Randomized, double-blind, double-dummy, placebo-controlled, Phase III clinical trial on the efficacy and safety of a 12-weeks add-on treatment with LT-02 (gastro-resistant phosphatidylcholine granules) vs. placebo in patients with ulcerative colitis refractory to standard treatment with mesalamine

A disturbed mucosal barrier is thought to be an initiating factor of UC,
enabling attacks from
commensal colonic bacteria that lead to mucosal inflammation.62 In healthy
subjects,
intestinal mucosal cells are protected against colonic bacteria and other
injurious contents of
the gastrointestinal lumen by a surface barrier which consists in part of a
continuous,
hydrophobic and adherent mucus layer.4 This mucus consists of a hydrated
polymeric gel with
a thickness of 50-500 µm,42,66 with < 10% proteins, carbohydrates and lipids.2
Phospholipids
were found to form a continuous layer at the luminal side of the mucus gel,
within the mucus
as liposome-like aggregates and as a monolayer at the surface of the mucosal
cells.4,34 They
are largely responsible for establishing the hydrophobic surface and play a key
role in the
barrier properties of the underlying tissue.42
Phosphatidylcholine is considered the predominant phospholipid species present
in the distal
intestinal mucus.5,7,10,12 By in vitro and in vivo experiments in mice and rats
it was
demonstrated that PC is actively secreted into the ileum. This secretion is
stimulated by bile
salts. The absorption of bile salts attaches PC to the mucosal wall. PC is then
moved
continuously by colonic activity from cecum to rectum. Therefore, the rectum is
considered as
the last area supplied with PC.11
A significantly lower concentration of PC in the ileal and colonic mucus from
patients with
UC compared to patients with Crohn*s disease and to controls was shown by Braun
et al.6
The observed deficiency of intestinal mucus PC in UC patients and the cell
protective and
anti-inflammatory properties of PC led to the assumption of a potential
clinical activity for
exogenous PC in UC. It was hypothesized that daily oral administration and
subsequent
gastro-resistant release of PC into the ileum can restore the low intestinal PC
concentration
and the protective mucus barrier function and consecutively reduce ulceration
and
inflammation due to commensal bacteria, toxins and foreign bodies. The natural
flow of PC
from the ileum to the rectum would be restored. To test this hypothesis, a new
therapeutic
strategy with PC supplementation to the colonic mucus was developed. A PC
preparation
derived from soy lecithin was formulated into granules of microcrystalline
cellulose matrix
with gastric acid resistant coating for delayed-release in the intestine. Based
on the gastroresistant
formulation, PC is protected from degradation by gastric and pancreatic fluids,
thereby potentially reducing the systemic uptake and increasing the local
availability in the
intestine.
First results with the to-be-marketed formulation LT-02, containing >= 94% PC as
active
ingredient in gastro-resistant granules, in the Phase II study LT-02-UC-01
confirmed the
medical hypothesis and benefit of treating the PC deficiency in patients with
UC. The current
Phase III study will be performed to further investigate the clinical efficacy
and safety of
LT-02 in the treatment of UC.

Primary:
• To prove the superiority of a 12-week add-on treatment with 3.2 g/day
gastro-resistant phosphatidylcholine granules (LT-02) in at least one of two
different dosing regimens versus LT-02 placebo for the induction of
remission in patients with ulcerative colitis (UC) refractory to standard
treatment with mesalamine.

Secondary:
• To study safety and tolerability in the form of adverse events (AEs) and
laboratory parameters,
• To compare two different dosing regimens of LT-02,
• To assess patients* quality of life.

Open-label sub-study:
• To induce remission of UC in patients not in remission at week 12 or in
patients who were prematurely withdrawn >= 8 weeks after randomization due
to lack of efficacy without showing clinical response.

