Www.RomeCriteria.org 1729. Rome III 1780 1743 N Sartorius, WHO ICD-10, 1994 classification is a way of seeing the world at a point in time. There is

www.RomeCriteria.orgwww.RomeCriteria.org

17291729

Rome III

17801780

1743

N Sartorius, N Sartorius, WHO ICD-10, 1994WHO ICD-10, 1994N Sartorius, N Sartorius, WHO ICD-10, 1994WHO ICD-10, 1994

classification is a way of seeing the

world at a point in time. There is no doubt

that scientific progress and experience

classification is a way of seeing the

world at a point in time. There is no doubt

that scientific progress and experience

with the use of these guidelines

will ultimately require their

revision and update.

with the use of these guidelines

will ultimately require their

revision and update.

AA

Vision of Rome Foundation

Promote clinical recognition and legitimization of FGIDs

Develop a scientific understanding of the pathophysiological mechanisms to achieve optimum treatment

Promote clinical recognition and legitimization of FGIDs

Develop a scientific understanding of the pathophysiological mechanisms to achieve optimum treatment

17031703

Medline Citations for Irritable Bowel SyndromeMedline Citations for Irritable Bowel Syndrome

1555b1555b

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19631963 19671967 19711971 19751975 19791979 19831983 19871987 19911991 19951995 19991999 20032003

# citations

# citations

Rome PublicationsRome Publications

Gastroenterology International

Journal

Gastroenterology International

Journal

19891989 19901990 1994199419991999 20002000

20062006

1st IBS criteria1st IBS criteria

1992-19955 Rome I

publications

1992-19955 Rome I

publications

2003Rome

Foundation

2003Rome

Foundation

Gastroenterology Supplement

+Rome III BookDegnon Assoc.

Gastroenterology Supplement

+Rome III BookDegnon Assoc.

16831683

1st FGID classification

1st FGID classification

Rome I BookLittle Brown

Rome I BookLittle Brown

Rome IIGut

Supplement

Rome IIGut

Supplement

Rome II BookDegnon Assoc.

IBS Rome Criteria Medline CitationsRome Criteria Medline Citations

1555a1555aYearYear

# citations

# citations

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7070

8080

19921992 19931993 19941994 19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003 20042004

9090

100100

105105

20052005

Rome III

Rationale for Diagnostic Criteria Rationale for Diagnostic Criteria

16861686

Rome III - Rationale for Symptom Criteria

1203

Symptoms not explained by abnormal motility Symptoms defined by multiple factors

MotilityVisceral hypersensitivityInflammation and mucosal immune dysfunctionBrain-gut dysfunction

Epidemiological supportFactor analysis defines symptom-based subgroupsFrequencies similar across populations

Treatment implications Provides diagnostic standards

For clinical trials and clinical careModeled after DSM system in psychiatry

Symptoms not explained by abnormal motility Symptoms defined by multiple factors

MotilityVisceral hypersensitivityInflammation and mucosal immune dysfunctionBrain-gut dysfunction

Epidemiological supportFactor analysis defines symptom-based subgroupsFrequencies similar across populations

Treatment implications Provides diagnostic standards

For clinical trials and clinical careModeled after DSM system in psychiatry

FGID - Conceptual Model

PhysiologyPhysiology• Motility• Sensation• Inflammation• Altered bacterial

flora

• Motility• Sensation• Inflammation• Altered bacterial

flora

FGID• Symptoms

• Behavior

BrainCNS

GutENS

PsychosocialFactors

PsychosocialFactors

• LIfe stress• Psychologic state• Coping• Social support

• LIfe stress• Psychologic state• Coping• Social support

Early LifeEarly Life• Genetics• Environment• Genetics• Environment

OutcomeOutcome• Medications• MD visits• Daily function• Quality of life

• Medications• MD visits• Daily function• Quality of life

1035

Rome III

Rationale for Diagnostic Criteria Administrative Structure

Rationale for Diagnostic Criteria Administrative Structure

16871687

16821682

Rome Foundation, Inc. 1996Rome Foundation, Inc. 1996

Rome CommitteesRome Committees

14 Committees87 Members18 Countries


Intnl. Resource Committee

Intnl. Resource Committee

12 PharmaceuticalsFDA, IFFGD, NIH

12 PharmaceuticalsFDA, IFFGD, NIH

AdministrationAdministration



George DegnonCarlar Blackman

Kathy Haynes

George DegnonCarlar Blackman

Kathy Haynes

Working TeamsWorking Teams



CD CommitteeCD Committee

Board of DirectorsBoard of DirectorsD. Drossman (President) USAD. Drossman (President) USA

E. Corazziari Italy N. Talley USAM. Delvaux France W.G. Thompson CanadaR. Spiller UK W. Whitehead USAJ. Kellow Australia L. Chang USA

E. Corazziari Italy N. Talley USAM. Delvaux France W.G. Thompson CanadaR. Spiller UK W. Whitehead USAJ. Kellow Australia L. Chang USA

Rome III

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects

16891689

Rome III Book – August, 2006

Gastroenterology 13th Issue – April, 2006Reduced Versions of Chapters

New Working Teams Severity,

Brain Imaging,

Role of Physiology in FGID’s

Sponsored Research (Epidemiology, Validation, Spanish Translation of Rome III)

Validated Questionnaire with “Red Flags”

Translations in numerous languages Web site: www.romecriteria.org CD Slide Set (6 Committees) - 2008

Rome III Book – August, 2006

Gastroenterology 13th Issue – April, 2006Reduced Versions of Chapters

New Working Teams Severity,

Brain Imaging,

Role of Physiology in FGID’s

Sponsored Research (Epidemiology, Validation, Spanish Translation of Rome III)

Validated Questionnaire with “Red Flags”

Translations in numerous languages Web site: www.romecriteria.org CD Slide Set (6 Committees) - 2008 1690a1690a

Rome III – Activities/Projects

• UPDATE SLIDE

• Outcomes

• physiology

Rome III Working Teams

Guidelines for Brain Imaging in the FGIDsEmeran Mayer, USA, Chair Qasim Aziz, UK, Co-Chair Douglas Bremner, USA Mark Kern, USA Brad Kuo, USA Richard Lane, USA Bruce Naliboff, USA Irene Tracey, UK

Guidelines for Severity in the FGIDsDouglas A. Drossman, USA, ChairLin Chang, USA, Co-Chair Nicholas Bellamy, Australia Hugo Gallo Torres, FDA, USA Tony Lembo, USA Fermin Mearin, Spain Nancy Norton, IFFGD, USA Peter Whorwell, UK

Guidelines for Brain Imaging in the FGIDsEmeran Mayer, USA, Chair Qasim Aziz, UK, Co-Chair Douglas Bremner, USA Mark Kern, USA Brad Kuo, USA Richard Lane, USA Bruce Naliboff, USA Irene Tracey, UK

