high dose udca in the treatment of primary sclerosing ... · rationale for high dose udca in...

High dose UDCA inHigh dose UDCA inthe Treatment of Primary the Treatment of Primary SclerosingSclerosing CholangitisCholangitis

Falk Meeting,Freiberg2006Falk Meeting,Freiberg2006Dr RW ChapmanDr RW Chapman

John Radcliffe HospitalJohn Radcliffe HospitalOxford,UKOxford,UK

Specific Medical Therapy for PSCSpecific Medical Therapy for PSCImmunosuppressantsImmunosuppressants

--prednisoloneprednisolone--budesonidebudesonide--azathioprineazathioprine--ciclosporineciclosporine--tacrolimustacrolimus--methotrexatemethotrexate

AntifibroticsAntifibrotics--colchicinecolchicine

MiscellaneousMiscellaneous--nicotinenicotine--pentoxyphyllinepentoxyphylline

UrsodeoxycholicUrsodeoxycholic acid acid conventional dose 10conventional dose 10--15mg/kg15mg/kg

Summary: results of trials disappointing!Summary: results of trials disappointing!

Novel Approaches to TreatmentNovel Approaches to Treatment

High dose High dose UrsoUrso

Novel drugs Novel drugs egeg silymarinsilymarin; ; perfenidone;enteraceptperfenidone;enteracept

EndoscopicEndoscopic therapy therapy egeg balloon dilatationballoon dilatation

Combination therapyCombination therapyendoscopicendoscopic & drug therapy& drug therapydrug combinationsdrug combinations

The Optimum dose of The Optimum dose of UrsoUrso in in CholestaticCholestaticLiver Diseases (PBC/PSC)?Liver Diseases (PBC/PSC)?

Original dosages in PBC derived from gallstone dissolution data viz10mg/kg body wt

DB controlled trials of low dose UDCA (10DB controlled trials of low dose UDCA (10--15mg/kg) in PSC15mg/kg) in PSC

nonononoimpimp3636momo

105105LindorLindor19971997

n/an/anonoimpimp24 24 momo

4848Van Van HooHoo19981998

impimpnonoimpimp24 24 momo

2020StiehlStiehl19941994

impimpnonoimpimp12 12 momo

1414BeuersBeuers19921992

LiverLiverhistolhistol

SymptSymptimprovimprov

AlkAlkphosphos

Study Study duratdurat

Pt NoPt NoAuthorAuthor

Rationale for High Dose UDCA Rationale for High Dose UDCA in treatment of PSCin treatment of PSC

Low dose doesnLow dose doesn’’t work!t work!

In advanced In advanced cholestasischolestasis in PSC the enrichment of in PSC the enrichment of the bile acid pool is diminished cp cystic fibrosisthe bile acid pool is diminished cp cystic fibrosisStiehlStiehl et al,J et al,J HepatolHepatol 1995,1995,RostRost et et al,Hepatolal,Hepatol 20042004

BiliaryBiliary enrichment with UDCA is proportional to enrichment with UDCA is proportional to administered doseadministered doseRodaRoda et et al,Europal,Europ J Gastro 2002J Gastro 2002RostRost et et al,Hepatolal,Hepatol 20042004

HighHigh--dose UDCA on dose UDCA on biliarybiliaryenrichment in PSCenrichment in PSC

RostRost D,et al; D,et al; HepatologyHepatology 2004;40:6932004;40:693--698698

Biliary enrichment of UDCA

2 doses 10-13 mg/kg;<22mg/kg

Higher dose increased enrichment

Biliary enrichment at various doses ;plateau effect at 22-25mg/kg

High dose UDCA in PSC*High dose UDCA in PSC*

DBCT 26 PSC ptsDBCT 26 PSC ptsRandomised to placebo or UDCA(20 Randomised to placebo or UDCA(20 ––25mg /day) 25mg /day) Repeat liver biopsy/ERCP at 2 yrsRepeat liver biopsy/ERCP at 2 yrs22/26 completed the trial22/26 completed the trialSerum bile acids (HPLC) 0,1,2 yrsSerum bile acids (HPLC) 0,1,2 yrs

