23
`
`77
`
`Placebo
`31
`
`42
`17-70
`65:
`90
`
`61
`19
`29
`13
`
`58
`3
`
`26
`35
`
`2.4
`1242
`
`82
`3,46
`119
`
`237
`
`19.
`
`8)
`
`Pencillamine
`39
`
`42
`20-71
`62
`77
`
`72
`31
`31
`13
`
`72
`0'
`
`33
`21
`
`1.5
`973
`
`70
`3.26
`87
`
`150
`
`26
`
`74
`
`39 (n = 53)
`1.2 (n = 17)
`12
`
`24)
`4.1 (n (cid:9)
`1..6 (r). =- 7)
`5
`
`3.7 (n = 29)
`1,0 (n = 10)
`7
`
`lopathy), biochemical (e.g, increases in bilirubin, alkaline
`phosphatase, aminotransferases, and prothrombin time, or
`a decrease in albumin), and hepatic histologic. (e.g., his-
`tologic stages on liver biopsy) variables. A proportional
`hazards regression analysis (11) was used to compare
`treatment groups on overall survival, time to treatment
`failure, and progression, adjusting for entry histologic
`stage and the stratification factor (cirrhosis/portal hyper-
`tension). The two-sample t-test was used to compare the
`changes in biochemical variables.
`
`Results
`
`Study Population
`
`The two treatment groups were comparable at
`the time of randomization with regard to clinical,
`biochemical, cholangiographic, and hepatic his-
`tologic indices. Table 1 shows the characteristics of
`the study population at entry.
`
`Analysis of Treatment Effect
`
`Clinical, biochemical, and cholangiograph is
`changes. There was no consistent clinical improve-
`ment in either the drug or placebo group with regard
`to symptoms such as pruritus,, fatigue, cholangitis,
`portal-systemic encephalopathy, variceal bleeding,
`or specific features on physical examination, such as
`excoriations, hepatosplenomegaly, ascites, or hyper-
`pigmentation. No difference in time to treatment
`failure was detected between placebo and drug
`groups.
`Table 2 shows biochemical changes in the patients
`with data at entry and 1 yr after entry. Changes 'n
`laboratory values over the 1-yr period were similar
`in the drug and placebo groups with regard to levels
`of albumin, bilirubin, aspartate aminotransferw
`alkaline phosphatase, y-globulin, platelets, hemoglo-
`bin, and prothrombin time. There was a significant
`
`Ex. 1079 - Page 5
`
`