Guidelines for Severity in the FGIDsDouglas A. Drossman, USA, ChairLin Chang, USA, Co-Chair Nicholas Bellamy, Australia Hugo Gallo Torres, FDA, USA Tony Lembo, USA Fermin Mearin, Spain Nancy Norton, IFFGD, USA Peter Whorwell, UK

17961796

Basic Science – Jack Wood, USA, ChairLionel Bueno, France John Kellow, Australia

Epidemiology – Fermin Mearin, Spain, ChairGeorge Longstreth, USAPaul Moayyedi, CanadaNick Talley, USA

Diagnosis and Criteria – Arnold Wald, USA, ChairBrooks Cash, USAEnrico Corazziari, ItalyTony Lembo, USAStu Spechler, USAJan Tack, Belgium

Basic Science – Jack Wood, USA, ChairLionel Bueno, France John Kellow, Australia

Epidemiology – Fermin Mearin, Spain, ChairGeorge Longstreth, USAPaul Moayyedi, CanadaNick Talley, USA

Diagnosis and Criteria – Arnold Wald, USA, ChairBrooks Cash, USAEnrico Corazziari, ItalyTony Lembo, USAStu Spechler, USAJan Tack, Belgium

Rome III CD Committees

17971797

Psychosocial, HRQOL, Brain Imaging – Ami Sperber, Israel, ChairElspeth Guthrie, UKRona Levy, USABruce Naliboff, USAKevin Olden, USA

Management, Treatment Trial Design - William Chey, USA, ChairLin Chang, USAMichel Delvaux, FranceE. Jan Irvine, CanadaW. Grant Thompson, Canada

Pediatric – Carlo Di Lorenzo, USA, ChairMarc Benninga, NetherlandsErnesto Guiraldes, ChileJeffrey Hyams, USAPaul Hyman, USA

Psychosocial, HRQOL, Brain Imaging – Ami Sperber, Israel, ChairElspeth Guthrie, UKRona Levy, USABruce Naliboff, USAKevin Olden, USA

Management, Treatment Trial Design - William Chey, USA, ChairLin Chang, USAMichel Delvaux, FranceE. Jan Irvine, CanadaW. Grant Thompson, Canada

Pediatric – Carlo Di Lorenzo, USA, ChairMarc Benninga, NetherlandsErnesto Guiraldes, ChileJeffrey Hyams, USAPaul Hyman, USA

Rome III CD Committees

17981798

Rome III

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects Timeline for Slide Set Committees

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects Timeline for Slide Set Committees

16911691

Rome III – Timeline for CD Committees

Board selects Chair/Co-Chairs* – October 2005 Chairs/Co-Chairs select committees* – December 2005 Chairs/Co-Chairs conference call – December 2005 Content Development – February–May 2006 Orientation/Process Learning at DDW – May 2006 Graphic Development I – May–December 2006 CD Committee Meeting I – January 2007 Graphic Development II – January-April 2007 CD Committee Meeting II – May 2007 Graphic Development III – May-October 2007 Submission to Board and Release – January 2008

Board selects Chair/Co-Chairs* – October 2005 Chairs/Co-Chairs select committees* – December 2005 Chairs/Co-Chairs conference call – December 2005 Content Development – February–May 2006 Orientation/Process Learning at DDW – May 2006 Graphic Development I – May–December 2006 CD Committee Meeting I – January 2007 Graphic Development II – January-April 2007 CD Committee Meeting II – May 2007 Graphic Development III – May-October 2007 Submission to Board and Release – January 2008

* Criteria: 1) Research record, 2) Intl. recognition, 3) Ability to work in group4) Geographical diversity

* Criteria: 1) Research record, 2) Intl. recognition, 3) Ability to work in group4) Geographical diversity 17811781

Rome III Committees

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects Timeline for Slide Set Committees Chapter Structure

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects Timeline for Slide Set Committees Chapter Structure

16931693

Rome III Committees – Chapter Structure

Criteria Related ChaptersIntroductionDiagnostic Entities

Definition Epidemiology Diagnostic Criteria Justification for Change in Criteria Clinical Evaluation Physiological Features Psychological Features Treatment Recommendations for Future Research

Content Area ChaptersRevised chapters maintain same structureNew chapter formats created by chair/co-chair

Criteria Related ChaptersIntroductionDiagnostic Entities

Definition Epidemiology Diagnostic Criteria Justification for Change in Criteria Clinical Evaluation Physiological Features Psychological Features Treatment Recommendations for Future Research

Content Area ChaptersRevised chapters maintain same structureNew chapter formats created by chair/co-chair

16941694

Rome III Committees

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects Timeline for Slide Set Committees Chapter Structure Changes for Rome III

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects Timeline for Slide Set Committees Chapter Structure Changes for Rome III

16951695

Time Frame: “Criteria fulfilled in last 3 months with symptom onset at least 6 months prior to diagnosis”

Classification Changes: Rumination now a Functional Gastroduodenal Disorder FAPS is a separate Category (not Functional Bowel)

Two Pediatric Categories: Neonate/Toddler Child/Adolescent

Functional Dyspepsia De-emphasized for Research Postprandial Distress Syndrome Epigastric Pain Syndrome

More Restrictive Criteria for GB and SO Dysfunction Stool Consistency to Identify IBS Subtypes

Time Frame: “Criteria fulfilled in last 3 months with symptom onset at least 6 months prior to diagnosis”

Classification Changes: Rumination now a Functional Gastroduodenal Disorder FAPS is a separate Category (not Functional Bowel)

Two Pediatric Categories: Neonate/Toddler Child/Adolescent

Functional Dyspepsia De-emphasized for Research Postprandial Distress Syndrome Epigastric Pain Syndrome

More Restrictive Criteria for GB and SO Dysfunction Stool Consistency to Identify IBS Subtypes

17771777

Changes for Rome III – Classification and Criteria

Rome III Criteria* – Irritable Bowel Syndrome

Rome III Criteria* – Irritable Bowel Syndrome

Improvement with

defecation

Improvement with

defecation

Recurrent abdominal pain or discomfort at least 3 days/monthIn the last 3 months associated with 2 or more :

Recurrent abdominal pain or discomfort at least 3 days/monthIn the last 3 months associated with 2 or more :

Onset associated with

a change in frequency of

stool


a change in frequency of

stool


a change in form

(appearance) of stool


a change in form

(appearance) of stool

andand andand

Longstreth GF, Gastroenterology 2006Longstreth GF, Gastroenterology 2006 17821782

* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.