*Mitchell S et al,Gastro 2001

High Dose High Dose UrsoUrso in PSCin PSCHistological Disease stage over 2 yrsHistological Disease stage over 2 yrs

Histological stage worsened in placebo group cp UDCA

High Dose High Dose UrsoUrso in PSCin PSCERCP changes over 2yearsERCP changes over 2years

ERCP worsened in placebo group cp UDCA

High Dose High Dose UrsoUrso in PSCin PSCSerum bile acids (by HPLCSerum bile acids (by HPLC))

73%73%78%78%6%6%High doseHigh doseUDCAUDCA

7.3%7.3%7.8%7.8%3%3%Placebo Placebo groupgroup

atat2years2years

atat1 years1 years

atat0 year0 year

% of % of UDCA UDCA fraction fraction of bile of bile acid poolacid pool

High Dose High Dose UrsoUrso in PSCin PSCSummary of resultsSummary of results

Well toleratedWell toleratedNo effect on colitis activityNo effect on colitis activitySignificant improvements in alkaline Significant improvements in alkaline phosphos/GGT/GGTNo improvements in symptomsNo improvements in symptomsMajority of treated group had improved Majority of treated group had improved inflaminflam/fibrosis scores/fibrosis scores4/10 had regression disease stage 4/10 had regression disease stage –– not not

seen in placebo groupseen in placebo group

High dose High dose UrsoUrso as a therapy for as a therapy for patients with PSC*patients with PSC*

patients / methodspatients / methods

30 PSC pts30 PSC ptstreated with 25treated with 25--30 mg/kg/daily for one 30 mg/kg/daily for one year year ––open studyopen studycompared with historical PSC controlscompared with historical PSC controlsvizviz placebo (52 pts) and mod doseplacebo (52 pts) and mod doseursourso 1313--15mg/kg/daily (53 pts15mg/kg/daily (53 pts))

*Harnois et al;Am J Gastro 2001

High dose UDCA as a therapy for High dose UDCA as a therapy for patients with PSC*patients with PSC*Results at one yearResults at one year

Marked improvement in Marked improvement in LFTLFT’’ssChanges in Mayo Risk Score wereChanges in Mayo Risk Score weresignificantly different at one year significantly different at one year between 3 groupsbetween 3 groupsExpected survival at 4 yearsExpected survival at 4 years-- High dose High dose improvedimproved vsvs placeboplacebo

(p=0.04)(p=0.04)-- Mod dose Mod dose vsvs placeboplacebo-- no differenceno difference

(p=0.4)(p=0.4)Harnois et al;Am J Gastro 2001

97 pts high dose UDCA (1797 pts high dose UDCA (17--23 23 mg/kg) for 5 yearsmg/kg) for 5 years101 pts placebo101 pts placebo

ScandanavianScandanavian trial high dose UDCAtrial high dose UDCA::changes in serum biochemistrychanges in serum biochemistry

Alk phos

ALT

bilirubin

Red =placebo

High dose High dose ScandanavianScandanavian TrialTrial

Death /Transplantation:

7.2% UDCA vs 10.9% placebo(ns)

High dose UDCA High dose UDCA ScandanavianScandanavian study:study:

potential problemspotential problems

Study underpowered Study underpowered (only 10% placebo pts (only 10% placebo pts reached endpoint)reached endpoint)

High dropout rateHigh dropout rate

Dose too low ! (15 Dose too low ! (15 --20mg/kg)20mg/kg)

Study period too short Study period too short (even at 5 yrs!)(even at 5 yrs!)

StongStong possibility of type II errorpossibility of type II error

*Lindor et al:N Engl J Med 1997

Olsson et al:J Hepatol2004

Low dose UDCA High dose UDCA

5 yr Survival

Glass half empty!

Glass half full! UDCA+?

High dose UDCA

Current status?

