Primary:* To prove the superiority of a 48-weeks treatment with 3.2 g/day delayedreleasephosphatidylcholine (LT-02) versus placebo for the maintenance ofremission in patients with ulcerative colitis (UC)Secondary:* To study safety and tolerability…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Percentage of patients who are relapse-free and are not a treatment failure
after 48 weeks of treatment. Relapse is defined as a rectal bleeding score of
*1 and a mucosal appearance score of *2 as described in the mDAI score.
Treatment failure is defined as premature withdrawal, experiencing UC flare,
or need for other UC treatment
Secondary outcome
Secondary efficacy variables for the DB phase:
* Mean change from baseline in the total mDAI at V6/EOT.
* Percentage of patients maintaining remission defined as a mDAI score *2
with no subscore >1 at V6/EOT visit,
* Number and percentage of patients in each level of change from baseline in
the mDAI stool frequency subscore at V2-V5, and V6/EOT,
* Number and percentage of patients in each level of change from baseline in
the mDAI rectal bleeding subscore at V2-V5, and V6/EOT,
* Number and percentage of patients in each level of change from baseline in
the mDAI Physician*s rating of disease subscore at V2-V5, and V6/EOT,
* Time to clinical relapse or discontinuation,
* Number and percentage of patients in each level of change from baseline in
the mDAI mucosal appearance subscore at V6/EOT,
Total mDAI and change in mDAI clinical subscores in the course of the DB
phase,
* Percentage of patients with endoscopic remission defined as mDAI mucosal
appearance score of *1,
* Total and change in Clinical Activity Index acc. to Rachmilewitz (CAI) and
its subscores in the course of the DB phase,
* Number and percentage of patients in each level of change from baseline in
the CAI in the course of the DB phase,
* Percentage of patients in clinical remission (CAI *4, with stool frequency and
rectal bleeding subscores of *0*) in the course of the DB phase,
* Endoscopic Index (EI) and its change in the course of the DB phase,
* Percentage of patients in endoscopic remission (EI *3),
* Percentage of patients with endoscopic improvement (decrease *1 point in
EI), and endoscopic deterioration (increase *1 point in EI),
* Number and percentage of patients in each level of change from baseline in
the EI in the course of the DB phase,
* Histological Index (HI) and its change in the course of the DB phase,
* Percentage of patients in the categories histologic remission (HI * 1), mild
(HI=2), moderate (HI=3), and severe (HI=4) activity at EOT/withdrawal visit,
* Percentage of patients with a histologic deterioration,
* Number and percentage of patients in each level of change from baseline in
the HI in the course of the DB phase,
* Time in study,
* Time to clinical relapse,
* Number of stools per week,
* Number of bloody stools per week,
* Number of days with urgency per week,
* Patient*s quality of life,
* Work Productivity and Activity Impairment (WPAI),
* Number of days hospitalized,
* Patient*s Global Satisfaction.
Further secondary efficacy variables for the OLRI/OLE phase:
* Percentage of patients previously withdrawn from the DB-phase due to lack
of efficacy and being back in clinical remission at Week 12 (LOCF) of the
OLRI phase,
* Number and percentage of patients in each level of change from baseline
(OLRI V1/OLE V1) in the mDAI subscores (1, 2, and 4) in the course of the
OLRI/OLE phase,
* CAI and its change from baseline (OLRI V1/OLE V1) in the course of the
OLRI/OLE phase,
* Percentage of patients in clinical remission defined as CAI *4 with *0* for
*stools* and *blood in stools* subscores,
* Time in study,
* Time to clinical relapse or discontinuation,
* Patient*s quality of life,
* WPAI,
* Number of days hospitalized,
* Patient*s Global Satisfaction.