00

2525

5050

7575

100100

%Hard or lumpy

stools

%Hard or lumpy

stools

00 2525 5050 7575 100100

% Loose or watery stools% Loose or watery stools

IBS-UIBS-U

IBS-CIBS-C IBS-MIBS-M

IBS-DIBS-D

Rome III – Subtypes of IBSRome III – Subtypes of IBS

17091709

Functional Dyspepsia (B1a)Rome IIIRome III

Postprandial Distress

Syndrome(B1a)


Syndrome(B1a)

EpigastricPain

Syndrome(B1b)

EpigastricPain

Syndrome(B1b)

17921792

EPSPDS

FD

Diagnostic Criteria* for Functional Dyspepsia

Rome IIIRome III



17931793

Must include one or more of the following:Must include one or more of the following:

And No evidence of structural disease (including

at upper endoscopy) that is likely to explain the symptoms

And No evidence of structural disease (including

at upper endoscopy) that is likely to explain the symptoms

Bothersome postprandial

fullness


fullness

Earlysatiation

Earlysatiation

Epigastricpain

Epigastricpain

Epigastricburning

Epigastricburningoror orororor

Diagnostic Criteria* forPostprandial Distress Syndrome

Rome IIIRome III



17941794

Must include one or both of the following:Must include one or both of the following:

Bothersome postprandial fullness

occurring after ordinary-sized meals

at least several times a week

Bothersome postprandial fullness

occurring after ordinary-sized meals


Early satiation

that prevents finishing a regular meal

and occurs at least several times a week

Early satiation



oror

Diagnostic Criteria* forEpigastric Pain Syndrome

Must include all of the following:Must include all of the following:

Rome IIIRome III



17951795

generalized or localized to other abdominal or chest regions


relieved by defecation or flatulence


fulfilling criteria for gallbladder or sphincter of Oddi disorders


Pain or burning which is: intermittent, localized to the epigastrium of at least moderate severity,

at least once per week, and NOT:

Pain or burning which is: intermittent, localized to the epigastrium of at least moderate severity,


Rome III

Diagnostic Criteria: Must include episodes of pain located in the epigastrium and/or right upper quadrant and ALL of the following:

Episodes lasting 30 minutes or longer Recurrent symptoms occurring at different intervals (not daily) Pain:

Builds up to a steady level Is moderate to severe enough to interrupt daily activities Is not relieved by:

Bowel movements Postural change Antacids

Other structural symptoms that could explain symptoms are excluded

Supportive Criteria: The pain may present with one or more of: Association with nausea or vomiting Radiates to the back and/or right infra subscapular region Awakens from sleep in the middle of the night

Diagnostic Criteria: Must include episodes of pain located in the epigastrium and/or right upper quadrant and ALL of the following:

Episodes lasting 30 minutes or longer Recurrent symptoms occurring at different intervals (not daily) Pain:

Builds up to a steady level Is moderate to severe enough to interrupt daily activities Is not relieved by:

Bowel movements Postural change Antacids

Other structural symptoms that could explain symptoms are excluded

Supportive Criteria: The pain may present with one or more of: Association with nausea or vomiting Radiates to the back and/or right infra subscapular region Awakens from sleep in the middle of the night 18001800

Functional Gall Bladder and Sphincter of Oddi DisordersFunctional Gall Bladder and Sphincter of Oddi Disorders

Rome III

Diagnostic Criteria: Must include ALL of the following:Diagnostic Criteria: Must include ALL of the following:

Functional Gall Bladder DisorderFunctional Gall Bladder Disorder

Criteria for functional gallbladder and sphincter of Oddi disorder


Gallbladder is presentGallbladder is present

Normal liver enzymes, conjugated bilirubin, and amylase/lipase

Normal liver enzymes, conjugated bilirubin, and amylase/lipase

18011801

Diagnostic Criteria: Must include BOTH of the following:Diagnostic Criteria: Must include BOTH of the following:



Normal amylase/lipaseNormal amylase/lipase

Functional Biliary Sphincter of Oddi DisorderFunctional Biliary Sphincter of Oddi Disorder

Rome III

18021802

Supportive Criterion:Elevated serum transaminases, alkaline phosphatase, or conjugated bilirubin temporarily related to at least two pain episodes

Supportive Criterion:Elevated serum transaminases, alkaline phosphatase, or conjugated bilirubin temporarily related to at least two pain episodes

Diagnostic Criteria: Must include BOTH of the following:Diagnostic Criteria: Must include BOTH of the following:Functional Pancreatic Sphincter of Oddi DisorderFunctional Pancreatic Sphincter of Oddi Disorder



Abnormal amylase/lipaseAbnormal amylase/lipase

Rome III Committees

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects Timeline for Committees Chapter Structure Changes for Rome III Issues and Limitations

Rationale for Diagnostic Criteria Administrative Structure Activities/Projects Timeline for Committees Chapter Structure Changes for Rome III Issues and Limitations

16981698

Rome III Committees – Issues and Limitations

Criteria Not Fully Evidence BasedLimited data for most functional GI disorders Original criteria by consensusChanges based on new evidenceNew changes need validation

The Field is Expanding and GrowingInformation not “set in stone”Knowledge can quickly become outdated Classifications will change – e.g., “Organification”

Need for Quality ControlDisclosure of relationships with PharmaceuticalsConfidentiality statementsInternational Resource CommitteeEmbargo on information until final editing stages

Criteria Not Fully Evidence BasedLimited data for most functional GI disorders Original criteria by consensusChanges based on new evidenceNew changes need validation

The Field is Expanding and GrowingInformation not “set in stone”Knowledge can quickly become outdated Classifications will change – e.g., “Organification”

Need for Quality ControlDisclosure of relationships with PharmaceuticalsConfidentiality statementsInternational Resource CommitteeEmbargo on information until final editing stages

17781778

Future Issues for Rome Foundation

Global educational programs

Support for validation studies

Partner with regulatory agencies

Working team initiatives

Mechanism for research support

Diversification in structure

Global educational programs

Support for validation studies

Partner with regulatory agencies

Working team initiatives

Mechanism for research support

Diversification in structure17031703

What’s new?Functional dyspepsia• Dyspepsia as previously defined unhelpful• De-emphasize functional dyspepsia• New syndromes suggested for research: PDS and EPS

Nausea and vomiting• Two new syndromes (CIN and CVS)

“Pain or discomfort centered in the upper abdomen”

Rome Working Teams I and IIRome Working Teams I and II

“Pain or discomfort centered in the upper abdomen”

Rome Working Teams I and IIRome Working Teams I and II

Definition of Dyspepsia Definition of Dyspepsia

Talley et al. Gut 1999;45:II37-42 Talley et al. Gut 1999;45:II37-42

Rome III discards this definitionRome III discards this definition

http://www.livius.org/a/italy/rome/lacus/lacus_curtius3.jpg

Functional Dyspepsia: Rationale for Changes from Rome II

No single symptom present in all patients with functional dyspepsia

Considerable variation in symptom pattern between patients

Despite Rome II recommendations, studies still include heartburn and acid regurgitation as “dyspepsia”1

1Armstrong et al. Can J Gastroenterol 2002; 16; 439-50 Peura et al. Am J Med 2004; 116: 740-8 Moayyedi et al. Gastroenterology 2004; 127: 1329-37

