literature review

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Literature ReviewLiterature Review

Peter R. McNally, DO, FACP, FACGPeter R. McNally, DO, FACP, FACGUniversity Colorado at Denver University Colorado at Denver

School of MedicineSchool of MedicineCenter for Human SimulationCenter for Human Simulation

Aurora, Colorado 80045Aurora, Colorado 80045

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Miehlke S, Madisch A, Bethke B, Miehlke S, Madisch A, Bethke B, Morgner A, et al.Morgner A, et al.

Oral Budesonide for Maintenance Treatment of Oral Budesonide for Maintenance Treatment of Collagenous Colitis: A Randomized, Double-Collagenous Colitis: A Randomized, Double-

Blind, Placebo-Controlled Trial. Blind, Placebo-Controlled Trial. Gastroenterology. 2008;135:1510-1516. Gastroenterology. 2008;135:1510-1516.

Dresden, Germany

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IntroductionIntroduction

• Collagenous colitis is an idiopathic disorder Collagenous colitis is an idiopathic disorder characterized by chronic diarrhea, a normal characterized by chronic diarrhea, a normal macroscopic colonoscopy, but characteristic macroscopic colonoscopy, but characteristic mucosal changes on biopsy.mucosal changes on biopsy.

• Incidence “microscopic colitis” 8.6 per 100,000 in Incidence “microscopic colitis” 8.6 per 100,000 in US 1985-2001 with secular US 1985-2001 with secular ↑ 20 per 100,000 @ 2001↑ 20 per 100,000 @ 2001

• ♀ ♀ >> ♂ (ratio 2-4:1)>> ♂ (ratio 2-4:1)• Incidence increases with age, arthritis, autoimmune Incidence increases with age, arthritis, autoimmune

disorders, celiac disease and use of NSAID’sdisorders, celiac disease and use of NSAID’s

Schiller LR. Diagnosis and management of microscopic colitis syndrome. J Clin Gastroenterol. 2004;38(5 Suppl):S27-30. Pardi DS, Loftus EV, Smyrk TC, et al. The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota. Gut. 2007;56:504-8.

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Courtesy, Leslie Sobin, MD. Armed Forces Institute Pathology. Wash, DC.

Collagenous Colitis TreatmentAcute:

•Anti-diarrheal agents are helpful for 1/3 of patients.•Bismuth subsalicylate and 5-aminoslaysilates benefit some.•Budesonide is effective acute treatment.

Chronic: •No medical treatment has been tested for safety or efficacy in maintenance trials

Chande N, McDonald JW, MacDonald JK. Interventions for treating collagenous colitis. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003575

IntroductionIntroduction

Collagenous colitis: thickened sub-epithelial collagen band > 10 μm (normal 0-3 μm). Note: the diameter of an RBC is 6–8 µm.

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AimAim

To evaluate the efficacy of long-term To evaluate the efficacy of long-term maintenance therapy with oral budesonide maintenance therapy with oral budesonide (Entocort CIR capsules, AstraZeneca, (Entocort CIR capsules, AstraZeneca, Lund, Sweden) for maintenance of clinical Lund, Sweden) for maintenance of clinical remission of collagenous colitis, including remission of collagenous colitis, including effects on histology and HRQOL.effects on histology and HRQOL.

Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

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Study Design:Study Design:Study PopulationStudy Population• Enrollment from 38 centers in GermanyEnrollment from 38 centers in Germany• Men and women > 18 yrsMen and women > 18 yrs• Symptomatic and biopsy proven collagenous colitisSymptomatic and biopsy proven collagenous colitis• Inclusion CriteriaInclusion Criteria

– > 3 watery/loose stool per day> 3 watery/loose stool per day• ((>> 4 of 7 previous days) 4 of 7 previous days)

– Diarrhea symptoms Diarrhea symptoms >> 4 weeks duration 4 weeks duration• Exclusion CriteriaExclusion Criteria

– Infectious cause for diarrheaInfectious cause for diarrhea– Inflammatory Bowel Disease, Celiac disease, MalignancyInflammatory Bowel Disease, Celiac disease, Malignancy– Prior Large bowel surgery Prior Large bowel surgery – Current Rx: 5-ASA, NSAIDs, >165mg ASA/dayCurrent Rx: 5-ASA, NSAIDs, >165mg ASA/day– Alcohol/drug abuse or PregnancyAlcohol/drug abuse or Pregnancy


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Study DesignStudy Design

Collagenous colitis + Diarrhea

Budesonide (B) 9mg/d for 6 weeks

Clinical Remission

Placebo (P) 6mg/d for 6 mo

Budesonide (B) 6mg/d for 6 mo

Open-Label Induction Phase Double-Blind Maintenance Phase

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Study DesignStudy Design

• Primary End Point: Relapse Rate @ T 6wk & 6 moPrimary End Point: Relapse Rate @ T 6wk & 6 mo– Definition of Relapse: > 3 stools/day on 4 Definition of Relapse: > 3 stools/day on 4

consecutive daysconsecutive days• Secondary End PointsSecondary End Points

– Time to relapseTime to relapse– Proportion of patients in remissionProportion of patients in remission

