Literature Review

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Literature Review Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

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Literature Review. Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045. Introduction. Crohn’s disease is a lifelong, disabling disorder with 2/3 rd of patients requiring surgery in their lifetime. - PowerPoint PPT Presentation

Transcript of Literature Review

Page 1: Literature Review

Literature ReviewLiterature Review

Peter R. McNally, DO, FACP, FACGUniversity Colorado Denver

School of MedicineCenter for Human Simulation

Aurora, Colorado 80045

Page 2: Literature Review

Introduction Introduction

Crohn’s disease is a lifelong, disabling disorder with 2/3rd of patients requiring surgery in their lifetime.

In 1998, introduction of anti-TNF-α agents to treat Crohn’s disease was a tremendous medical advance. Anti-TNF-α treatment promotes complete mucosal healing in ~50% of pts & remission rates of 40-50% are expected in pts with mod-severe disease.

Michelassi F, et al. Ann Surg. 1991;214:230-238. Reguelo M, et al. Gastroenterol. 2009;136:441-450. D’Haenes G, et al. Gastroenterol. 1999;116:1029-34.

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Introduction Introduction

Concerns for ↑ rates of opportunistic infections, lymphoma and splenic T-cell lymphoma have tempered enthusiastic use of anti-TNF-α agents, especially in combination with azathioprine (AZA) and 6-mercaptopurine (6MP).

The study by Colombel and the Sonic Study group reviewed in this edition of www.VHJOE.org scientifically confirms, IFX-AZA combination therapy is more effective and as safe as mono therapy with either IFX or AZA.

Kandiel A, et al. Gut. 2005;54:1121-1125. Lichtenstein GR, et al. Gastroenterol Hepatol. 2006;4:2275-2285.

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Jean Frederic Colombel, M.D., William J. Sandborn, M.D., Walter Reinisch, M.D., Gerassimos J. Mantzaris, M.D., Ph.D., Asher

Kornbluth, M.D., Daniel Rachmilewitz, M.D., Simon Lichtiger, M.D., Geert D’Haens, M.D., Ph.D., Robert H. Diamond, M.D., Delma L. Broussard, M.D., Kezhen L. Tang, Ph.D., C. Janneke van der

Woude, M.D., Ph.D., and Paul Rutgeerts, M.D., Ph.D., for the SONIC Study Group*

Jean Frederic Colombel, M.D., William J. Sandborn, M.D., Walter Reinisch, M.D., Gerassimos J. Mantzaris, M.D., Ph.D., Asher

Kornbluth, M.D., Daniel Rachmilewitz, M.D., Simon Lichtiger, M.D., Geert D’Haens, M.D., Ph.D., Robert H. Diamond, M.D., Delma L. Broussard, M.D., Kezhen L. Tang, Ph.D., C. Janneke van der

Woude, M.D., Ph.D., and Paul Rutgeerts, M.D., Ph.D., for the SONIC Study Group*

Infliximab, Azathioprine, or Combination

Therapy for Crohn’s Disease.

NEJM. 2010;362:1383-95.

*Members of the Study of Biologic and Immunomodulator Naïve *Members of the Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) Study GroupPatients in Crohn’s Disease (SONIC) Study Group

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Abbreviations UsedAbbreviations Used

AZA Azathioprine IFX Infliximab TNF Tumor necrosis factor 6MP 6 mercaptopurine PBO Placebo CDAI Crohn’s Disease Activity Index TPMT Thiopurine methyltransferase 5-ASA 5-aminosalicylic acid or Mesalamine ATI Antibody to Infliximab ADA Adalimumab CTZ Certolizumab pegol

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MethodsMethods

Study Design: randomized, double-blind trial, efficacy evaluation of infliximab (IFX) mono-therapy vs. Azathioprine (AZA) mono-therapy vs. combination therapy (IFX + AZA) in 508 adults with moderate-to-severe Crohn’s disease .

All Crohn’s disease patients were naive to previous immunosuppressive or biologic therapy.

Patients were randomly assigned to 3 groups: Group 1: intravenous infusion of 5 mg/kg of IFX at weeks 0, 2, and 6 and then every 8

weeks plus daily oral placebo (PBO) capsules Group 2: 2.5 mg/kg of oral azathioprine plus a placebo (PBO) infusion on the standard

schedule Group 3: IFX plus AZA combination

Patients received study medication through week 30 and then could continue in a blinded study extension through week 50.