1Armstrong et al. Can J Gastroenterol 2002; 16; 439-50 Peura et al. Am J Med 2004; 116: 740-8 Moayyedi et al. Gastroenterology 2004; 127: 1329-37

Dyspepsia Usually PolysymptomaticDyspepsia Usually Polysymptomatic

99% >2; > 80% >5; < 0.1% 1 symptom99% >2; > 80% >5; < 0.1% 1 symptom

Aliment Pharmacol Ther. 2003;17:1481-91

Functional Dyspepsia (FD): Rome II

12 weeks (within 12 months) of persistent or recurrent dyspepsia 12 weeks (within 12 months) of persistent or recurrent dyspepsia (pain or discomfort centered in upper abdomen)(pain or discomfort centered in upper abdomen)

No evidence of organic disease likely No evidence of organic disease likely to explain symptoms (including EGD)to explain symptoms (including EGD)

Not irritable bowel syndrome (IBS)Not irritable bowel syndrome (IBS)

Subgroups (ulcer-like, dysmotility-like) based on predominant Subgroups (ulcer-like, dysmotility-like) based on predominant symptomsymptom

Talley et al. Gut 1999;45(Suppl. 1):I28–31Talley et al. Gut 1999;45(Suppl. 1):I28–31

Subdividing FD by Predominant Symptom

Karamanolis et al. Gastroenterology 2006; 130:296-303 Karamanolis et al. Gastroenterology 2006; 130:296-303

Pre

vale

nce

(%

of

pat

ien

ts)

n = 720; 489 women; mean age, 41

0

5

10

15

20

25

30

35

40

45

50

Delayed solid

emptying

Delayed liquid

emptying

Hypersensitivity

to gastric

distention

Impaired

accommodation

H. pylori

infection

Predominant discomfort (n=562)

Predominant pain (n=158)

*

*

GE Delay Hypersens

Sens 85% 33%

Spec 25% 44%

Unexplained pain or discomfort centered in upper abdomen (Rome II FD)

De-emphasize FDDe-emphasize FD

Not one disorder

Lack of evidence for the predominant symptom as criterion

Support from factor analysis in tertiary care and in general population

Expert opinion

Functional Dyspepsia

Rome III functional dyspepsiaRome III functional dyspepsia

EPSPDS

FD


fullness


fullness

Earlysatiation

Earlysatiation

Epigastricpain

Epigastricpain

Epigastricburning

Epigastricburningoror orororor

Functional Dyspepsia

Rome IIIRome III


Syndrome


Syndrome

EpigastricPain

Syndrome

EpigastricPain

SyndromeEPSPDS

FD

FD retained for clinical practice PDS and EPS proposed for research based on factor analysis and expert opinion

FD retained for clinical practice PDS and EPS proposed for research based on factor analysis and expert opinion

Diagnostic Criteria* forPostprandial Distress Syndrome (PDS)



Must include one or both of the following:Must include one or both of the following:

Bothersome postprandial fullness occurring after ordinary-sized meals


Bothersome postprandial fullness occurring after ordinary-sized meals


Early satiation



Early satiation



oror

Rome IIIRome III

Factor Analysis Supports EPS and PDS45% of the U.S. population report upper

GI symptoms

Telephone survey of 21,128 adults

Camilleri et al. Clin Gastroenterol Hepatol. 2005;3:543-52 Camilleri et al. Clin Gastroenterol Hepatol. 2005;3:543-52

Study Population n Result Westbrook 2002 Population sample 2300 3 dyspeptic symptom factors

Fischler 2003 Tertiary care 438 4 dyspeptic symptom factors

Jones 2003 Population sample 888 3 dyspeptic symptom factors

Kwan 2003 Tertiary care 1012 3 dyspeptic symptom factors

Whitehead 2003 Tertiary care 1041 4 dyspeptic symptom factors

Camilleri 2005 Population sample 21128 3 dyspeptic symptom factors

Piessevaux submitted Population sample 2025 3 or 4 dyspeptic symptom factors

Tack in preparation Tertiary care 638 3 dyspeptic symptom factors

Factor analyses in populations and referral practice

All found a meal related factorAll found a meal related factor

Diagnostic Criteria* forEpigastric Pain Syndrome (EPS)

Must include all of the following:Must include all of the following:



Pain or burning which is: Intermittent, Localized to the epigastrium of at least moderate severity,


Pain or burning which is: Intermittent, Localized to the epigastrium of at least moderate severity,


Rome IIIRome III







Distinct Dyspepsia Subgroups: New Data

EPS 135 (39%)

CIN n=37 (11%)

PDS (early satiety)

114 (32%)

25 (7%)

16 (5%)

9 (3%)

7 (2%)

Observed (n) Expected (n)

p-value

EPS vs. CIN

16 35 0.006

EPS vs. PDS

32 83 <0.001

PDS vs. CIN

23 33 0.078

Comparison of overlap of subgroups between observed and expected

* Assuming the subgroups were independent* Assuming the subgroups were independent Choung et al. DDW 2006 Choung et al. DDW 2006

Olmsted County population dataOlmsted County population data

Rome III

Overlap with GERD

Heartburn does not exclude a diagnosis of FD (PDS or EPS)if dyspepsia persists despite a trial of adequate acid suppression

Evidence: expert opinion

Overlap with GERD

Heartburn does not exclude a diagnosis of FD (PDS or EPS)if dyspepsia persists despite a trial of adequate acid suppression

Evidence: expert opinion

Overlap with IBS

Coexisting IBS no major impact on symptom pattern or putative pathophysiological mechanisms

Corsetti et al. Am J Gastroenterol. 2004;99:1152-9 Corsetti et al. Am J Gastroenterol. 2004;99:1152-9

0

5

10

15

20

25

30

35

40

45

50

Delayed emptying H. pylori positive Hypersensitivity Impairedaccommodation

Prev

alen

ce (%

of p

atie

nts)

Dyspepsia

Dyspepsia + IBS*

* P<0.05

Rome IIIRome III

Nausea and Vomiting

Cyclic vomiting syndrome (CVS) now a recognized syndrome in adults

AJG 2001; 96: 684-8

Cyclic vomiting syndrome (CVS)At least 3 months, with onset at least 6 month previously, of:

Stereotypical episodes of vomiting regarding onset (acute) and duration (less than one week)

3 or more discrete episodes in the prior year Absence of nausea and vomiting between episodes

Supportive criteria: History of migraine headaches or a family history of migraine headaches

Rome IIIRome III

Chronic idiopathic nausea (CIN)

Separate from FD (factor analyses)

Bothersome nausea, occurring at least several times per week in the last 3 months

Not usually associated with vomiting

Absence of abnormalities at upper endoscopy or metabolic disease that explains the nausea

Rome IIIRome III

Rome III: What’s new?Functional dyspepsia• Dyspepsia as previously defined unhelpful: focus on early

satiation and/or postprandial fullness and/or epigastric pain• De-emphasize functional dyspepsia• New syndromes suggested for research: PDS and EPS

Nausea and vomiting• Two new syndromes (CIN and CVS)

Irritable Bowel Syndrome

Functional Bloating

Functional Constipation

Functional Diarrhea

Unspecified Functional Bowel Disease

Functional Bowel DisordersFunctional Bowel Disorders

• Introduction of a frequency threshold of 3 days/ month over 3 months for symptoms

• Reduction of the duration of symptoms before one can make firm diagnosis from 12 to 6 months

• Refining of subtypes

• Introduction of a frequency threshold of 3 days/ month over 3 months for symptoms

• Reduction of the duration of symptoms before one can make firm diagnosis from 12 to 6 months

• Refining of subtypes

Main Changes in IBS CriteriaMain Changes in IBS Criteria

Rome II Diagnostic criteria for IBS

Rome II Diagnostic criteria for IBS

At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two of three features:

Relieved with defecation; and/or

Onset associated with a change in frequency of stool; and/or

Onset associated with a change in form (appearance) of stool.

