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Laharie 2012 PDF
Laharie 2012 PDF
Summary
Background Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute Published Online
severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs October 10, 2012
http://dx.doi.org/10.1016/
for this indication. S0140-6736(12)61084-8
See Online/Comment
Methods In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute http://dx.doi.org/10.1016/
severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful S0140-6736(12)61259-8
course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. *These authors contributed
Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer- equally
derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by †Deceased
oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at CHU de Bordeaux, Hôpital
day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The Haut-Lévêque, Service
d’Hépato-Gastroentérologie,
primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between Bordeaux, France
day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, (Prof D Laharie MD); Université
colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and Bordeaux, Laboratoire de
ClinicalTrials.gov (NCT00542152). Bactériologie, Bordeaux, France
(Prof D Laharie); CHU de Nantes,
Hôtel-Dieu, Hépato-
Findings 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive Gastroentérologie, Institut des
infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute Maladies de l’Appareil Digestif,
risk difference 6%; 95% CI –7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the Nantes, France
(A Bourreille MD); CHRU de Lille,
infliximab group had severe adverse events. Hôpital Claude Huriez, Service
des Maladies de l’Appareil
Interpretation Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis Digestif—Endoscopie
refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre Digestive, Lille, France
(J Branche MD,
experience. Prof J-F Colombel MD); Hôpital
Saint-Louis, Service d’Hépato-
Funding Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Gastroentérologie, APHP—
Université Paris VII, Paris,
Organization for the study of Inflammatory Bowel Disease.
France (Prof M Allez MD,
Prof M Lémann MD); Hôpital
Introduction thus practice guidelines do not state which treatment is Beaujon, Gastroentérologie,
Ulcerative colitis is a chronic inflammatory disorder of preferable.9,10 Assuming that ciclosporin was superior to Maladies Inflammatoires
Chroniques de l’Intestin et
the colon characterised by mucosal ulceration, rectal infliximab, we compared the efficacy and safety of these
Assistance Nutritive, APHP—
bleeding, diarrhoea, and abdominal pain.1 In 15–25% of drugs in patients with acute severe ulcerative colitis Université Paris VII, Clichy,
cases, patients present with severe colitis that necessitates refractory to intravenous corticosteroids. France (Prof Y Bouhnik MD);
admission to hospital.2,3 Intravenous corticosteroids are CHU de Nice, Hôpital de
l’Archet 2, Service de
the conventional medical treatment in this circumstance. Methods Gastroentérologie et Nutrition
However, roughly 40% of patients are resistant to Study design and patients Clinique, Nice, France
treatment.4,5 Previously, colectomy was the only available Our 98 day randomised, parallel, open-label trial (J Filippi MD); CHU de Bordeaux,
option for these patients. The development of ciclosporin, compared ciclosporin with infliximab in patients Hôpital Saint André, Service
d’Hépato-Gastroentérologie,
a calcineurin inhibitor that selectively inhibits T-cell admitted to hospital with severe colitis. We did our trial
Université Bordeaux Segalen,
immunity, and infliximab, a monoclonal antibody that at 27 centres in France, Spain, Belgium, and Finland Bordeaux, France
targets tumour necrosis factor α, has provided effective from June 1, 2007, to Aug 31, 2010. The study was (Prof F Zerbib MD); CHU de
alternatives to surgery.6–8 However, no randomised designed by investigators from the Groupe d’Etudes Rouen, Hôpital Charles Nicolle,
Service de Gastroentérologie,
controlled trials have been done to compare the efficacy Therapeutiques des Affections Inflammatoires Appareil Digestif
and safety of ciclosporin with those of infliximab, and Digestives (GETAID).
Environnement et Nutrition Patients were consecutively recruited. Eligible patients culosis or tuberculin skin test; active hepatitis B or C
Equipe Avenir 4311, Université were at least 18 years of age and had an acute severe virus infections; HIV infection; uncontrolled bacterial or
de Rouen, Rouen, France
(Prof G Savoye MD); CHU de
flare of ulcerative colitis defined by a Lichtiger score active viral infection; a history of myocardial infarction,
Besançon, Hôpital Jean Minjoz, of greater than 10 points. The Lichtiger score is a clinical heart failure, or malignant disease in the past 5 years
Service de Gastroentérologie, index of eight factors and ranges from 0 to 21 points; (except for basal-cell skin cancer); renal failure; or
Besançon, France acute severe ulcerative colitis is defined as a score of uncontrolled high blood pressure. The institutional
(M Nachury MD); CHU de
Toulouse, Hôpital Rangueil,
more than 10.6 All patients had been given an unsuc- review board at each centre approved the protocol, and all
Service de Gastroentérologie et cessful course of high-dose intravenous steroid therapy patients provided written informed consent.