Colombel JF, et al. NEJM. 2010;362:1383-95

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MethodsMethods

Study Subjects (inclusion criteria)

All > 21 yrs of age, giving informed written consent Crohn’s of > 6 weeks duration & mod-severe severity CDAI (Crohn’s Disease Activity Index)

Remission < 150 points Mild 150-220 points Moderate 220-450 points Severe > 450 points

Failed Rx: 2nd course corticosteroids < 12 mo; or mesalamine (>2.4 g/day); or budesonide (>6 mg/day)

No previous AZA, 6-MP, MTX, anti-TNF-α treatment.

Best WR, et al. Development of a Crohn’s disease activity index. Gastroenterol 1976; 70:439-44.

Colombel JF, et al. NEJM. 2010;362:1383-95

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MethodsMethods

Study Subjects (exclusion criteria)

Short bowel syndrome, an ostomy, symptomatic bowel stricture, abscess, recent abdominal surgery (< 6 mo)

History of tuberculosis or other granulomatous infection

(+) chest x-ray or PPD skin test Recent opportunistic infection (<6 mo) Active infection Hepatitis B or C HIV infection or Multiple Sclerosis or Cancer Homozygous mutant TPMT phenotype

Colombel JF, et al. NEJM. 2010;362:1383-95

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DemographicsDemographics

Characteristic AZAN=170

IFXN=169

ComboN=169

All PtsN=508 P-value

Gender ♂ (%) 52 50 52 51 0.83

White race (%) 91 93 94 93 0.22

Median Age 35 35 34 34 0.95

Median Kg 70 69 72 70 0.45

Median DurationOf Disease (yr)

2.4 2.2 2.2 2.3 0.60

Median CRP 1.0 1.1 1.0 1.1 0.40

CDAI 287+53 289+55 290+57 287+57 0.59

Colombel JF, et al. NEJM. 2010;362:1383-95

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DemographicsDemographics

Characteristic AZAN=170

IFXN=169

ComboN=169

All PtsN=508 P-value

GI area involved (%)

Ileum or Colon 100 96 99 98

Ileum only 40 33 32 35 0.34

Colon only 19 28 24 24

Ileum & Colon 41 39 44 41

Proximal GI Tract 4 7 10 7 0.15

Colombel JF, et al. NEJM. 2010;362:1383-95

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DemographicsDemographics

Characteristic AZAN=170

IFXN=169

ComboN=169

All PtsN=508 P-value

Prednisone

0 77 69 72 73 0.59

< 20 mg 8.2 11.2 8.3 9.3

> 20 mg 15.3 19.5 19.5 18.1

Budesonide (%) 14.7 16.6 11.2 14.2 0.36

5-ASA (%) 61 52 50 54 0.09

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study DesignStudy Design

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study DesignStudy Design

Colombel JF, et al. NEJM. 2010;362:1383-95

508 Pts Randomized

170 pts AZA + PBO 169 pts IFX + AZA169 pts IFX + PBO

86 pts at 30 wk 121 pts at 30 wk111 pts at 30 wk

62 pts through 50 wk 85 pts through 50 wk 90 pts through 50 wk

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Study ResultsStudy Results

Variable AZAN=170

IFXN=169

P-valueIFX vs.

AZA

ComboN=169

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Pts Steroid Free Remission (%)

Wk 6 14 30 <0.001 33 0.55 <0.001

Wk 10 24 37 0.006 47 0.07 <0.001

Wk 18 26 43 <0.001 53 0.06 <0.001

Wk 26 30 44 0.006 57 0.02 <0.001

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study ResultsStudy Results

Variable AZAN=170

IFXN=169

P-valueIFX vs.

AZA

ComboN=169

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Pts Steroid Free Remission (%)

Wk 34

All Pts 27 37 0.04 43 0.22 0.001

Pts carried to 50-wk 31 41 0.03 53 0.03 <0.001

Pts enter Trial Extension (EXT)

60 64 0.41 68 0.56 0.20

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study ResultsStudy Results

Variable AZAN=170

IFXN=169

P-valueIFX vs.

AZA

ComboN=169

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Pts Steroid Free Remission (%)

Wk 42

All Pts 26 40 0.007 46 0.27 <0.001

Pts carried to 50-wk 30 44 0.06 55 0.04 <0.001

Pts enter Trial EXT 59 69 0.13 71 0.67 0.06

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study ResultsStudy Results

Variable AZAN=170

IFXN=169

P-valueIFX vs.

AZA

ComboN=169

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Pts Steroid Free Remission (%)

Wk 50

All Pts 24 35 0.03 46 0.04 <0.001

Pts carried to 50-wk 28 40 0.03 56 0.002 <0.001

Pts enter Trial EXT 55 61 0.32 72 0.07 0.01

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study ResultsStudy Results

Variable AZAN=170

IFXN=169

P-valueIFX vs.