What about even Higher Dose What about even Higher Dose UDCA in PSC?*UDCA in PSC?*

2 year DBRCT pilot study in 33 PSC 2 year DBRCT pilot study in 33 PSC pts pts Munich & OxfordMunich & OxfordPts randomised to UDCA either Pts randomised to UDCA either 10mg/kg; 20 or 30 mg/10mg/kg; 20 or 30 mg/kgmkgmLiver biopsy 0 and 2 years assessed Liver biopsy 0 and 2 years assessed using Ludwig Scoreusing Ludwig Score

*Cullen S. Rust C, Fleming K, Beuers U, Chapman RW: EASL 2006

High dose UDCA High dose UDCA Improvement in liver function TestsImprovement in liver function Tests

T-test (within treatment group)

10mg 20mg 30 mg

Bilirubin p=0.77 p=0.71 p=0.57

Alk Phos p=0.01 p=0.01 p=0.03

AST p=0.08 p=0.03 p=0.09

ALT p=0.05 p=0.02 p=0.06

GGT p=0.01 p=0.01 p=0.01

High Dose UDCA in PSCHigh Dose UDCA in PSCMayo Risk Scores;Mayo Risk Scores;

difference in survival probabilities from difference in survival probabilities from baseline to end of the studybaseline to end of the studyM ayo scor es - Di f f er ence i n sur vi val pr obabi l i t i es f r om basel i ne t o end of st udy

0

0.5

1

1.5

2

2.5

3

3.5

1 year 2 year s 3 year s 4 year s

T i me ( y e a r s )

A l l

10mg/ kg

20mg/ kg

30mg/ kg

Time in yrs1 yr 4yrs

Survival probabilities

High dose UDCA in PSCHigh dose UDCA in PSCChange in Ludwig score

All patientsn=31

Low dose UDCA (10mg/kg)n=11

Standard dose UDCA (20mg/kg)n=11

High dose UDCA (30mg/kg)n=9

Improved 6 19% 1 9% 2 18% 3 33%

No change 17 55% 7 64% 8 73% 2 22%

Worsening 3 10% 2 18% 0 0% 1 11%

No biopsy 5 16% 1 9% 1 9% 3 33%

High Dose UDCA in PSC*High Dose UDCA in PSC*

Very high dose (Very high dose (ieie 30mg/kgm) well 30mg/kgm) well toleratedtoleratedCholestaticCholestatic LFTLFT’’ss -- improved in all groupsimproved in all groupsTrend towards improvement in the Trend towards improvement in the Ludwig score in standard and high dose Ludwig score in standard and high dose groupsgroupsSignificantly increased survival ( using Significantly increased survival ( using Mayo Risk score) in 30mg/kg groupMayo Risk score) in 30mg/kg groupHowever SMALL pilot study!However SMALL pilot study!

*Cullen S et al; EASL 2006*Cullen S et al; EASL 2006

UDCA treatment for PSCUDCA treatment for PSCUDCA anticancer roleUDCA anticancer role

Evidence in favour of reduction of Evidence in favour of reduction of colon cancer risk in PSC/IBDcolon cancer risk in PSC/IBD

Tentative evidence for reduction in Tentative evidence for reduction in risk of risk of cholangiocacholangioca : not proven: not proven

Effect of UDCA dose is unknown inEffect of UDCA dose is unknown inchemoprotectionchemoprotection

High dose UDCA in PSCHigh dose UDCA in PSC

Data still suggestive that UDCA Data still suggestive that UDCA indicated in high doseindicated in high dose

Large US study in progressLarge US study in progress

New studies are unlikely to occur New studies are unlikely to occur vizviz cancer protective effectcancer protective effect

on colon & ? bile ductson colon & ? bile ducts

High Dose High Dose UrsoUrso in PSCin PSC--combination combination therapy: the future?therapy: the future?

