First multicenter study of modified release phosphatidylcholine "LT-02" in ulcerative colitis: a randomized, placebo-controlled trial in mesalazine-refractory courses

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 http://clinicaltrials.gov/show/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.

Figure 1

Study flowchart. Inclusion criteria were as follows: proven mesalazine-refractory ulcerative colitis (European consensus definition (16) with an inadequate response to mesalazine for 6 weeks at a dose of ≥3 g/day for over 4 weeks or documented intolerance to mesalazine (a documented intolerance required previous doctors' letters or medical notes that stated that an adverse event possibly related to mesalazine led to a discontinuation of its therapy); active disease with blood in stool for at least 6 weeks; SCCAI ≥5 and SCCAI subscore for “blood in stool” ≥2 at baseline visit (V2); comedication was allowed if on a stable dose for 4 weeks (e.g., 5-ASA, systemic acting steroids (if taken for ≥8 weeks before the start of the study), azathioprine (2–2.5 mg/kg), 6-mercaptopurine (1–1.5 mg/kg), both if taken for ≥3 months); and a negative pregnancy test at V1 and V2 plus the use of adequate contraception, if applicable. Exclusion criteria were as follows: toxic megacolon or fulminant courses; therapy with cyclosporine, tacrolimus, methotrexate, or TNF-α-antagonists within 3 months before study entry; current treatment with opiates or loperamide; current antibiotic treatment; rectal applications of aminosalicylates, steroids, or budesonide; oral application of topically acting steroids; ulcerative proctitis with a disease extent <10 cm; inflammatory or bleeding disorders of the gastrointestinal tract other than UC, or diseases that may cause diarrhea or gastrointestinal bleeding; condition after surgery of the colon; any other uncontrolled systemic diseases (e.g., cardiac, renal, pulmonary, hepatic) or severe chronic diseases (e.g., malignancies, HIV infection); and pregnant or nursing women. 5-ASA, 5-aminosalicylic acid; AE, adverse event; Discont. Intervent., discontinued intervention; INR, international normalized ratio; SCCAI, Simple Clinical Colitis Activity Index; TNF-α, tumor necrosis factor-α UC, ulcerative colitis.

Figure 2

Primary end-point analysis.The comparison between placebo and the highest dose group revealed an estimate of −1.56 and a two-sided P value of 0.03 with a 95% confidence interval of −2.96 to −0.16. SCCAI, Simple Clinical Colitis Activity Index.

Figure 3

Time to first symptom resolution: all active LT-02 groups pooled vs. placebo. LT-02 patients reached the end point of first symptom resolution more than 2 weeks earlier than placebo (P=0.02, preplanned, two-sided log-rank test). In total, almost twice as many LT-02 patients reached complete symptom resolution compared with placebo.

Figure A1

The course of the trial. Patients were screened for inclusion and exclusion criteria (see legend of Figure 1) at V1. If patients still fulfilled the study criteria at baseline (V2, 1 week after V1), they were then randomized into the study and received their first study medication at the study center after baseline investigations (interview, physical examination, sigmoidoscopy/colonoscopy, lab tests). At the interim visits 2 and 6 weeks after baseline (V3 and V4w), the Simple Clinical Colitis Activity Index (SCCAI), possible disease exacerbations, changes in medication, and adverse events (AEs) were assessed. The treatment period ended 12 weeks after baseline at V5 that involved the final study assessment (interview, physical examination, lab test, sigmoidoscopy). Responders of all study arms entered a 8-week follow-up period without study medication; those patients were asked to continue their comedication as taken before, unless they relapsed.

Figure A2

Complete remission rates by dose groups. The rates of complete remission were 15.0% under placebo compared with 31.4% in the 3.2 g LT-02 group (P=0.089); the other rates were 27.5% (0.8 g LT-02) and 22.0% (1.6 g LT-02). Complete remission was defined by a mean Simple Clinical Colitis Activity Index (SCCAI) of <3 without blood in stool. When adding a normal stool frequency to this definition, the remission rate then increased by factor 2.3, from 12.5% in the placebo group to 28.6% in the highest LT-02 dose group (P=0.105). The blue columns show the rates for partial remission defined by an SCCAI <5.

Figure A3

Time to relapse (Simple Clinical Colitis Activity Index (SCCAI) ≥5) in the responder group after discontinuation of the study medication. A total of 69 patients who had a time to clinical relapse or information on censoring related to clinical relapse were included in the analysis. Patients treated with LT-02 relapsed later and less frequently than placebo patients (preplanned, two-sided log-rank test, P=0.016).