AZA

ComboN=169

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Mucosal Healing

Baseline Lesions (%) 68 59 0.08 66 0.18 0.70

Pts included 26 wk analysis

64 55 0.09 63 0.12 0.88

Mucosal Healing 17 30 0.02 44 0.06 <0.001

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study Results: (%) Corticosteroid-free Clinical Remission wk-26

Study Results: (%) Corticosteroid-free Clinical Remission wk-26

16.5

30.1

43.9

05

101520253035404550

AZA IFX IFX + AZA

P < 0.001

P < 0.02P < 0.006

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study Results: (%) Mucosal Healing wk-26Study Results: (%) Mucosal Healing wk-26

30

44.4

56.8

0

10

20

30

40

50

60

AZA IFX IFX + AZA

P < 0.001

P = 0.02 P = 0.06

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study Results: Safety DataStudy Results: Safety Data

Variable AZAN=161

IFXN=163

P-valueIFX vs.

AZA

ComboN=179

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Mean duration of Treatment Main Study

21.1 24.1 - 24.9 - -

Mean Duration in Study Extension

18.9 18.8 - 18.7 - -

Mean Duration Post Tx Follow Up

5.1 5.4 - 5.3 - -

Total Pt-yrsOf Follow UP

108.1 126.9 - 142.2 - -

Pts with Any Adverse Events # (%)

144(89) 145(89) 1.00 161(90) .86 1.00

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study Results: Safety DataStudy Results: Safety Data

Variable AZAN=161

IFXN=163

P-valueIFX vs.

AZA

ComboN=179

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Adverse Event & Discontinuation Rx (%)

26.1 17.8 0.08 20.7 0.58 0.25

Any Serious Adverse Event (%)

26.7 23.9 0.61 15.1 0.04 0.01

Infection

Any # (%)

73(45.3)

75(46)

0.91 75(41.9)

0.45 0.58

Serious # (%)

9(5.6)

8(4.9)

0.81 7(3.9)

0.79 0.61

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study Results: Safety DataStudy Results: Safety Data

Variable AZAN=161

IFXN=163

P-valueIFX vs.

AZA

ComboN=179

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Adverse event of Interest # (%)

Colon cancer 2(1.2)

0 - 0 - -

Sepsis 1(0.6)

0 - 0 - -

Tuberculosis 0 0 - 1(0.6)

- -

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study Results: Safety DataStudy Results: Safety Data

Variable AZAN=161

IFXN=163

P-valueIFX vs.

AZA

ComboN=179

P-valueCombo

vs.IFX

P-value Combo

vs. AZA

Infusions

# of pts with infusion reaction # (%)

9(5.6)

27(16.6)

0.002 9(5.0)

<0.001 1.00

No of Infusions

Mean # per patient 5.4 6.1 - 6.1 - -

Total # 862 990 - 1097 - -

With Infusion Reaction

10 45 - 11 - -

Colombel JF, et al. NEJM. 2010;362:1383-95

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Safety dataSafety data

Infusion Reactions

IFX + AZA 5.0% (9/179)

IFX + PBO 16.6% (27/163)

AZA + PBO 5.6% (9/161)

Colombel JF, et al. NEJM. 2010;362:1383-95

P=0.002

P=0.001

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Study Results: Development of IFX – AB (ATI)Study Results: Development of IFX – AB (ATI)

14.6

0.9

0

2

4

6

8

10

12

14

16

AZA IFX IFX + AZA

Colombel JF, et al. NEJM. 2010;362:1383-95

% AT I(+)

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Study Results: IFX Trough Levels (μg/ml)Study Results: IFX Trough Levels (μg/ml)

1.6

3.5

0

0.5

1

1.5

2

2.5

3

3.5

4

AZA IFX IFX + AZA

P < 0.001

Colombel JF, et al. NEJM. 2010;362:1383-95

IFX μg/ml

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Study ConclusionsStudy Conclusions

1. IFX + AZA treatment issuperior to IFX & AZA mono-therapy for treatment of mod-severe Crohn’s disease.

10 End Point – Remission by CDAI @ 26 wk► Combo IFX + AZA = 56.8%► IFX + PBO = 44.4%► AZA + PBO = 30.0%

20 End Point Healing Pre Rx Post 26wk

► Combo IFX + AZA = 65.7% 43.9%► IFX + PBO = 58.6% 30.1%► AZA + PBO = 67.6% 16.5%

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study ConclusionsStudy Conclusions