Nutrition, Toulouse, France defined as a minimum of 0·8 mg/kg per day of
(J Moreau MD); Hôpital Henri methylprednisolone or equivalent for at least 5 days. Randomisation and masking
Mondor, Service
d’Hépato-Gastroentérologie,
None of the patients had previously received ciclosporin Study drugs were started on day 0 (inclusion visit).
APHP—Université Paris Sud 11, or infliximab. Patients were not given treatment with Patients were randomly assigned (1:1) to receive
Créteil, France azathioprine or mercaptopurine at baseline, unless the ciclosporin by continuous intravenous infusion at an
(Prof J-C Delchier MD); Hôpital drugs had been started less than 4 weeks before initial dose of 2 mg/kg per day or a one-off 5 mg/kg dose
St-Antoine, Service de
Gastroentérologie, Paris, France
inclusion at a dose of 2·0–2·5 mg/kg per day of of infliximab by intravenous infusion during 2 h.
(Prof J Cosnes MD); azathioprine or equivalent, in which case the same dose Randomisation was done centrally with computer-
Gastroenterology Department, was maintained. Contraception use was mandatory derived permutation tables of size two or four and
Hospital Clinic, Barcelona,
throughout the study and at least 3 months after for all stratified by centre. Patients were assigned identification
Spain (E Ricart MD); Centro de
Investigación Biomédica en Red patients of childbearing potential. codes, which were sent to the investigator after receipt
de Enfermedades Hepáticas y We excluded patients with proctitis only; an indication and validation of the inclusion form by the statistical
Digestivas, Madrid, Spain for immediate colectomy as judged by the physician; centre (this centre was independent from the funding
(E Ricart); Université Catholique
a history of colorectal dysplasia; Crohn’s disease; a source). Treatment allocation was included in a sealed
de Louvain Saint Luc, Service de
Gastroentérologie, Brussels, positive stool test for enteric pathogens or Clostridium opaque envelope with the patient’s identification code.
Belgium (Prof O Dewit MD); difficile B toxin; a positive chest radiograph for tuber- Patients and investigators were not masked to treatment.
Hospital Ramon y Cajal, Unidad
de EII, Servicio de
Gastroenterología, Madrid,
Spain (A Lopez-Sanroman MD); 115 patients randomly assigned
CHU Amiens, Hôpital Nord,
Service d’Hépato-
Gastroentérologie, Amiens,
58 allocated to receive ciclosporin 57 allocated to receive infliximab
France (Prof J-L Dupas MD);
57 received ciclosporin 56 received infliximab
Hôpital Bicêtre, Service 1 mistakenly received infliximab 1 requested to receive ciclosporin
d’Hépato-Gastroentérologie,
APHP—Université Paris Sud 11,
Le Kremlin Bicêtre, France 8 treatment failure 9 treatment failure
(Prof F Carbonnel MD); CHU 2 colectomy decided 1 withdrawal
6 non-responders (including 3 who had 3 colectomy decided
Clermont-Ferrand, Service
colectomies on or before day 98) 5 non-responders (including 2 who
Hépatologie-
had colectomies on or before day 98)
Gastroentérologie,
Clermont-Ferrand, France
(Prof G Bommelaer MD); Hôpital 50 responders at day 7 48 responders at day 7
Louis Mourier, Service
d’Hépato-Gastroentérologie,
Pôle Maladie Appareil Digestif, 13 treatment failure 11 treatment failure
APHP—Université Paris VII, 2 withdrawals 1 withdrawal
1 colectomy 1 severe adverse event
Colombes, France
10 clinical relapse (including 4 who had 1 colectomy
(Prof B Coffin MD); CHU de
colectomies on or before day 98) 8 clinical relapse (including 6 who had
Saint-Etienne, Hôpital Nord, colectomies on or before day 98)
Service de Gastroentérologie et
Hépatologie, Saint-Etienne,
France (X Roblin MD); Division 37 evaluable at day 98 37 evaluable at day 98
of Gastroenterology, University
Hospital of Leuven, Leuven,
Belgium (Prof G Van Assche MD); 14 treatment failure 11 treatment failure
3 clinical relapse 4 clinical relapse
Hospital Universitari Mútua de
11 non-remission off steroids 7 non-remission off steroids
Terrassa, Department of
Gastroenterology, University of
Barcelona, Terrassa, Spain 23 remission off steroids at day 98 26 remission off steroids at day 98
(M Esteve MD); Department of
Medicine, Helsinki University,
Helsinki, Finland 58 intention-to-treat population* 57 intention-to-treat population*
(Prof M Färkkilä MD); Clinic of
Gastroenterology, Helsinki
Figure 1: Trial profile
University Central Hospital,
*All patients who were randomly assigned were included in the intention-to-treat population.