Studies of combination therapy Studies of combination therapy with with UDCA (low dose)UDCA (low dose)

--antibioticsantibiotics((metronidazolemetronidazole) ) --PosPos [DBCT] [DBCT]

--immunomodulatoryimmunomodulatory((mycophenolatemycophenolate mofetilmofetil) ) --Neg (DBCT)Neg (DBCT)

--immunosuppressant immunosuppressant ( ( predpred 1mg/kg;Azathioprine 1mg daily)1mg/kg;Azathioprine 1mg daily)

-- PosPos (Uncont)(Uncont)--rifampicin (no trial)rifampicin (no trial)

High Dose High Dose UrsoUrso in PSCin PSC--combination therapycombination therapy

Studies of combination therapy Studies of combination therapy with UDCAwith UDCA

--antibioticsantibiotics((metronidazolemetronidazole) ) --

Positive [DBCT]Positive [DBCT]

--immunomodulatoryimmunomodulatory((mycophenolatemycophenolate mofetilmofetil) ) --

Negative[DBCTNegative[DBCT]]

--immunosuppressant immunosuppressant (( dd 1 /k A thi i1 /k A thi i

High dose UDCA in PSCHigh dose UDCA in PSC

Data still suggestive that UDCA Data still suggestive that UDCA indicated in high doseindicated in high dose

Large US study in progressLarge US study in progress

New studies are unlikely to occur New studies are unlikely to occur vizviz cancer protective effectcancer protective effect

on colon & ? bile ductson colon & ? bile ducts

Cochrane ReviewCochrane Review

Gluud & Chen 2002

Potential Benefits of Potential Benefits of UrsodeoxycholicUrsodeoxycholicacid in Colon Cancer*acid in Colon Cancer*

Toxic bile acids Toxic bile acids vizviz deoxycholicdeoxycholic acid induce cell acid induce cell proliferation proliferation --induces induces dysplasiadysplasia and colon cancer and colon cancer [in vitro model] NB Effects reversed by UDCA[in vitro model] NB Effects reversed by UDCA

In vivo In vivo –– reduced prevalence of Colon reduced prevalence of Colon Polyps/cancer in PBC treated with UDCAPolyps/cancer in PBC treated with UDCA

Colonic Colonic dysplasiadysplasia / cancer increased in PSC/UC / cancer increased in PSC/UC compared with UC alonecompared with UC alone

*Martinez et al;Nutr Cancer 1998;31:111-8

Proportion of PSC/UC pts free of colonic Proportion of PSC/UC pts free of colonic cancer / cancer / dysplasiadysplasia**

**PardiPardi et al,Gastro 2003;124:889et al,Gastro 2003;124:889--33

n=29n=29

n=23n=23

NB Similar results in Oxford

Novel treatment for PSCNovel treatment for PSCUDCA anticancer roleUDCA anticancer role

Strong evidence in favour of reduction of Strong evidence in favour of reduction of colon cancer risk in PSC/IBDcolon cancer risk in PSC/IBD

Tentative evidence for reduction in risk of Tentative evidence for reduction in risk of cholangiocacholangioca : not proven: not proven

Effect of UDCA dose is unknownEffect of UDCA dose is unknown


Novel drugsNovel drugs


EndoscopicEndoscopic therapytherapy


High Dose High Dose UrsoUrso in PSCin PSC--combination therapycombination therapy

Studies of combination therapy with UDCAStudies of combination therapy with UDCA

--antibiotics(metronidazole)Positiveantibiotics(metronidazole)Positive [DBCT] [DBCT]

--immunomodulatoryimmunomodulatory((mycophenolatemycophenolate mofetilmofetil) Negative[DBCT]) Negative[DBCT]

--immunosuppressant immunosuppressant ( ( predpred 1mg/kg;Azathioprine 1mg daily)1mg/kg;Azathioprine 1mg daily)

Positive [Positive [UncUnc]]

Novel Treatments of PSCNovel Treatments of PSCConclusionConclusion

UDCA indicated in PSC/UC ptsUDCA indicated in PSC/UC ptsbecause of reduced risk of colonic because of reduced risk of colonic neoplasianeoplasia

Further trials required of combination studies of Further trials required of combination studies of UDCA with other agentsUDCA with other agents

antibiotics antibiotics egeg metronidazolemetronidazole

endoscopicendoscopic therapies therapies

Novel drug therapies for PSCNovel drug therapies for PSCEtanerceptEtanercept (anti TNF antibody)(anti TNF antibody)

