Effect of tight control management on Crohn's disease (CALM)

a multicentre, randomised, controlled phase 3 trial

Jean Frederic Colombel, Remo Panaccione, Peter Bossuyt, Milan Lukas, Filip Baert, Tomas Vaňásek, Ahmet Danalioglu, Gottfried Novacek, Alessandro Armuzzi, Xavier Hébuterne, Simon Travis, Silvio Danese, Walter Reinisch, William J. Sandborn, Paul Rutgeerts, Daniel Hommes, Stefan Schreiber, Ezequiel Neimark, Bidan Huang, Qian Zhou & 6 others Paloma Mendez, Joel Petersson, Kori Wallace, Anne M. Robinson, Roopal B. Thakkar, Geert D'Haens

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Background Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. Methods CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18–75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150–450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. Findings Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran–Mantel–Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9–28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. Interpretation CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. Funding AbbVie.

Original languageEnglish
Pages (from-to)2779-2789
Number of pages11
JournalThe Lancet
Volume390
Issue number10114
DOIs
Publication statusPublished - 2018

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Crohn Disease
Prednisone
Control Groups
Nasopharyngitis
Leukocyte L1 Antigen Complex
Biomarkers
Azathioprine
C-Reactive Protein
Therapeutics
Ulcer
Arthralgia
Immunologic Factors
Physiologic Monitoring
Random Allocation
Biological Products
Treatment Failure
Nausea
Headache
Adalimumab
Outpatients

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Colombel, J. F., Panaccione, R., Bossuyt, P., Lukas, M., Baert, F., Vaňásek, T., ... D'Haens, G. (2018). Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial. The Lancet, 390(10114), 2779-2789. https://doi.org/10.1016/S0140-6736(17)32641-7

Effect of tight control management on Crohn's disease (CALM) : a multicentre, randomised, controlled phase 3 trial. / Colombel, Jean Frederic; Panaccione, Remo; Bossuyt, Peter; Lukas, Milan; Baert, Filip; Vaňásek, Tomas; Danalioglu, Ahmet; Novacek, Gottfried; Armuzzi, Alessandro; Hébuterne, Xavier; Travis, Simon; Danese, Silvio; Reinisch, Walter; Sandborn, William J.; Rutgeerts, Paul; Hommes, Daniel; Schreiber, Stefan; Neimark, Ezequiel; Huang, Bidan; Zhou, Qian; Mendez, Paloma; Petersson, Joel; Wallace, Kori; Robinson, Anne M.; Thakkar, Roopal B.; D'Haens, Geert.

In: The Lancet, Vol. 390, No. 10114, 2018, p. 2779-2789.

Research output: Contribution to journalArticle

Colombel, JF, Panaccione, R, Bossuyt, P, Lukas, M, Baert, F, Vaňásek, T, Danalioglu, A, Novacek, G, Armuzzi, A, Hébuterne, X, Travis, S, Danese, S, Reinisch, W, Sandborn, WJ, Rutgeerts, P, Hommes, D, Schreiber, S, Neimark, E, Huang, B, Zhou, Q, Mendez, P, Petersson, J, Wallace, K, Robinson, AM, Thakkar, RB & D'Haens, G 2018, 'Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial', The Lancet, vol. 390, no. 10114, pp. 2779-2789. https://doi.org/10.1016/S0140-6736(17)32641-7
Colombel, Jean Frederic ; Panaccione, Remo ; Bossuyt, Peter ; Lukas, Milan ; Baert, Filip ; Vaňásek, Tomas ; Danalioglu, Ahmet ; Novacek, Gottfried ; Armuzzi, Alessandro ; Hébuterne, Xavier ; Travis, Simon ; Danese, Silvio ; Reinisch, Walter ; Sandborn, William J. ; Rutgeerts, Paul ; Hommes, Daniel ; Schreiber, Stefan ; Neimark, Ezequiel ; Huang, Bidan ; Zhou, Qian ; Mendez, Paloma ; Petersson, Joel ; Wallace, Kori ; Robinson, Anne M. ; Thakkar, Roopal B. ; D'Haens, Geert. / Effect of tight control management on Crohn's disease (CALM) : a multicentre, randomised, controlled phase 3 trial. In: The Lancet. 2018 ; Vol. 390, No. 10114. pp. 2779-2789.
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abstract = "Background Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. Methods CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18–75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150–450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. Findings Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24{\%}) patients in the clinical management group and 32 (26{\%}) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46{\%}] of 122 patients) than in the clinical management group (37 [30{\%}] of 122 patients), with a Cochran–Mantel–Haenszel test-adjusted risk difference of 16·1{\%} (95{\%} CI 3·9–28·3; p=0·010). 105 (86{\%}) of 122 patients in the tight control group and 100 (82{\%}) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17{\%}] of 122 patients), nasopharyngitis (18 [15{\%}]), and headache (18 [15{\%}]) in the tight control group, and worsening Crohn's disease (35 [29{\%}] of 122 patients), arthralgia (19 [16{\%}]), and nasopharyngitis (18 [15{\%}]) in the clinical management group. Interpretation CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. Funding AbbVie.",
author = "Colombel, {Jean Frederic} and Remo Panaccione and Peter Bossuyt and Milan Lukas and Filip Baert and Tomas Vaň{\'a}sek and Ahmet Danalioglu and Gottfried Novacek and Alessandro Armuzzi and Xavier H{\'e}buterne and Simon Travis and Silvio Danese and Walter Reinisch and Sandborn, {William J.} and Paul Rutgeerts and Daniel Hommes and Stefan Schreiber and Ezequiel Neimark and Bidan Huang and Qian Zhou and Paloma Mendez and Joel Petersson and Kori Wallace and Robinson, {Anne M.} and Thakkar, {Roopal B.} and Geert D'Haens",
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TY - JOUR

T1 - Effect of tight control management on Crohn's disease (CALM)

T2 - a multicentre, randomised, controlled phase 3 trial

AU - Colombel, Jean Frederic

AU - Panaccione, Remo

AU - Bossuyt, Peter

AU - Lukas, Milan

AU - Baert, Filip

AU - Vaňásek, Tomas

AU - Danalioglu, Ahmet

AU - Novacek, Gottfried

AU - Armuzzi, Alessandro

AU - Hébuterne, Xavier

AU - Travis, Simon

AU - Danese, Silvio

AU - Reinisch, Walter

AU - Sandborn, William J.

AU - Rutgeerts, Paul

AU - Hommes, Daniel

AU - Schreiber, Stefan

AU - Neimark, Ezequiel

AU - Huang, Bidan

AU - Zhou, Qian

AU - Mendez, Paloma

AU - Petersson, Joel

AU - Wallace, Kori

AU - Robinson, Anne M.

AU - Thakkar, Roopal B.

AU - D'Haens, Geert

PY - 2018

Y1 - 2018

N2 - Background Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. Methods CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18–75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150–450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. Findings Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran–Mantel–Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9–28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. Interpretation CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. Funding AbbVie.

AB - Background Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. Methods CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18–75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150–450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. Findings Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran–Mantel–Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9–28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. Interpretation CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. Funding AbbVie.

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