Thompson et al Gut 1999;45 Suppl 2:II43-II47 Thompson et al Gut 1999;45 Suppl 2:II43-II47

Rome III Diagnostic Criteria for IBS*

Rome III Diagnostic Criteria for IBS*

Recurrent abdominal pain or discomfort

3 days per month in the last three months

associated with two or more of the following Improvement with defecation; and/or Onset associated with a change in frequency of stool; and/or Onset associated with a change in form (appearance) of stool

* Criteria fulfilled for the last 3 months with symptom onset 6 months prior to diagnosis

Subclassifying IBSWhy bother?

Important for choosing therapies which alter bowel habit Subtypes likely to have different pathophysiology

Transit Stool consistency Rectal sensitivity?

Diarrhea-predominant 1 or more of 2, 4, or 6 and none of 1, 3, or 5 (or 2 of 2, 4 or 6 and 1 of 1 or 5 but not 3)

Diarrhea-predominant 1 or more of 2, 4, or 6 and none of 1, 3, or 5 (or 2 of 2, 4 or 6 and 1 of 1 or 5 but not 3)

Previous Features Used to Subclassify IBS Patients

Constipation-predominant 1 or more of 1, 3, or 5 and none of 2, 4, or 6 (or 2 of 1, 3 or 5 and 1 of 2, 4 or 6)

Constipation-predominant 1 or more of 1, 3, or 5 and none of 2, 4, or 6 (or 2 of 1, 3 or 5 and 1 of 2, 4 or 6)

1. Fewer than three bowel movements a week

2. More than three bowel movements a day

3. Hard or lumpy stools

4. Loose (mushy) or watery stools

5. Straining during a bowel movement

6. Urgency (having to rush to have a bowel movement)

1. Fewer than three bowel movements a week

2. More than three bowel movements a day

3. Hard or lumpy stools

4. Loose (mushy) or watery stools

5. Straining during a bowel movement

6. Urgency (having to rush to have a bowel movement)

Problems With Old SystemProblems With Old System

Complex to apply and caused confusion in both patients and clinicians!

Multidimensional but different dimensions don’t correlate well

Failed to deal adequately with patients with both hard and loose stools

IBS Patients with Features of Both Constipation and Diarrhea are Common

Reference N IBS-D IBS-C IBS-M

Mearin 2003 209 10 24 37

Tillisch 2005 1102 32 17 32

Drossman 2005

317 36 34 31

• Assessed from stool form

Rome III subtyping is based on Stool Consistency alone

Rome III subtyping is based on Stool Consistency alone

Defining Stool ConsistencyBristol Stool Form Scale

Hard Hard

NormalNormal

LooseLoose

Why Stool Consistency as Main Determinant of Subtype?

Correlates best with colonic transit

Colonic Transit & Stool FormColonic Transit & Stool Form

Colonic transittime (hours)

Colonic transittime (hours)

Bristol stool form scoreBristol stool form score

1 2 3 4 5 6 7

80

40

0

O'Donnell et al Br Med J 1990;300:439-40 O'Donnell et al Br Med J 1990;300:439-40

Why Stool Consistency as Main Determinant of Subtype?

Correlates best with colonic transit

Correlates best with what patients and community samples think of as “diarrhoea”

Principle determinant of incontinence

Other features occur in IBS with both loose & hard stools Stool frequency <3/weeks or >3/day

Urgency, Sense of incomplete evacuation

Principle determinant of incontinence

Other features occur in IBS with both loose & hard stools Stool frequency <3/weeks or >3/day

Urgency, Sense of incomplete evacuation

Association of bowel symptoms with stool consistency

Tillisch et al Am J Gastroenterol. 2005; 100:896-904Tillisch et al Am J Gastroenterol. 2005; 100:896-904

Proposed New Subtyping Based on Stool Consistency Alone

IBS with constipation - IBS-C IBS with diarrhoea - IBS-D IBS mixed type - IBS-M (IBS unsubtyped - IBS-U)

IBS-mixed : patients with both hard & loose stools over periods of hours or days

IBS-mixed : patients with both hard & loose stools over periods of hours or days

Alternating IBS

Patients who change subtype over periods of weeks and months

00 2525 5050 7575 10010000

2525

5050

7575

100100

IBS-MIBS-M

IBS-DIBS-D

IBS-CIBS-C

IBS-UIBS-U

%Loose or Watery Stools%Loose or Watery Stools

% Hard or Lumpy Stools

% Hard or Lumpy Stools

Rome III Subtypes of IBS

46%46%

3.9%3.9% 32%32%

17%17%

Tillisch et al Am J Gastroenterol. 2005;100:896-904 Tillisch et al Am J Gastroenterol. 2005;100:896-904

Quantifying Stool FormDate Pain Pain

Severity

Urgency

Y/N

Bloating

Y/N

1 2 3 4 5 6 7 8

Pain: grade 0-10 0= absent 5=moderate 10 very severeStool form1= separate hard lumps, like nuts 6 = fluffy pieces with ragged edges2= sausage shaped but lumpy 7 = watery, no solid pieces 3= like a sausage or snake, but with cracks

on its surface4= like a sausage or snake, smooth and soft5= soft blobs with clear cut edges

Pain: grade 0-10 0= absent 5=moderate 10 very severeStool form1= separate hard lumps, like nuts 6 = fluffy pieces with ragged edges2= sausage shaped but lumpy 7 = watery, no solid pieces 3= like a sausage or snake, but with cracks

on its surface4= like a sausage or snake, smooth and soft5= soft blobs with clear cut edges

Changes to IBS classificationRome III Summary

No change to basic criteria

Length of time needed to define chronicity reduced to 6 months

Threshold 3 days / month introduced for frequency of pain / discomfort

Subtyping simplified (stool consistency)

Stability of subtypes and link to other features like visceral sensitivity and response to treatment remain to be determined

Stability of subtypes and link to other features like visceral sensitivity and response to treatment remain to be determined