Pilot study :25 mg twice weekly s/c [10 PSC pts]Pilot study :25 mg twice weekly s/c [10 PSC pts]treated for 1 year*treated for 1 year*No improvement in No improvement in LFTLFT’’ss ((bilirubinbilirubin 2x!)2x!)2 /5 pts improved itch2 /5 pts improved itch

NB: PSC pts refractory: all had failed UDCA and /or MTXNB: PSC pts refractory: all had failed UDCA and /or MTXNO trials of NO trials of infiximabinfiximab ((etanerceptetanercept no good in IBD)no good in IBD)

*Epstein MP,Kaplan MM*Epstein MP,Kaplan MMDig Dig DisDis SciSci 20042004


Novel drugsNovel drugs


EndoscopicEndoscopic therapytherapy


Novel drug therapies for PSCNovel drug therapies for PSC

SilymarinSilymarin (antioxidant)(antioxidant) aka milk aka milk thistlethistlePilot study :140 mg Pilot study :140 mg tdstds 1 year [22 PSC pts]1 year [22 PSC pts]No effectNo effect

AnguloAngulo et al,2003et al,2003

PerfenidonePerfenidone ((antifibroticantifibrotic))

Pilot study :2400mg daily 1year [24 Pilot study :2400mg daily 1year [24 PSCptsPSCpts]]No benefit ;adverse effects 23/24No benefit ;adverse effects 23/24

AnguloAngulo et al,Dig et al,Dig DisDis SciSci 2002;47:1572002;47:157

Low Dose UDCA in PSCLow Dose UDCA in PSCSurvival free of treatment failureSurvival free of treatment failure**

*Lindor et al:N Engl J Med 1997

High Dose High Dose UrsoUrso in PSCin PSC

Mitchell et al:Gastroenterology 2001

High Dose High Dose UrsoUrso in PSCin PSCAims of the StudyAims of the Study

RandomisedRandomised placebo controlled pilot study placebo controlled pilot study using high dose UDCA(20mg/kg/day)in using high dose UDCA(20mg/kg/day)in order to;order to;Determine effect of high dose UDCA on Determine effect of high dose UDCA on clinical,biochemical,cholangiographicclinical,biochemical,cholangiographichistological features of PSC over 2yrhistological features of PSC over 2yrAssess side effect profile and effect on Assess side effect profile and effect on activity of colitisactivity of colitis

High Dose High Dose UrsoUrso in PSCin PSCPatients / MethodsPatients / Methods

26 pts with PSC 26 pts with PSC randomisedrandomised to UDCA to UDCA or placeboor placeboFull Full assesmentassesment at entry at entry ((clinical;biochem;liverbiopsy;ERCPclinical;biochem;liverbiopsy;ERCP))Repeat liver biopsy/ERCP at 2 yrsRepeat liver biopsy/ERCP at 2 yrsSerum bile acids at 0;1yr;2yrSerum bile acids at 0;1yr;2yr

--measured by HPLCmeasured by HPLC

High Dose High Dose UrsoUrso in PSCin PSCResults Results -- ClinicalClinical

22 of 26 pts completed the trial:22 of 26 pts completed the trial:3 pts withdrawn:3 pts withdrawn:..One pt in UDCA group One pt in UDCA group –– main ductmain duct

stricture/transplantstricture/transplant.One pt in placebo group .One pt in placebo group –– varicealvaricealhaemorrhagehaemorrhage.One pt died unrelated cause.One pt died unrelated cause

High Dose UDCA in PSCHigh Dose UDCA in PSCResults Results -- ClinicalClinical

No improvement in symptomsNo improvement in symptoms ieiefatigue/malaise/fatigue/malaise/pruritispruritis –– despite despite improvement in biochemistryimprovement in biochemistry

No adverse events/side effectsNo adverse events/side effects-- in in particular no particular no diarrhoeadiarrhoea/worsening of /worsening of activity of inflammatory bowel diseaseactivity of inflammatory bowel disease