`

`October 1988 (cid:9)
`
`PENICILLAMINE IN PSC 1039
`
`Table 2. Biochemical Data at Entry and at 1 Year°
`
`Variable
`
`Bilirubin (mg/di)
`
`Alkaline phosphatase
`(U/L)
`Aspartate aminotrans-
`ferase (U/L)
`Albumin (g/dl)
`
`y-Globulin
`
`Prothrombin time (s)
`
`Hemoglobin (g/dI)
`
`Platelets (x 103/mm 3)
`
`Urinary copper (mg/
`24 h)
`Hepatic copper (11,g/g)
`
`Group
`
`Drug
`Placebo
`Drug
`Placebo
`Drug
`Placebo
`Drug
`Placebo
`Drug
`Placebo
`Drug
`Placebo
`Drug
`Placebo
`Drug
`Placebo
`Drug
`Placebo
`Drug
`Placebo
`
`n
`
`32
`28
`32
`28
`32
`28
`32
`28
`32
`28
`39
`31
`39
`31
`32
`28
`28
`27
`21
`23
`
`At entry
`Mean ± SE
`
`3.4 ± 1.3
`3.9 ± 1.0
`1196 -± 123
`1475 ± 169
`87 ± 8
`105 ± 15
`3.4 ± 0.1
`3.4 ± 0.1
`1.7 ± 0.1
`1.6 ± 0.1
`10,6 ± 0.14
`10.7 ± 0.3
`13.1 ± 0.3
`13.0 ± 0.3
`284 ± 28
`244 ± 21
`121 ± 24
`110 ± 18
`233 ±.49.
`292 ±. 65
`
`Median.
`
`1.3
`2.2
`984
`1239
`68
`82
`3.3
`3.5
`1.7
`1.6
`10.4
`10.1
`13.1
`13.6
`244
`258
`76
`80
`123
`212
`
`32
`28.
`32
`28
`32
`28
`32
`27
`32
`27
`32
`28
`32
`28
`32
`28
`28
`27
`21
`23
`
`At 1 yr
`Mean ± SE
`
`4.9 ± 1.1
`4.5 ± 1.2
`1371 ± 188
`1327 ± 1.34
`94 ± 14
`117 ± 16
`3.1 ± 0.1
`3.4 ± 0.1
`1.6 ± 0.4
`1.7 .± 0.1
`10.7 ± 0.14
`11.2 ± 0.3
`13.1 ± 0.4
`12.9 -± 0.3
`231 ± 22
`197 ± 17
`358 ± 50
`112 ± 23
`176 ± 49
`256 ± 39
`
`Median
`
`2.5
`1.8
`1140
`1200
`60
`99
`3.2
`3.4
`1.6
`1.7
`106
`108
`13.2
`13.1
`226
`181
`295
`67
`91
`189
`
`° In those subjects with both 1- and 3-yr data, the biochemical values were similar within each group at 1 and 3 yr. However, 50% of the
`subjects in each group did not have urine copper values, for example, at year 3. Thus, to minimize the possible influence of selection
`bias, the 1-yr data (available in most subjects) 'are presented' above along with the entry data for the same subjects.
`
`obtained showed no change over the course of the
`study on serial cholangiograms. Twenty-one (39%)
`patients showed deterioration in the form of increas-
`ing stricture formation or increasing irregularities of
`the mucosal surfaces of the ducts. Of those 21, 11
`were on penicillamine and 10 were on placebo. Only
`1 patient on penicillamine showed cholangiographic
`evidence of improvement during the trial. A second
`patient on the drug showed possible improvement.
`Thus, penicillamine treatment was not associated
`with reversal of cholangiographic abnormalities and
`did not protect against cholangiographic deteriora-
`tion when compared with placebo.
`Hepatic histology. Figure 1 shows the effect
`of penicillamine versus placebo on the development
`of abnotitialities on liver biopsy in the two groups of
`patients studied. The rate of progression from early
`to advanced disease histologically was as rapid with
`the drug regimen as it was with placebo. Also,
`morphologic features such as inflammation and cho-
`lestasis did not differ substantially between groups
`on entry or on sequential biopsies. The only notable
`difference between groups was a decreased intensity
`in copper staining in specimens from patients on
`penicillamine.
`Survival. Penicillamine did not produce an
`overall improvement in survival as compared with
`placebo (Figure 2); the median survival times were
`>4 yr for both the drug and -placebo groups.
`
`difference between the drug and placebo groups in
`hepatic copper concentration and in urinary copper
`excretion at 1 yr after entry; in the penicillamine
`group a median decrease of 55% in hepatic copper
`was observed, whereas hepatic copper increased by
`1% in the placebo group. Also, urinary copper was
`increased by 250% in the penicillamine group but
`decreased by 20% in the placebo group.
`All patients at entry had cholangiographic find-
`ings consistent with PSC. Thirty of the 54 (56%)
`patients in whom follow-up cholangiograms were
`
`D'-pen
`Placebo
`
`Progression, %
`
`2
`1 (cid:9)
`Years from entry
`Figure 1. The effect of penicillamine (0-pen) on hepatic his-
`tologic progression is shown. Histologic progression is
`defined as an increase of at least one stage (e.g., stage III
`to stage IV) on serial liver biopsy.
`
`3
`
`Ex. 1079 - Page 6
`
`(cid:9)
`