FUNCTIONAL GALLBLADDER AND

SPHINCTER OF ODDI DISORDERS

NOT EXPLAINED BY STRUCTURAL ABNORMALITIES

Epigastric or right upper quadrant

pain

Motility abnormalities of the Gallbladder, the Biliary, and Pancreatic Sphincter of

Oddi

DIAGNOSTIC CRITERIA FOR FUNCTIONAL GALLBLADDER AND SPHINCTER OF ODDI DISORDERS

time

PAINSteady

30 min

severe

moderate

mild

Pain located in the epigastrium

and/or right upper quadrant

Epigastric or right upper quadtrant pain

Recurrent symptoms occurring

at different intervals (not daily)

Episodes lasting 30 minutes or longer The pain builds up to a steady level

The pain is moderate to severe enough to interrupt the patient’s daily activities or lead to an emergency department visit

Not Relieved by 1. Bowel Movements 2. Postural Change 3. Antacids

Supportive Criteria The pain may present with one or

more of the following:

a. Associated with nausea and vomiting

b. Radiates to the back and/or right infra subscapular region

c. Awakens from sleep in the middle of the night

EVIDENCE : C

ONSENSUS

Structural

alterations

ROME III ALGORITHM FOR FUNCTIONAL GB DISORDERS

Diagnostic criteria for functional GB and SO disorders LFTs/pancreatic, enzyme, US

Esophagogastroduodenoscopy

Normal findingsAppropriate

investigation andtreatment

GB CCK cholescintigraphy

GBEF < 40% GBEF > 40%

Cholecystectomy Reassess

EVIDENCE C

Structural alterations explaining

the symptoms

ROME III ALGORITHM FOR FUNCTIONAL BILIARY SO DISORDERS

CholecystectomizedDiagnostic criteria for functional GB and SO disorders

LFTs/pancreatic enzymes, USEsophagogastroduodenoscopy

EUS, MRCP

Appropriate Investigation

and treatment

BiliaryType I

BiliaryType II

BiliaryType III

Pain andOne or two of type

I criteria

Pain andNone of the type

I criteria Milwaukee Classification

Pain and LFTs in 2 occasions andAt ERCP Dilated CBD >12mm and Delayed contrast

drainage

Milwaukee Classification Revised Pain and LFTs in 2 occasions andAT US Dilated CBD >8mm

EVIDENCE :

CONSENSUS


the symptoms




EUS, MRCP


and treatment

BiliaryType II

BiliaryType I

ES

BiliaryType III

ERCPwith SOM Normal

SOMAbnormal

SOM

ES Reassesses

EVIDENCE:

B


the symptoms




EUS, MRCP


and treatment

BiliaryType II

BiliaryType I

BiliaryType III

Pharmacological trials

ResponseNoresponse

ERCPwith SOM

NormalSOM

AbnormalSOM

ES Reassesses

EVIDENCE:

C



and treatment


the symptoms

Cholecystectomized ,Criteria for functional GB and SO Disorders

Clinical history, LFTs/pancreatic enzymes, USEsophagogastroduodenoscopy

EUS, MRCP

BiliaryType I

ES

AbnormalSOM

BILI[CHOLEDOCHO]SCINTIGRAPHY

Response

Pharmacological trials

BiliaryType III

BiliaryType II

Reassesses

NormalSOM

ES

ERCPwith SOM

Noresponse

EVIDENCE B

ROME III ALGORITHM FOR FUNCTIONAL PANCREATIC SO DISORDERS

Criteria for functional GB and SO disorders, Elevated amylase and lipase

No obvious association with alchool, gallstones, drugs, Ca2+ US, Esophagogastroduodenoscopy, CT, EUS,MRCP

Diagnostic ERCP

EVIDENCE B

No Structural

abnormalities

Abnormal

Structural

abnormalities

Sphincterotomy

Reassess

SO manometry

Normal

Functional Esophageal

FunctionalAbdominal Pain

FunctionalBilliary

FunctionalAnorectal

FunctionalGastroduodenal

IBS & Functional Bowel

Rome IIIDiagnostic

Questionnaire

Rome IIIDiagnostic

Questionnaire

Rationale for Changing to Ordinal Scales to Measure Symptom Frequency

• Rome II questionnaire applied the same frequency threshold to all symptoms

• Some symptoms are not clinically meaningful unless they occur daily while others are significant if they occur at all

• Rome II questions were difficult to understand because they incorporated multiple frequency thresholds

• Scales for judging relative severity would be useful

Goals of the Questionnaire Development and Validation Process

• Develop a questionnaire that incorporates the Rome III criteria as an aid to diagnosis

• Insure that questions are understandable

• Validate the questionnaire & the criteria by comparing to diagnoses made by clinicians

Study ICompare 4 Alternative Response Scales

• Subjects 120 healthy controls & 84 FGID

• Design: 4 versions of the questionnaire were completed in counterbalanced order

– Binary: No or rarely vs. often

– Specific Frequency: Monthly, weekly, daily

– Relative Frequency: Occasionally, often, always

– Bothersome: A little bit, moderately, quite a bit

Subjects are Inconsistent in How They Use the Binary Response Scale

0%

20%

40%

60%

80%

100%

never monthly >weekly

"never or rarely" "often"

Frequency of Abdominal Pain or Discomfort

Principal Findings of Study I • For intermediate symptom frequencies, ordinal scales are

more reliable

• Specific Frequency Scales give the best balance between sensitivity & specificity but Relative Frequency Scales perform almost as well

• Bothersome Scale performs similar to Relative Frequency Scale but is not appropriate to some symptoms

Two Scales Selected for Rome III

Specific Frequency Scale

Never

Less than 1 day a month

One day a month

One day a week

More than 1 day a week

Every day

Relative Frequency Scale

Never or rarely

Sometimes

Often

Most of the time

Always

Questionnaire Development

• Rome board suggested initial questions

• Working teams provided additional items

• Questionnaire Committee met for 2 days to insure that the questions matched the diagnostic criteria

• Data from the validation study were referred back to the Rome board & working teams for revisions to criteria & thresholds

Sample QuestionSample QuestionIn the last 3 months, how

often did you have discomfort or pain anywhere in your abdomen?