ScandanavianScandanavian trial high dose UDCA:trial high dose UDCA:changes in serum biochemistrychanges in serum biochemistry

Alk phos

ALT

bilirubin

Red =placebo

High dose High dose UrsoUrso in PSCin PSCSerum BiochemistrySerum Biochemistry

p=.93p=.934343444441414141AlbuminAlbumin

p=.01p=.01178178476476595595560560GgtGgt

p=0.1p=0.14747878780806161AstAst

p=.03p=.03455455834834875875791791AlkAlk phosphos

p=.08p=.081616161624241919bilirubinbilirubin

P P valuevalue

UDCAUDCA2yr2yr

UDCAUDCA0yr0yr

PlacPlac2yr2yr

PlacPlac0 yr0 yr

MeanMean

High Dose High Dose UrsoUrso in PSCin PSCLiver Histology Liver Histology

Portal inflammation scores over 2 yrsPortal inflammation scores over 2 yrs

Comparison of 3 doses of UDCA on Comparison of 3 doses of UDCA on duodenal bile acid enrichment at 1 yrduodenal bile acid enrichment at 1 yr

Low Dose UDCA in PSC*Low Dose UDCA in PSC*Survival Free of Treatment FailureSurvival Free of Treatment Failure

Stage 1 or 2 diseaseStage 1 or 2 disease

*Lindor et al;N Engl J Med 1997

Low dose UDCA* High dose in PSC**Low dose UDCA* High dose in PSC**Survival Free of Liver TransplantationSurvival Free of Liver Transplantation

*Lindor et al;N Engl J Med 1997 **Olsson et al;J Hepatol 2004

Low dose UDCA in PSC*Low dose UDCA in PSC*Survival Free of Liver Survival Free of Liver

TransplantationTransplantation

*Lindor et al;N Engl J Med 1997

Management of PSCManagement of PSCManagement of chronic Management of chronic cholestasischolestasisManagement of end stage liver diseaseManagement of end stage liver diseaseManagement of complications spec to PSC Management of complications spec to PSC -- --dominant stricturedominant stricture

--biliarybiliary sludgesludge--cholangiocarcinomacholangiocarcinoma

Specific Medical Therapy Specific Medical Therapy ––to prevent diseaseto prevent diseaseprogressionprogression

Liver TransplantationLiver Transplantation

Comparison of 3 doses of UDCA inComparison of 3 doses of UDCA inPBC PBC –– randomized trial*randomized trial*

Effect on Mayo Risk ScoreEffect on Mayo Risk Score

Low dose 5-7mg/kg;stand 13-15;high23-25mg/’kg/daily

*Angulo et el;J Hepatol 1999

Low doseLow dose

Mod /high dose

Primary Primary SclerosingSclerosing CholangitisCholangitis

Chronic Chronic cholestaticcholestaticliver diseaseliver diseaseStricturingStricturing and and dilatation of dilatation of biliarybiliarytreetreeProgresses to Progresses to cirrhosis/liver cirrhosis/liver failurefailurePredisposes to Predisposes to cancer (bile cancer (bile duct;colon;pancduct;colon;panc))

Comparison of 3 doses of UDCA inComparison of 3 doses of UDCA inPBC PBC –– randomized trial*randomized trial*

Effect on Alkaline Effect on Alkaline PhosphatasePhosphatase

Low dose 5-7 mg/kg/daily

Mod 13-15mg/kg;high 23-25mg/kg/daily

*Angulo et al;J Hepatol 1999

Comparison of 3 doses of UDCA in Comparison of 3 doses of UDCA in PBC PBC –– ConclusionsConclusions**

UrsodeoxycholicUrsodeoxycholic Acid in doses of 5Acid in doses of 5--25 mg/kg/day is well tolerated25 mg/kg/day is well tolerated

Dose of 13Dose of 13--15 mg/kg/day is the 15 mg/kg/day is the preferred dose in the treatment of preferred dose in the treatment of PBCPBC

*Angulo et al:JHepatol1999

high dose udca in the treatment of primary sclerosing ... · rationale for high dose udca in...

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