First multicenter study of modified release phosphatidylcholine "LT-02" in ulcerative colitis: a randomized, placebo-controlled trial in mesalazine-refractory courses
Max Karner, Andreas Kocjan, Juergen Stein, Stefan Schreiber, Georg von Boyen, Peter Uebel, Carsten Schmidt, Limas Kupcinskas, Ion Dina, Frank Zuelch, Gerhard Keilhauer, Wolfgang Stremmel, Max Karner, Andreas Kocjan, Juergen Stein, Stefan Schreiber, Georg von Boyen, Peter Uebel, Carsten Schmidt, Limas Kupcinskas, Ion Dina, Frank Zuelch, Gerhard Keilhauer, Wolfgang Stremmel
Abstract
Objectives: Phosphatidylcholine is a key component of the mucosal barrier. Treatment with modified release phosphatidylcholine aims to improve the impaired barrier function. The primary objective is to evaluate the efficacy of LT-02, a newly designed modified release phosphatidylcholine formula, in a multicenter setting.
Methods: This is a double-blinded, randomized, placebo-controlled, superiority study conducted in 24 ambulatory referral centers in Germany, Lithuania, and Romania. A total of 156 patients with an inadequate response to mesalazine, a disease activity score (Simple Clinical Colitis Activity Index (SCCAI)) of ≥ 5, and bloody diarrhea underwent treatment with 0, 0.8, 1.6, or 3.2 g LT-02. The primary end point was defined a priori as changes in SCCAI from baseline to the end of treatment. The primary statistical model was a general linear least-squares model. The study was funded by the sponsor Lipid Therapeutics, Heidelberg, Germany, and registered at https://ichgcp.net/clinical-trials-registry/NCT01011322.
Results: Baseline characteristics and dropouts were well balanced between all groups. The primary analyses revealed an SCCAI drop of 33.3% in the placebo group (from 9.0 to 6.0 points) compared with 44.3% in the 0.8 g LT-02 (from 8.8 to 4.9, P>0.05) and 40.7% in the 1.6 g groups (from 8.6 to 5.1, P>0.05). The 3.2 g group improved 51.7% from 8.5 to 4.1 (P=0.030 in comparison with placebo). The remission rate was 15% (6/40) in the placebo group compared with 31.4% (11/35) in the highest LT-02 dose group (P=0.089). Mucosal healing was achieved in 32.5% of placebo patients compared with 47.4% of LT-02 patients (P=0.098); the rates for histologic remission were 20% compared with 40.5%, respectively (P=0.016). There were 17 (48.6%) treatment-emergent adverse events in the highest dose group (and 0 serious adverse events (SAEs)) compared with 22 (55%) in the placebo group (4 SAEs).
Conclusions: The primary end point analysis showed a statistically significant improvement in disease activity during LT-02 treatment in comparison with placebo. The drug was found to be very safe.
Figures
References
- Loftus EV., Jr Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–1517.
- Baumgart DC, Macdonald JK, Feagan B. Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis. Cochrane Database Syst Rev. 2008. p. CD007216.
- Shibolet O, Regushevskaya E, Brezis M, et al. Cyclosporine A for induction of remission in severe ulcerative colitis. Cochrane Database Syst Rev. 2005. p. CD004277.
- De Vries HS, van Oijen MG, de Jong DJ. Serious events with infliximab in patients with inflammatory bowel disease: a 9-year cohort study in the Netherlands. Drug Saf. 2008;31:1135–1144.
- Fidder H, Schnitzler F, Ferrante M, et al. Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-center cohort study. Gut. 2009;58:501–508.
- Hoie O, Wolters FL, Riis L, et al. Low colectomy rates in ulcerative colitis in an unselected European cohort followed for 10 years. Gastroenterology. 2007;132:507–515.
- DeSchryver-Kecskemeti K, Eliakim R, Carroll S, et al. Intestinal surfactant-like material. A novel secretory product of the rat enterocyte. J Clin Invest. 1989;84:1355–1361.
- Lichtenberger LM. The hydrophobic barrier properties of gastrointestinal mucus. Annu Rev Physiol. 1995;57:565–583.
- Stremmel W, Hanemann A, Braun A, et al. Delayed release phosphatidylcholine as new therapeutic drug for ulcerative colitis - a review of three clinical trials. Expert Opin Investig Drugs. 2010;Dec:19:1623–19:1630.
- Ehehalt R, Wagenblast J, Erben G, et al. Phosphatidylcholine and lysophosphatidylcholine in intestinal mucus of ulcerative colitis patients. A quantitative approach by nanoElectrospray-tandem mass spectrometry. Scand J Gastroenterol. 2004;39:737–742.
- Braun A, Treede I, Gotthardt D, et al. Alterations of phospholipid concentration and species composition of the intestinal mucus barrier in ulcerative colitis: a clue to pathogenesis. Inflamm Bowel Dis. 2009;15:1705–1720.
- Podolsky DK. Inflamatory bowel disease. N Engl J Med. 2002;347:417–429.
- Treede I, Braun A, Jeliaskova P, et al. TNF-alpha-induced up-regulation of pro-inflammatory cytokines is reduced by phosphatidylcholine in intestinal epithelial cells. BMC Gastroenterol. 2009;9:53.
- Treede I, Braun A, Sparla R, et al. Anti-inflammatory effects of phosphatidylcholine. J Biol Chem. 2007;282:27155–27164.
- Braun A, Schönfeld U, Welsch T, et al. Reduced hydrophobicity of the colonic mucosal surface in ulcerative colitis as a hint at a physicochemical barrier defect. Int J Colorectal Dis. 2011;26:989–998.
- Gibson PR, Muir JG. Reinforcing the mucus: a new therapeutic approach for ulcerative colitis. 2005;54:900–903.
- Croft NM.Phospholipid in UC: novel, safe and works—is it too good to be true Gastroenterology 20061301003–1004.discussion 1004–5.
- Stremmel W, Merle U, Zahn A, et al. Retarded release phosphatidylcholine benefits patients with chronic active ulcerative colitis. Gut. 2005;54:966–971.
- Stremmel W, Braun A, Hanemann A, et al. Delayed release phosphatidylcholine in chronic-active ulcerative colitis: a randomized, double-blinded, dose finding study. J Clin Gastroenterol. 2010;44:e101–e107.
- Stremmel W, Ehehalt R, Autschbach F, et al. Efficacy of retarded release phosphatidylcholine for treatment of chronic, steroid refractory ulcerative colitis. Ann Intern Med. 2007;147:603–610.
- Stange EF, Travis SP, Vermeire S, et al. European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis of the European Crohn's and Colitis Organisation (ECCO) J Crohns Colitis. 2008;2:1–23.
- Walmsley RS, Ayres RC, Pounder RE, et al. A simple clinical colitis activity index. Gut. 1998;43:29–32.
- Higgins PD, Leung J, Schwartz M, et al. The quantitative validation of non-endoscopic disease activity indices in ulcerative colitis. Aliment Pharmacol Ther. 2007;25:333–342.
- Higgins PD, Schwartz M, Mapili J, et al. Is endoscopy necessary for the measurement of disease activity in ulcerative colitis. Am J Gastroenterol. 2005;100:355–361.
- Jowett SL, Seal CJ, Phillips E, et al. Defining relapse of ulcerative colitis using a symptom-based activity index. Scand J Gastroenterol. 2003;38:164–171.
- Higgins PD, Schwartz M, Mapili J, et al. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis. Gut. 2005;54:782–788.
- Lane P. Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharm Stat. 2008;7:93–106.
Source: PubMed