Further secondary efficacy variables for the OLI phase:
* Percentage of patients in deep remission (defined as mDAI Score * 1 with a
score of *0* points for rectal bleeding and stool frequency, and * 1 point
(LOCF),
* Percentage of patients in remission (defined as mDAI Score * 2 with no score
> 1) at week 12 (LOCF),
* Total mDAI and its subscores and their changes in the course of the OLI
phase,
* Total Clinical Activity Index acc. to Rachmilewitz (CAI) and its subscores
and their changes in the course of the OLI phase,
* Percentage of patients with clinical remission (defined as CAI * 4, with stool
frequency and rectal bleeding subscores of *0*) in the course of the OLI
phase,
* Percentage of patients with clinical improvement (CAI) defined as a decrease
of * 3 points compared to baseline in the course of the OLI phase,
* Times to first resolution of clinical symptoms,
* Number of stools per week,
* Number of bloody stools per week,
* Number of days with urgency per week,
* Percentage of patients with mucosal healing (defined as a mDAI mucosal
appearance score of ** 1* at week 12 (LOCF) associated with a decrease of
* 1 point compared to baseline [OLI V1]),
* Percentage of patients with improved mDAI mucosal appearance score at
week 12 (LOCF),
* Endoscopic Index acc. to Rachmilewitz (EI) compared to baseline at week 12
(LOCF),
* HI in the course of the OLI phase,
* Percentage of patients with histologic remission (HI * 1) at week 12 (LOCF),
* Percentage of patients with improved HI at week 12 (LOCF),
* Physician's Global Assessment (PGA),
* Patient*s quality of life,
* Work Productivity and Activity Impairment (WPAI),
* Patient*s Global Satisfaction
Background summary
A disturbed mucosal barrier is thought to be an initiating factor of UC,
enabling attacks from
commensal colonic bacteria that lead to mucosal inflammation. 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. This mucus consists of a hydrated
polymeric gel with
a thickness of 50-500 *m, with < 10% proteins, carbohydrates and lipids.
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. They
are largely responsible for establishing the hydrophobic surface and play a key
role in the
barrier properties of the underlying tissue.
Study objective
Primary:
* To prove the superiority of a 48-weeks treatment with 3.2 g/day delayedrelease
phosphatidylcholine (LT-02) versus placebo for the maintenance of
remission in patients with ulcerative colitis (UC)
Secondary:
* To study safety and tolerability in the form of adverse events (AEs) and
laboratory parameters,
* To assess patients* quality of life.
Open-label sub-study:
* To re-induce and/or maintain remission of UC in patients who prematurely
dropped-out due to lack of efficacy or who completed the double-blind phase
still being in remission.
Study design
This is a double-blind, double-dummy, randomized, placebo- and active
controlled, multi-center, comparative, 48-week, confirmative Phase III clinical
trial. The trial will be conducted with three arms in the form of a parallel
group
comparison and will primarily serve to confirmatorily compare oral daily
treatment with 3.2 g delayed-release phosphatidylcholine (LT-02) granules
versus placebo for the maintenance of remission in patients with UC. The third
arm, i.e. mesalamine, will serve as an internal control for assay sensitivity
and
will only be compared to placebo and LT-02 in an exploratory manner. This trial
has an optional interim analysis after approximately the first 200 consecutive
enrolled patients (full analysis set [FAS]) have reached their primary endpoint,
i.e., have either reached week 48 or discontinued early. The decision to perform
the interim analysis will be solely based on recruitment. The study will be
performed according to a 2-stage group-sequential adaptive design with possible
sample size adjustment and treatment arm selection.
At the beginning of study enrolment, only patients being brought into remission
during the double-blind (DB) or open-label (OL) phase of the trial PCG-2/UCA
(EudraCT No. 2012-003702; acronym: PROTECT-1) will be allowed to be
enrolled. Once enrolment of trial PCG-2/UCA is completed, the study will allow
the enrollment of patients being brought into remission by OL-induction (OLI)
treatment with LT-02. These patients will be recruited according to the major
in-and exclusion criteria of study PCG-2/UCA,
thus it will be ensured that the patient population in principle, i.e.,
patients not adequately responding to a
sufficient dose of mesalamine, will be the same.
Screening phase prior to open-label induction (OLI) (only available, if
recruitment of study PCG-2 has been completed):
During 7 up to 10 days prior to OLI V1, 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).