• Time 6wk, 2, 4, 6 moTime 6wk, 2, 4, 6 mo

– HRQOL outcomesHRQOL outcomes– ∆ ∆ HistologyHistology


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Study ToolsStudy Tools

• Health Related Quality of Life(HRQOL) SF-36Health Related Quality of Life(HRQOL) SF-36– 4 physical health domains (controls > 50.2)4 physical health domains (controls > 50.2)– 4 mental health domains (controls > 51.2)4 mental health domains (controls > 51.2)– Measurements taken @ T0, 6wk, 2,4,6 moMeasurements taken @ T0, 6wk, 2,4,6 mo

• Short Inflammatory Bowel Disease Questionaire Short Inflammatory Bowel Disease Questionaire (sIBDQ)(sIBDQ)

• Safety Assessments (Global Tolerability)Safety Assessments (Global Tolerability)– ““Very Good,” “Good,” “Moderate,” or “Bad”Very Good,” “Good,” “Moderate,” or “Bad”


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Colonoscopy & Histology EvaluationsColonoscopy & Histology Evaluations

Colonoscopy and biopsyColonoscopy and biopsyTime 0 n = 48Time 0 n = 48Time 6 mo n = 25 (17B, 8P) Time 6 mo n = 25 (17B, 8P)

Only if in remissionOnly if in remission

Histology EvaluationHistology Evaluation Measurement of Measurement of

subepithelial collagen subepithelial collagen band band

Inflammation: absent, mild, Inflammation: absent, mild, moderate, severemoderate, severe

Degeneration surface Degeneration surface epithelium: absent or epithelium: absent or presentpresent

Trichrome stain, blue band of thickened sub-epithelial collagen and mild lympocytic inflammation. Courtesy, Shalini Tayal, MD. Denver Health Med Center. Denver, CO .


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Flow of Patients Through StudyFlow of Patients Through Study

167elgible pts clinical and histologic diagnosis of collagenous colitis

48 pts started 6 wk budesonide induction

46 pts randomized(23 budesonide, 23 placebo)

119 pts excluded or refused

2 pts failed budesonide induction

25 pts completed study(17 budesonide, 8 placebo)

21 pts withdrawnAE (3 budesonide, 1placebo)

Relapase (3 budesonide, 1 placebo)


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Demographics & Clinical CharacteristicsDemographics & Clinical Characteristics

VariableVariable N=48N=48

Mean age, yrs (range)Mean age, yrs (range) 57.5 (34-78)57.5 (34-78)

Women, n (%)Women, n (%) 35 (75)35 (75)

Stool consistency, n (%)Stool consistency, n (%)

waterywatery

looseloose

mixedmixed

26(54)26(54)

11(23)11(23)

7(15)7(15)

Abdominal Pain n (%)Abdominal Pain n (%) 8(17)8(17)

Weight Loss, n (%)Weight Loss, n (%)

Mean wt loss prev 6 mo kg (range)Mean wt loss prev 6 mo kg (range)

24(50%)24(50%)

6.7(2-17)6.7(2-17)

Duration of diarrhea before Duration of diarrhea before diagnosis, months (range)diagnosis, months (range)

27 (1-66)27 (1-66)


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ResultsResults

• HRQOL SF-36 ScoresHRQOL SF-36 Scores• SF-36 SF-36 T0T0 Study Pts Study Pts Control Control • Physical domainPhysical domain 39.539.5 50.250.2 p<0.05p<0.05• Mental DomainMental Domain 44.144.1 51.251.2

p<0.05p<0.05• SF-36 T6wk Rx Study Pts = ControlSF-36 T6wk Rx Study Pts = Control


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Results: Kaplan-Meier curves of patients with relapse of Results: Kaplan-Meier curves of patients with relapse of collagenous colitis during maintenance therapy with collagenous colitis during maintenance therapy with Budesonide or PlaceboBudesonide or Placebo


P = .022

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Results: Histologic FindingsResults: Histologic Findings

VariableVariable Time 0Time 0

48 pts48 pts

T 6mo 23 pts T 6mo 23 pts RemissionRemission

Mucosal Mucosal erythremaerythrema

11/48 (23%)11/48 (23%) None None

(17 B/8 P)(17 B/8 P)

Histologic Histologic ImprovementImprovement

14/15 B14/15 B

5/8 P5/8 P

Baseline Baseline Collagen bandCollagen band

13.3 13.3 μμ m B m B

13.2 13.2 μμ m P m P

∆↓↓ ∆↓↓ p= .005p= .005

∆↓ ∆↓ p=.043p=.043

Baseline Baseline inflammationinflammation

∆↓∆↓8/10 (80%)8/10 (80%)

∆↓ ∆↓ 5/6 (83%)5/6 (83%)