Never

Less than 1 day a month

One day a month

Two to three days a month

One day a week

More than one day a week

Every day

Study II: Validation Study• Subjects

– 554 healthy controls (75% participation)

– 399 FGIDs (66% participation)

• 328 IBS, 27 constipation, 10 FD, 32 miscellaneous

• There were 4 study sites: UNC, Mayo Clinic, University of Michigan, & University of Toronto

• Test – retest agreement on diagnosis assessed in 53 controls & 51 patients over 2 weeks

Understandability• 18 of 77 questions were rated difficult to understand by

1% or more of subjects

• 4 questions were rated difficult by 2%

• All but one of these 18 questions were revised

• No revision for, “In the last 3 months, how often did you feel uncomfortably full after a regular sized meal.” (Rated difficult by 1.2%)

Selecting Frequency Thresholds so ThatLess Than 10% of Controls are “Abnormal”

0%

5%

10%

15%

20%

25%

30%

35%

40%

Healthy


0%

5%

10%

15%

20%

25%

30%

35%

40%Healthy

IBS

0%

5%

10%

15%

20%

25%

30%

35%

40%Healthy

IBS




Effects of Different Thresholdson Sensitivity & Specificity

>1 day a week 48.5% 98.2%

1 day a week 55.5% 94.3%

2-3 days per month 70.7% 87.8%

539 healthy controls & 326 IBS patients 539 healthy controls & 326 IBS patients

Abdominal pain Sensitivity SpecificityFrequency threshold of IBS Dx of IBS DxAbdominal pain Sensitivity SpecificityFrequency threshold of IBS Dx of IBS Dx

Specificity: Percent of Healthy Controls Who Would be

MisclassifiedMisdiagnosed Controls

Estimated

Specificity

IBS 12.2% 87.8%

Constipation 3.5% 96.5%

Diarrhea 0.1% 99.1%

Functional dyspepsia 5.9% 94.1%

Postprandial distress 0.7% 99.3%

Epigastric pain 0 100%

Chronic idiopathic nausea 0.9% 99.1%

Reliability: Test-Retest Agreement Over a 2-Week Interval

Specificity Test-Retest Agreement

IBS 87.8% 81.7%

Constipation 96.5% 93.3%

Diarrhea 99.1% 96.2%

Functional dyspepsia 94.1% 84.6%

Postprandial distress 99.3% 85.6%

Epigastric pain 100% 98.1%

Chronic idiopathic nausea 99.1% 96.2%

Conclusions• A major innovation of Rome III is ordinal scale with

individual frequency thresholds

• Rome III diagnostic questionnaire is reliable:– Questions reflect the criteria & are understandable– Test-retest reliability is excellent– Specificity of diagnostic criteria is excellent

Application of Diagnostic CriteriaApplication of Diagnostic Criteria

Consensus derived criteriaConsensus derived criteria

QuestionnaireQuestionnaire

ValidationValidation

Published trial and survey dataPublished trial and survey data

Can it be applied to my patient?Can it be applied to my patient?

Consensus derived criteriaConsensus derived criteria

QuestionnaireQuestionnaire

ValidationValidation

Published trial and survey dataPublished trial and survey data

Can it be applied to my patient?Can it be applied to my patient?

To Interpret Data Obtained UsingTo Interpret Data Obtained UsingRome III Questionnaire, I Must Consider:Rome III Questionnaire, I Must Consider:

1.1. Was the questionnaire altered?Was the questionnaire altered?

2.2. What was the purpose of the study?What was the purpose of the study?

3.3. How was the study population selected?How was the study population selected?

4.4. Can the data (evidence) from Can the data (evidence) from thatthat trial or trial or survey be survey be applied to my patient?applied to my patient?

1.1. Was the questionnaire altered?Was the questionnaire altered?

2.2. What was the purpose of the study?What was the purpose of the study?

3.3. How was the study population selected?How was the study population selected?

4.4. Can the data (evidence) from Can the data (evidence) from thatthat trial or trial or survey be survey be applied to my patient?applied to my patient?

1. 1. Was the Questionnaire Altered?Was the Questionnaire Altered?

Questions – how were they asked? Questions – how were they asked?

Also, algorithms, inclusions and exclusionsAlso, algorithms, inclusions and exclusions

Determined by consensus, existing dataDetermined by consensus, existing data To suit their study, investigators may adjust:To suit their study, investigators may adjust:

Time requisite (acute vs. chronic)Time requisite (acute vs. chronic) Cut-off levels for inclusionCut-off levels for inclusion ExclusionsExclusions

Frequency Scale “Cut-offs”Frequency Scale “Cut-offs”

How often in last 3 months did you have pain?How often in last 3 months did you have pain?

a. Nevera. Neverb. Once a month or lessb. Once a month or lessc. Two to three times/monthc. Two to three times/month

d. Once a weekd. Once a weeke. Several times a weeke. Several times a weekf. Every dayf. Every day

Cut-offs determine who is included!Cut-offs determine who is included!

1. (cont) Was the questionnaire altered?1. (cont) Was the questionnaire altered?

Rome IIIRome III



a. Nevera. Neverb. Once a month or lessb. Once a month or less

c. Two to three times/monthc. Two to three times/monthd. Once a weekd. Once a weeke. Several times a weeke. Several times a weekf. Every dayf. Every day



SurveySurvey



a. Nevera. Neverb. Once a month or lessb. Once a month or lessc. Two to three times/monthc. Two to three times/monthd. Once a weekd. Once a week

e. Several times a weeke. Several times a weekf. Every dayf. Every day



Clinical trialClinical trial

ExclusionsExclusionsQ8. ..did you often have heartburn..?Q8. ..did you often have heartburn..?Q9. ..did you .. have difficulty swallowing..?Q9. ..did you .. have difficulty swallowing..?

Rome II coding:Rome II coding:Functional heartburnFunctional heartburn; ; Q8=yes, and no to dysphagiaQ8=yes, and no to dysphagiaFunctional dysphagiaFunctional dysphagia; ; Q9=yes, and no to heartburnQ9=yes, and no to heartburn

1.1. If “yes” to both, If “yes” to both, neitherneither disorder exists because, disorder exists because, according to the coding, one excludes the other.according to the coding, one excludes the other.

2.2. Data not applicable to excluded patients.Data not applicable to excluded patients.


1.1. To aid diagnosisTo aid diagnosis

2.2. To select subjects for clinical researchTo select subjects for clinical research

3.3. To survey populationsTo survey populations

2. 2. What was the Purpose of the Study?What was the Purpose of the Study?

2. 2. What was the Purpose of the Study?What was the Purpose of the Study?

1.1. To aid diagnosisTo aid diagnosis Severity/frequency relevantSeverity/frequency relevant InclusiveInclusive Symptoms nowSymptoms now

2.2. To select subjects for clinical researchTo select subjects for clinical research Severity/frequency more relevantSeverity/frequency more relevant ExclusiveExclusive Symptoms nowSymptoms now

3.3. To survey populationsTo survey populations Severity/frequency less importantSeverity/frequency less important InclusiveInclusive Symptoms ever, or during defined periodSymptoms ever, or during defined period

3. 3. How was the Study Population Selected?How was the Study Population Selected?

Were Rome III criteria used?Were Rome III criteria used?

How were subjects recruited (adverts, How were subjects recruited (adverts, tertiary care, CROs)? tertiary care, CROs)?

Were there investigator adjustments (e.g. Were there investigator adjustments (e.g. time requirement, cut-offs, exclusions)?time requirement, cut-offs, exclusions)?

4. 4. Can Data from a Trial or Survey be Applied to Can Data from a Trial or Survey be Applied to my Patient?my Patient?

Does my patient fulfill the same criteria?Does my patient fulfill the same criteria?