2. Combo IFX + AZA is as safe as IFX & AZA mono-therapy.

Total Percentage of Serious Infections► Combo IFX + AZA = 3.9 %► IFX + PBO = 4.9 %► AZA + PBO = 5.6 %

Infusion Reactions► Combo IFX + AZA = 5.0 %► IFX + PBO = 16.6%► AZA + PBO = 5.6%

Colombel JF, et al. NEJM. 2010;362:1383-95

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Study ConclusionsStudy Conclusions

3. Comb IFX + AZA appears to decrease the development of ATI and higher trough IFX levels.

Percentage of ATI detected at wk 30► Combo IFX + AZA = 0.9 %► IFX + PBO = 14.6 %

Trough IFX levels at week 30► Combo IFX + AZA = 3.5 μg ml► IFX + PBO = 1.6μg ml

Colombel JF, et al. NEJM. 2010;362:1383-95

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Reviewer CommentsReviewer Comments

Colombel, and the other members of the SONIC Study Group are praised for conducting a much needed study on the efficacy of IFX + AZA vs. mono therapy with IFX or AZA in patients with mod-severe Crohn’s disease.

The investigators’ research shows that IFX +AZA is clearly more effective than mono therapy with IFX or AZA and in the short term (12 mo), just as safe.

P R McNally, DO, FACP, FACG

Colombel JF, et al. NEJM. 2010;362:1383-95

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Reviewer CommentsReviewer Comments

However, Colombel, et al, fail to answer the following questions?

1. Are the short term “6-12 mo” improved efficacy and reduced serious infections seen with IFX + AZA durable?

2. Will > 12 mo of IFX + AZA therapy prove to be the Achille’s heal, with increased development of serious infections and malignancy ?

Colombel JF, et al. NEJM. 2010;362:1383-95

P R McNally, DO, FACP, FACG

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Reviewer CommentsReviewer Comments

2. Greater remission rates for IFX + AZA vs. IFX + PBO may be related to reduced immunogenicity toward the chimeric anti-TNF-α (IFX), as ATI’s are reduced and trough levels of IFX are higher in the combined IFX-AZA group.

IFX + AZA IFX + PBO

ATI 0.9% 14.6%

Trough IFX 3.5 μg/ml 1.6 μg/ml

Colombel JF, et al. NEJM. 2010;362:1383-95

P R McNally, DO, FACP, FACG

Page 34: Literature Review

Reviewer CommentsReviewer Comments

3. Many studies of biologic therapy among Crohn’s disease patients have shown that the initiation of therapy earlier in the onset of the disease predicts much higher remission rates.

The “Sonic Trial” study evaluated patients with short duration of Crohn’s disease (ave of 2 yrs). The “ high” ~60% remission rate for IFX +AZA seen in the Sonic Trial may be a reflection of the subject enrollment criteria.

Colombel JF, et al. NEJM. 2010;362:1383-95

P R McNally, DO, FACP, FACG

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Reviewer CommentsReviewer Comments

4. Immunogenicity of the 3 FDA approved anti-TNF-α agents (IFX, ADA, CTZ) are different.

- Remission rates for ADA + AZA or CTZ + AZA cannot be assumed to be the same as seen with IFX + AZA in the Sonic Trial!

- Safety for ADA + AZA or CTZ + AZA cannot be assumed to be the same as seen with IFX + AZA in the Sonic Trial!

Colombel JF, et al. NEJM. 2010;362:1383-95

P R McNally, DO, FACP, FACG

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Reviewer CommentsReviewer Comments

5. Is there an “exit strategy” ? Can combo IFX + AZA treatment “step-down” to just IFX or AZA after 1-2 years of healed mucosa and disease free remission?

Colombel JF, et al. NEJM. 2010;362:1383-95

P R McNally, DO, FACP, FACG

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Reviewer ConclusionsReviewer Conclusions

1. Crohn’s disease is an incredibly devastating and debilitating disorder. More work needs to be done to develop a stratified treatment strategy, that will balance risks of combination IFX + AZA therapy with benefits of disease suppression.

2. Treatment strategies should be guided by: Staging Criteria = Montreal Criteria Genetic Markers = NOD2 (SNP8, SNP12, SNP13) Antibodies to gut microbiotica (ASCA, OmpC, CBir1, Anti-I2, PANCA) Serial assessment for mucosal healing

3. Sonic trial results are specific for IFX + AZA and should not be empirically applied to ADA + AZA or CTZ + AZA.

Mucosal healing

P R McNally, DO, FACP, FACG