Table 1: Demographic and clinical characteristics of patients Table 2: Suboutcomes of treatment failure for ciclosporin and infliximab
monitoring board with two specialists in inflammatory Mann-Whitney test. Treatment was judged unsuccessful
bowel disease who were not involved in the study). in patients withdrawn before assessment day; such
patients were included in the analysis with the maximum
Statistical analysis score of 21. We used the Mann-Whitney test13 to compare
We did our analyses on an intention-to-treat basis. We time to clinical response in the ciclosporin group with
used descriptive statistical techniques to assess patients’ that in the infliximab group; patients withdrawn before
baseline characteristics. The proportion of patients in assessment day were deemed to have had no clinical
whom treatment did not work in the ciclosporin group response. We compared median differences between
was compared with that in the infliximab group with the groups in scores on the inflammatory bowel disease
χ² test and expressed as absolute difference with 95% CIs questionnaire between day 0 and 98 with the Mann-
or as relative difference—ie, odds ratios (ORs) with Whitney test. We calculated colectomy-free survival
95% CIs. This approach was also used to compare rates Kaplan-Meier14 curves for each treatment group from
of clinical response at day 7 and mucosal healing at day randomisation to day 98 and compared them with the
98 between the groups. In these analyses, we deemed log-rank test;15 differences were expressed as hazard
treatment in patients who were withdrawn before day 7 ratios (HRs) with 95% CIs.16 We did safety analyses for all
or day 98 to be unsuccessful. treated patients, irrespective of treatment duration.
Median Lichtiger scores from day 0 to day 7 were We used a logistic regression model17 to assess pre-
See Online for appendix compared between the treatment groups with the dictors of treatment failure, with treatment as a factor in
the model (appendix). We estimated from the final model
14 Ciclosporin ORs with 95% CIs for the treatment effect of ciclosporin
Infliximab
12 relative to infliximab.
For the primary outcome, we estimated that random-
10 isation of 100 patients would provide an 80% power to
Lichtiger score
p=0·60
0·6
explored predictors of treatment effect. We used SPSS
software for our analyses. The significance threshold was
0·4
0·05 for all analyses.
0·2
Role of the funding source
Ciclosporin No commercial entity had any role in the study. The
Infliximab HR 0·80 (95% CI 0·35–1·85) funding sources had no role in study design or data
0
0 14 28 42 56 70 84 98 collection, analysis, or interpretation. DL, J-YM, J-FC,
Time (days) and ML had full access to all the study data. All authors
Number at risk
Ciclosporin 58 55 53 49 48 48 48 43 made the decision to submit the report for publication
Infliximab 57 54 51 47 47 47 46 42
and vouch for the veracity and completeness of the data
Figure 3: Kaplan-Meier curves for colectomy-free survival and their analyses.
In the infliximab group, nine patients in whom treatment was unsuccessful had rescue therapy before day 98:
four were switched to ciclosporin (two colectomies), three received extra (ie, not on days 0, 14, or 42) infliximab Results
infusions of 5 mg/kg (one colectomy), and two received scheduled infliximab infusions of 10 mg/kg (ie, a double
Of the 115 randomly assigned patients, 58 were assigned
dose on day 14 or 42; one colectomy). In the ciclosporin group, six patients in whom treatment was unsuccessful
had rescue therapy before day 98: five received infliximab, including four infusions of 5 mg/kg (two colectomies) to the ciclosporin group and 57 to the infliximab group
and one of 10 mg/kg (one colectomy) and we increased one patient’s steroid dose (no colectomy). HR=hazard ratio. (figure 1). Four of these patients had major inclusion
similar in the two groups except for Lichtiger score, Pulmonary event 1¶ 0
which was higher in the infliximab than in the ciclosporin Worsening of ulcerative colitis 3 7
group (table 1). Degenerative arthrosis 0 1
At day 98, we noted treatment failure in 35 of the Total events 10 17
58 (60%) patients given ciclosporin compared with 31 of Total patients (%) 9 (16%) 14 (25%)
57 (54%) given infliximab (absolute risk difference 6%, *A 66-year-old man developed myocardial ischaemia during the study and died
95% CI –7 to 19; OR 1·3, 95% CI 0·6 to 2·7; p=0·52). during follow-up (day 137) from a myocardial infarction. †Venous
Table 2 shows suboutcomes included in the primary thromboembolism. ‡Central-venous-catheter-related septicaemia with non-aureus
Staphylococcus. §Increased aminotransferases leading to treatment withdrawal (at
outcome (which were not predefined as endpoints). We
least two cases related to azathioprine). ¶Suspected pneumonia (unconfirmed).
did not record any difference between the two groups for
these suboutcomes. Table 3: Severe adverse events during the study period according to
50 of 58 (86%) patients given ciclosporin had a clinical treatment received
Brian Feagan for providing expert suggestions. ML died suddenly on 18 Dupont WD, Plummer WD. Power and sample size calculations.
Aug 26, 2010. We remember our esteemed friend and colleague who A review and computer program. Control Clinical Trials 1990; 11: 116.
initiated this study and recognise his contributions to advancing the 19 Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal
understanding and treatment of inflammatory bowel disease. classification of inflammatory bowel disease: controversies,
consensus, and implications. Gut 2006; 55: 749–53.
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