`

`1040 LARUSSO ET AL.
`
`GASTROENTEROLOGY Vol. 95, No. 4
`
`D-pen
`Placebo
`
`(10)
`
`Progression variables
`
`• Ascites/varices
`• Bilirubin (> 3 mg/c11 t )
`• Histologic stage
`• Referral for OLT
`• Death by liver failure
`
`Progression, %
`
`(27)
`
`(26)
`
`(21)
`
`Placebo
`D-pen
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Cu
`
`2
`1 (cid:9)
`Years from entry
`
`3
`
`Figure 2. The effect of penicillamine (n-pen) on survival is
`shown. The graph represents the Kaplan—Meier esti-
`mated survival with censoring of patients referred for
`liver transplantation.
`
`0
`
`2 (cid:9)
`
`3
`
`Years from entry
`
`Figure 3. The effect of penicillamine (u-pen) on overall progres-
`sion. The graph represents the Kaplan—Meier estimate.
`OLT = orthotopic liver transplantation.
`
`Overall progression. Penicillamine did not
`affect overall progression of the disease compared
`with placebo (Figure 3) as assessed by a combination
`of clinical, biochemical, and hepatic histologic var-
`iables. The number of subjects requiring liver trans-
`plantation was similar in the placebo (5 of 31) and in
`the penicillamine (7 of 39) groups.
`Toxicity. Major side effects led to the perma-
`nent discontinuation of penicillamine therapy in 8
`of 39 patients (21%) taking penicillamine. In addi-
`tion, there were 20 minor reactions among the
`penicillamine group and 9 among the placebo group
`that may have been drug related (Table 3). When
`toxicity was included in the definition of treatment
`failure, then time to treatment failure was signifi-
`cantly (p < 0.05) shorter in the penicillamine group.
`No patients died as a result of known side effects
`of penicillamine. Presumed major side effects of
`penicillamine always resolved after the drug had
`been discontinued.
`
`Discussiori
`In our study, penicillamine (750 mg/day) had
`no beneficial effect on the course, complications, and
`survival of patients with PSC. This lack of benefit
`over a 3-yr period was evident even though penicil-
`lamine resulted in a marked cupruresis and a signif-
`icant decrease in hepatic copper content.
`As this is the first randomized trial of any medical
`therapy in PSC, we are unable to compare our results
`with a published study. However, use of penicil-
`lamine has been evaluated in PBC (10,12), a chronic
`cholestatic syndrome with many similarities to PSC
`(7). As in our study, penicillamine produces a
`cupruresis and a decrease in hepatic copper content
`in PBC, but does not affect survival. Although certain
`
`biochemical tests (e.g., serum aspartate aminotranr-
`ferase) may be improved by penicillamine in PBC,
`we found no benefit of penicillamine on any bio-
`chemical parameters in our patients with PSC. Sim-
`ilar to studies of penicillamine in PBC, we saw no
`beneficial effect of the drug on the histologic progres-
`sion of PSC.
`Penicillamine was not only ineffective in our pa-
`tients with PSC, its use was associated with a high
`incidence of ,serious side effects. This high rate of
`drug toxicity is similar to that seen in PBC and
`rheumatoid arthritis (10,12,13). Indeed, in each of
`these two diseases, approximately one-third of pa-
`tients receiving penicillamine have side effects seri-
`ous enough to necessitate permanent discontinua-
`
`Table 3. Possible Drug-Belated Side Effects.
`
`Reaction
`
`Placebo
`(n = 31)
`
`Penicillarnige
`(n = 39)
`
`Allergic
`Cytopenia
`Diarrhea
`Proteinuria
`Hair loss
`Hemolysis
`Arthralgias
`Dysgeusia
`Lichen pianos
`
`Total
`
`Drug discontinued because of
`side effects (all reversible)
`Fatal drug reactions
`
`0
`5
`0
`3
`0
`0
`1
`0
`0
`91,
`
`0
`
`0
`
`2"
`5°
`2
`12'
`1
`3
`1
`1
`1
`
`28"
`
`8 (21%)
`
`0
`
`Both patients with allergic reactions, 1 of 5 with cytopenia, and
`5 of 12 with proteinuria had the drug permanently discor Ha-
`uer]. b Reactions in 8 of 31 (26%). Reactions in 25 of 39 (64%).
`
`Ex. 1079 - Page 7
`
`

`

`October 1988 (cid:9)
`
`PENICILLAMINE IN PSC 1041
`
`tion of the drug. Although the high incidence of side
`effects induced by penicillamine in patients with
`rheumatoid arthritis may be associated with the
`increased occurrence of the HLA-DRw3 antigen (14),
`e did not assess HLA antigen status in our patients
`with PSC.
`The results of our study have several implications.
`First, they suggest that therapy aimed at diminishing
`hepatic copper overload in patients with PSC is not
`likely to be beneficial. This conclusion further sug-
`gests that hepatic copper overload is indeed a sec-
`ondary manifestation of the chronic cholestasis
`caused by PSC and does not have a primary patho-
`genetic role in its progression (3). Also, although
`penicillamine has immunosuppressive effects, they
`appear to be relatively weak (5,6). Therefore, we do
`not believe that our negative study should be inter-
`preted as evidence against a role for therapeutic
`trials of immunosuppressive agents in PSC, particu
`larly as recent, accumulating data support altered
`immunity as an important pathogenetic factor in this
`disease (15,16). Indeed, we are currently conducting
`just such a trial using cyclosporiny A a potent
`immunosuppressive agent. Given the chronic, fi-
`brotic nature of PSC and recent encouraging data
`with colchicine in PBC (17), it would seem reason-
`able to also consider therapeutic trials using antifi-
`brogenic agents in. PSC, perhaps in combination with
`immunosuppressive agents. Recent uncontrolled
`data from our group showing improvement in liver
`tests in a small group of patients with PSC given
`colchicine plus prednisone supports this approach
`(18). Finally, although our results showing no bene-
`ficial effect of.penicillamine in PSC are disappoint-
`ing, the availability of a large, homogeneous popu-
`lation of patients and the opportunity to follow these
`patients serially in the context of a therapeutic trial
`has allowed us to generate important and novel data
`on the clinical, biochemical, radiologic, and his-
`°logic features of this previously obscure syndrome
`12,3,7,8,15,16,19). Indeed, from the viewpoint of
`natural history, our results showing clinical, bio-
`.themical, or hepatic histologic progression, alone or
`in combination, in the overwhelming majority of our
`patients suggest that PSC is often a progressive
`disease (20),
`In conclusion, our results suggest that penicil-
`lamine is .not effective in the treatment