This is a double-blind, double-dummy, randomized, placebo-controlled,
multicenter,
comparative, 12-week, confirmative Phase III clinical trial. The trial will
be conducted with three arms in the form of a parallel group comparison and
will serve to compare oral daily add-on treatment with 3.2 g
phosphatidylcholine (LT-02, gastro-resistant granules) in two different dosing
regimens versus placebo (LT-02 Placebo, gastro-resistant granules) for the
induction of remission in UC patients non-responsive to standard mesalamine
treatment. The trial will be performed according to a 2-stage group-sequential
adaptive design with potential sample size adjustment and treatment arm
selection after the planned interim analysis.
Screening phase:
During 7 up to 10 days prior to baseline, the non-response to a standard
treatment with >= 2.4 g/d mesalamine (or therapeutic equivalent) will be
confirmed. Patients will complete a daily diary during the screening period
while continuing the current oral (and if applicable also rectal) treatment with
mesalamine at a stable dose of >= 2.4 g/day (or therapeutic equivalent).
Double-blind, double-dummy, randomized (1:1:1) treatment phase:
Eligible patients will be randomized to receive a 12-week, double-blind,
doubledummy
add-on treatment to stable dosage of concomitant oral mesalamine
>= 2.4 g/d (or therapeutic equivalent) with:
Group A: 0.8 g PC in LT-02 four-times daily (QID) with additional placebo
sachets taken with morning and evening dose
Group B: 1.6 g PC in LT-02 twice daily (BID) with placebo sachets taken
during lunchtime and afternoon doses
Group C: LT-02 placebo QID
Randomization will be stratified by patient*s 5-ASA pre-treatment, i.e.,
*>= 2.4 g/d mesalamine (or therapeutic equivalent) for >= 6 weeks prior to
baseline?* (*yes* vs *no*).
Treatment schedule:
Study
Arm
Morning
(2 sachets)
Lunchtime
(1 sachet)
Afternoon
(1 sachet)
Evening
(2 sachets)
Group A 0.8 g PC Placebo 0.8 g PC 0.8 g PC 0.8 g PC Placebo
Group B 0.8 g PC 0.8 g PC Placebo Placebo 0.8 g PC 0.8 g PC
Group C Placebo Placebo Placebo Placebo Placebo Placebo
Note: One sachet LT-02 contains gastro-resistant granules with 0.8 g PC, one
sachet LT-02 Placebo contains
PC-free gastro-resistant granules
The dose, formulation, and intake regimen of oral mesalamine used within the
6 weeks prior to baseline has to be kept stable throughout the complete
treatment phase.
Follow-up phase:
All patients completing the trial and coming into remission will have the option
to enter a double-blind, placebo-controlled maintenance of remission trial for
treatment with LT-02 or placebo for up to 48-weeks (trial code: PCG-4/UCR;
EudraCT No.: 2013-001205-84). All other patients completing the trial and who
are not in remission or who were prematurely withdrawn >= 8 weeks after
randomization due to lack of efficacy and with no clinical improvement in
modified Disease Activity Index (mDAI) defined as a total decrease of > 1 point
in the sum of the subscores 1, 2, and 4 compared to baseline in mDAI at End of
treatment (EOT)/Withdrawal visit, will have the option to enter an open-label
induction of remission sub-study for treatment with LT-02 (PCG-5/OLT).
Otherwise, patients will be followed-up 4 weeks after EOT/Withdrawal visit.
Open-label (OL) sub-study:
During the OL sub-study (PCG-5/OLT), patients will receive a 12-week, openlabel,
uncontrolled treatment with 1.6 g PC in LT-02 BID as add-on treatment to
a stable dose of >= 2.4 g/d mesalamine (or therapeutic equivalent).

LT-02 (gastro-resistant granules containing 0.8 g phosphatidylcholine [PC] per
sachet) as add-on therapy to a standard dose of >= 2.4 g/d mesalamine (or
therapeutic equivalent)

During the study, the patients have to undergo the following procedures:
pregnancy test (if applicable), physical exam (4x), max 3 endospies including
biopsies, questionnaires (every visit), diary (every visit), drawing of blood
(all visits), stool samples (every visit) and answering question eg. medical
history, adverse events, use of co-medication (all visits).