Is he or she similar to the study population?Is he or she similar to the study population?

Do the time requisites, scales, and exclusions used in Do the time requisites, scales, and exclusions used in the study exclude my patient?the study exclude my patient?

In a trial where placebo effect>therapeutic gain, will my In a trial where placebo effect>therapeutic gain, will my patient realize a similar placebo effect?patient realize a similar placebo effect?

Summary: When Applying Results of a Study where Summary: When Applying Results of a Study where the Rome Criteria were Used, Ask:the Rome Criteria were Used, Ask:

1.1. How were criteria translated into questions: How were criteria translated into questions: – Time requirement, cut-offs, and exclusions?Time requirement, cut-offs, and exclusions?

2.2. Were there unique adjustments for:Were there unique adjustments for:– Clinical Trial?Clinical Trial? - - severe cases nowsevere cases now

– Epidemiological survey?Epidemiological survey? - - include all casesinclude all cases

– Clinical Practice?Clinical Practice? -- precision precision

3.3. Does my local population or my patient resemble the Does my local population or my patient resemble the study’s population?study’s population?

4.4. Will my management help my patient achieve as great a Will my management help my patient achieve as great a placebo effect as those in the study?placebo effect as those in the study?

Use of the Rome CriteriaUse of the Rome Criteria

ClinicalTrials

ClinicalResearch

ClinicalPractice

Existing Trials

Expert Panels

Regulatory Authorities

Existing TrialsImproved methodology

Meta-analysesNegative trials?

Regulatory AuthoritiesEMEA PTC 2003

FDA Advices

Expert PanelsDefinition of a Responder, Vienna 1998

European Panel, APT 2003Rome I, Rome II

Challenges for FGIDs clinical trials Natural course of the condition

–Unstable symptom pattern–Fluctuating intensity

Multicomponent pathophysiology–Multiple therapeutic targets–Multiple endpoints

Bias of outcome measures–High placebo response–Difficulty to maintain double masking–Contamination by parallel interventions–Lack of placebo control for some interventions

• Psychotherapy, hypnotherapy, sphincterotomy

Avoiding harm–FGID non-life-threatening

Natural course of the condition–Unstable symptom pattern–Fluctuating intensity

Multicomponent pathophysiology–Multiple therapeutic targets–Multiple endpoints

Bias of outcome measures–High placebo response–Difficulty to maintain double masking–Contamination by parallel interventions–Lack of placebo control for some interventions

• Psychotherapy, hypnotherapy, sphincterotomy

Avoiding harm–FGID non-life-threatening

Definition of the Studied PopulationDefinition of the Studied Population

Compromise between the largest target in the population and a strictly homogenous group Compromise between the largest target in the population and a strictly homogenous group

Clearly define the FGID to be treated Define subgroups

Transit abnormalities Explicit inclusion/exclusion criteria

Gender Symptoms intensity Comorbidities Treatment exclusions

Clearly define the FGID to be treated Define subgroups

Transit abnormalities Explicit inclusion/exclusion criteria

Gender Symptoms intensity Comorbidities Treatment exclusions

The Standard Trial Design

• Superiority trial– The most robust design:

• parallel groups, randomized allocation, double blind

– Single intervention– Placebo-controlled

• Superiority trial– The most robust design:

• parallel groups, randomized allocation, double blind

– Single intervention– Placebo-controlled

Run-in Treatment Phase Run-out

Placebo

Intervention

Per

cen

tag

e o

f re

spo

nd

ers

Weeks

0

20

40

60

0 2 4 6 8 10 12 14 16

* * * **

****

*

Treatment Follow-up

**

**

*

**p < 0.001*p < 0.05

Alosetron (n = 237) Placebo (n = 221)

80

70

50

30

10

Camilleri et al. Lancet 2000; 355: 1035-1040.

0

10

20

30

40

50

60

70

-2 1 3 5 7 9 11 13 15

TegaserodPlacebo

Follow-upRun-in

Novick et al. APT 2002; 16:1877-1888.

From Rome II to Rome IIIFrom Rome II to Rome III

• Unsolved issues with standard design Duration of the treatment intervention

4 weeks versus 12 weeks Longer treatments: 6 months

Outcome measures

Alternative trial designs On-demand or « Pro Re Nata (PRN) » treatments Treatment – Re-treatment design

• Unsolved issues with standard design Duration of the treatment intervention

4 weeks versus 12 weeks Longer treatments: 6 months

Outcome measures

Alternative trial designs On-demand or « Pro Re Nata (PRN) » treatments Treatment – Re-treatment design

PlaceboPlacebo

Active DrugActive Drug

Treatment – Re-treatment

RR

NRNR


EMEA PTC 2003

PlaceboPlacebo NRNR

RR

No symptomNo symptom

Symptoms +Active DrugActive Drug

PlaceboPlacebo


NRNR

Carry-overUnblinding of the intervention

Enrichment in respondersNatural cycle of symptoms

Ethical considerations

Tack et al. Gut 2005; 54: 1707-1713

IBS-C symptoms

Abdominal discomfort/pain

=9.3% =16.6% =9.1% =15.91%

Re

sp

on

de

rs (

%)

Tegaserod

Placebo

1stT

RT

1stT

RT

0

10

20

30

40

50

RR

NRNR No sympNo symp

symp(37% R)symp(37% R)Active drugActive drug

Active drugActive drug

PlaceboPlacebo

PlaceboPlaceboNRNR

RR4 weeks4 weeks

1

4 weeks4 weeks

Definition of Outcome Measures

Primary outcome Global assessment Adequate relief Definition of a responder

Symptom questionnaire

Pain assessment

Primary outcome Global assessment Adequate relief Definition of a responder

Symptom questionnaire

Pain assessment

Secondary outcomes Mechanism of intervention Symptoms influenced by a

specific pharmacodynamic effect

Quality of life Health economics

Tolerance and safety

Secondary outcomes Mechanism of intervention Symptoms influenced by a

specific pharmacodynamic effect

Quality of life Health economics

Tolerance and safety

Definition of a Responder

SomewhatSomewhat

CompletelyCompletely

MarkedlyMarkedly

Symptom ReliefSymptom Relief

25 %25 % 75 %75 %50 %50 % 100 %100 % TimeTime

Conclusion

Rome criteria have driven significant methodological advances over the last two decades for the design of FGIDs clinical trials.

Alternative designs need to be further explored but should not replace standard comparative trials.

Outcome measures and definition of a responder are critical issues influencing the clinical relevance of the results.

Rome criteria have driven significant methodological advances over the last two decades for the design of FGIDs clinical trials.

Alternative designs need to be further explored but should not replace standard comparative trials.

Outcome measures and definition of a responder are critical issues influencing the clinical relevance of the results.

Documents

Www.RomeCriteria.org 1729. Rome III 1780 1743 N Sartorius, WHO ICD-10, 1994 classification is a way of seeing the world at a point in time. There is