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Results: Proportion of patients in clinical remission on Results: Proportion of patients in clinical remission on maintenance budesonide or placebomaintenance budesonide or placebo

78

39

74

39

74

35

0

10

20

30

40

50

60

70

80

2 mo 4 mo 6 mo

Budesonide

Placebo


P=.007 P=.017 P=.008

%

In R

emis

sion

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Adverse EventsAdverse Events

Induction PhaseInduction Phase Budesonide 9mg/d N=48Budesonide 9mg/d N=48

Pts with AEs, n (%)Pts with AEs, n (%) 5 (10)5 (10)

Freq of AEs (n)Freq of AEs (n) Headach(2), hearing (1), Headach(2), hearing (1), URI(1) dental infection (1)URI(1) dental infection (1)

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Adverse EventsAdverse Events

Maintenance Maintenance PhasePhase

Budesonide 6mg/dBudesonide 6mg/d

N=23N=23

PlaceboPlacebo

N=23N=23Pts with AEs, Pts with AEs,

n (%)n (%)

8 (35)8 (35) 8 (35)8 (35)

AE-related AE-related withdrawal n (%)withdrawal n (%)

3 (13)3 (13) 1 (4)1 (4)

AE-AE-discontinuingdiscontinuing

Dizzy (1), Sleep (1), Dizzy (1), Sleep (1), muscle pain (1), ulcer(1), muscle pain (1), ulcer(1), skin erythrema (1)skin erythrema (1)

Thrombosis (1), URI (1)Thrombosis (1), URI (1)

AE-continuingAE-continuing Headache (2), UTI (1), Headache (2), UTI (1), URI (1), back pain (1), URI (1), back pain (1), abd pain (1), wt gain (1), abd pain (1), wt gain (1), HTN (1)HTN (1)

Abd pain(3), bloating(2), Abd pain(3), bloating(2), URI(1), nausea(1), back URI(1), nausea(1), back pain(1), dental pain (1), pain(1), dental pain (1), skin erythrema(1), MVA skin erythrema(1), MVA (1)(1)

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Conclusions:Conclusions:

1.1. Budesonide 9 mg daily for 6 weeks was effective in Budesonide 9 mg daily for 6 weeks was effective in inducing remission (46/48, 98%) in most patients inducing remission (46/48, 98%) in most patients with collagenous colitis.with collagenous colitis.

2.2. Budesonide 6 mg daily for 6 months was effective Budesonide 6 mg daily for 6 months was effective in maintaining remission. Clinical relapse rates in maintaining remission. Clinical relapse rates were much lower in the budesonide group were much lower in the budesonide group compared to placebo 6/23 (26%) vs. 15/23 (65%), compared to placebo 6/23 (26%) vs. 15/23 (65%), respectfully.respectfully.


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Conclusions:Conclusions:

3.3. No serious side effects occurred during No serious side effects occurred during maintenance treatment with budesonide. maintenance treatment with budesonide. Tolerability of budesonide was considered “very Tolerability of budesonide was considered “very good” or “good” in 61% at 6 month.good” or “good” in 61% at 6 month.

4.4. Long term maintenance (6 mo) therapy with Long term maintenance (6 mo) therapy with budesonide (Entorcort CIR capsules) was well budesonide (Entorcort CIR capsules) was well tolerated and prevented clinical relapse in 75% of tolerated and prevented clinical relapse in 75% of patients with collagenous colitis.patients with collagenous colitis.


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Reviewer CommentsReviewer CommentsDr. Miehlke and colleagues have shown: Dr. Miehlke and colleagues have shown:

1.1. Acute treatment with budesonide 9 mg daily is Acute treatment with budesonide 9 mg daily is effective in Collagenous Colitis, n= 46/48 or 98% effective in Collagenous Colitis, n= 46/48 or 98% response.response.

2.2. Chronic (6 mo) maintenance with budesonide 6 mg Chronic (6 mo) maintenance with budesonide 6 mg daily is superior to placebo by clinical symptoms and daily is superior to placebo by clinical symptoms and QOL, with 80% vs. 20% (B vs. P) remission at 6 QOL, with 80% vs. 20% (B vs. P) remission at 6 months.months.

3.3. Chronic (6 mo) budesonide is safe and “well” Chronic (6 mo) budesonide is safe and “well” tolerated by most patients with Collagenous Colitis.tolerated by most patients with Collagenous Colitis.


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Reviewer CommentsReviewer CommentsMiehlke, et al, do not answer the following questions?Miehlke, et al, do not answer the following questions?

1.1. Why histologic improvement in inflammation is seen Why histologic improvement in inflammation is seen just a commonly in placebo as budesonide treatment just a commonly in placebo as budesonide treatment groups?groups?

2.2. What is the inciting factor of this disorder?What is the inciting factor of this disorder?

3.3. What is the natural history of collagenous colitis?What is the natural history of collagenous colitis?

4.4. Does duration of disease impact acute and durable long Does duration of disease impact acute and durable long term response to budesonide?term response to budesonide?


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