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P389 A double-blind clinical trial on Trichuris suis

ova (TSO) in active Crohn's disease resulted in a significant placebo effect both in patients and investigators without objective evidence of reduced inflammation

J. Schölmerich*1, K. Fellermann2, F.W. Seibold3, G. Rogler4, J. Langhorst5, S. Howaldt6, G. Novacek7, A.M. Petersen8, O. Bachmann9, H. Matthes10, N. Hesselbarth11, T. Klugmann12, J. Wehkamp13, J. Klaus14, C. Ott15, R. Greinwald16, R. Mueller16

1Klinikum der Johann Wolfgang Goethe-Universität Frankfurt a.M. , Ärztliche Direktion, Frankfurt a.M., Germany, 2UK-SH Campus Lübeck, Abt. Gastroenterologie, Lübeck, Germany, 3Spital Netz Bern Tiefenau, Abt. Gastroenterologie, Bern, Switzerland, 4University of Zurich, Division of Gastroenterology and Hepatology, Zurich, Switzerland, 5Kliniken Essen-Mitte, Integrative Gastroenterologie, Internal and Integrative Medicine, Essen, Germany, 6Hamburgisches Forschungsinstitut für CED, HaFCED GmbH&Co.KG, Hamburg, Germany, 7Medizinische Universität Wien, Universitätsklinik für Innere Medizin III, Vienna, Austria, 8Hvidovre University Hospital, Department of Gastroenterology, Hvidovre, Denmark, 9Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany, 10Gemeinschaftskrankenhaus Havelhöhe, Abt. Gastroenterologie, Berlin, Germany, 11Ärztehaus am Klinikum, Private Practice, Schwalmstadt, Germany, 12Gastroenterologische Gemeinschaftspraxis, Private practice, Leipzig, Germany, 13Robert-Bosch-Krankenhaus, Abt. Innere Medizin I, Stuttgart, Germany, 14Universitätsklinikum Ulm, Klinik für Innere Medizin I, Ulm, Germany, 15University Hospital of Regensburg, Dept. of Internal Medicine I, Regensburg, Germany, 16Dr Falk Pharma GmbH, Dept of Clinical Research & Development, Freiburg, Germany

Background

A randomized, double blind, placebo controlled phase II study with an planned interim analysis and using 3 doses of TSO in mildly to moderately active ileo-/colonic, uncomplicated Crohn's disease failed to show evidence of a therapeutic benefit regarding remission or response according to the CDAI as compared to placebo, but resulted in an unexpectedly high placebo remission rate of 43% [1]. The goal of this analysis was to explore tentative reasons for this high placebo response.

Methods

Primary endpoint was the rate of clinical remission (CDAI<150) at week 12 (LOCF; ITT analysis). Exploratory analyses of baseline data, change of biochemical parameters and components of the CDAI as well as physician global assessment were performed and in particular results of the primary endpoint of the two stages of the study were calculated (see Table 1 for stage definition).

Results

There was no effect of any of the baseline parameters analyzed (duration of disease, BMI, sex, age, CDAI) on the remission rate. CRP and calprotectin were initially somewhat more elevated in patients who did not achieve remission, but overall no clinically relevant change from baseline was seen in any of the groups. No significant difference in change of single CDAI components was found between treatment groups. In a small subpopulation of 37 patients mucosal healing was studied and occurred in 2 patients each with 250 TSO and placebo and 1 each in the other two groups. Physicians' global assessment showed success of treatment in 25.4% and benefit in 57.1% of all patients without any difference between groups. Interestingly, the observed clinical remission rates were not consistent between the 2 stages of the study (Table 1).

Number (%) of patients with clinical remission (CDA<150) at wk 12 (LOCF). Stage I/II contain patients enrolled before/after the recommendation of the interim analysis, respectively

TSO 250TSO 2.500TSO 7.500PlaceboTotal
Stage I15/39 (38.5%)10/39 (25.6%)20/39 (51.3%)14/39 (35.9%)59/156 (37.8%)
Stage II---15/32 (46.9%)14/33 (42.4%)16/31 (51.6%)45/96 (46.9%)
Overall15/39 (38.5%)25/71 (35.2%)34/72 (47.2%)30/70 (42.9%)104/252 (41.3%)

Conclusion

The high clinical remission rate (42.9%) in the placebo group according to CDAI was not accompanied by any relevant change of initially elevated biochemical parameters of inflammation or mucosal healing at endoscopy. This finding casts further doubt on the suitability of the CDAI as sole primary endpoint in Crohn's disease, as it is susceptible to record subjective symptom improvement which is not reflected by biochemical markers and/or endoscopic sign of inflammation. Physicians' global assessment was as well rather positive in all groups. The different remission rates in the two stages might be explained by the low group size in each stage as well as by a potential selection bias in favour of 'believers' in alternative medicine.

*on behalf of the International TSU-2 Study Group (TRUST-2)

References:

[1] Schölmerich J, et al., (2014), Efficacy and safety of Trichuris suis ova fo rtreatment o fmildly-to-moderately active Crohn's disease: A randomised, double-blind, placebo-controlled, phase II study, UEG Journal, 2(1S):A123 (OP392)