OLI treatment phase (only available, if recruitment of study PCG-2 has
been completed):
12-week OLI add-on treatment with 1.6 g LT-02 BID to underlying oral
mesalamine treatment.
Screening phase prior to maintenance phase (for patients rolled-over from
study PCG-2 or OLI phase):
Up to 10 days prior to baseline.
Double-blind (DB), double-dummy, randomized treatment for maintenance
of remission:
Patients in remission of UC at the EOT visit of study PCG-2/UCA, or later at
OLI V4, will be offered to continue in this maintenance trial. Results from the
EOT visit of the PCG-2/UCA study or OLI V4 will be regarded as baseline
values of this maintenance trial.
Patients will be randomized in a 2:1:1 ratio to receive a 48-week, double-blind,
double-dummy treatment with either:
Group A: 1.6 g LT-02 twice daily (BID) AND mesalamine placebo granules
three-times daily (TID),
Group B: LT-02 placebo BID AND mesalamine placebo granules TID, or
Group C: LT-02 placebo BID AND 500 mg mesalamine granules TID.
Randomization will be stratified by patient*s deep remission criterion, i.e.,
*modified Disease Activity Index (mDAI) score *1 with *0* points for rectal
bleeding and stool frequency at baseline* (*yes* vs *no*).
Open-label (OL) sub-study (PCG-5/OLT):
Open-label re-induction (OLRI) phase: Patients prematurely discontinued from
the DB-phase due to lack of efficacy will be offered an OL re-induction
treatment with 1.6 g LT-02 BID for up to 12 weeks.
Open-label extension (OLE) phase: Patients completing the DB-phase without
experiencing a relapse and those patients who have achieved a clinical response
in the OLRI phase can receive OLE-treatment with LT-02 BID for up to
48 weeks (counting from the start of OL-treatment).
Follow-up phase:
Patients will be followed-up 4 weeks after their last treatment visit in the DB
or
OL (OLI, OLRI, or OLE, respectively) phase, if not continuing in the study.
Intervention
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)
Study burden and risks
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).
leinenweberstr 5
Freiburg 79108
DE
leinenweberstr 5
Freiburg 79108
DE
Listed location countries
Age
Inclusion criteria
Inclusion criteria for DB maintenance phase:
1. Signed informed consent,
2. Men or women, 18 to 70 years of age,
3. Historically confirmed diagnosis of UC by endoscopy and histology,
4. Patients being in remission at baseline,
5. Negative pregnancy test in females of childbearing potential at baseline visit,
6. Women of child-bearing potential have to apply during the entire duration of the trial a highly effective method of birth control, which is defined as those which result in a low failure rate (i.e., less than 1% per year) when used constantly and correctly.
Exclusion criteria
Exclusion criteria for DB maintenance phase:
1. Crohn's disease, indeterminate colitis, ischemic colitis, radiation colitis, microscopic colitis (i.e., collagenous colitis and lymphocytic colitis), diverticular disease associated colitis,
2. Toxic megacolon or fulminant colitis,
3. Colon resection,
4. Malabsorption syndromes,
5. Celiac disease,
6. Bleeding hemorrhoids,
7. Other inflammatory or bleeding disorders of the colon and intestine, or diseases that may cause diarrhea or gastrointestinal bleeding,
8. History or presence of ischemic heart disease, myocardial infarction, peripheral arterial disease, ischemic stroke, or transient ischemic attack,
9. Any severe concomitant renal, endocrine, or psychiatric disorder, which in the opinion of the investigator might have an influence on the patient*s compliance or the interpretation of the results,
10. Any relevant known systemic disease (e.g., AIDS, active tuberculosis),
11. Severe co-morbidity substantially reducing life expectancy,
12. History of cancer in the last five years,
13. Abnormal hepatic function at the screening visit), liver cirrhosis,
14. Abnormal renal function at the screening visit,
15. Either HbA1c *6.5% (*48 mmol/mol) at baseline visit, OR HbA1c >5.6% (38 mmol/mol) AND fasting blood glucose *100 mg/dl (*5.6 mmol/l) at baseline visit,
16. Patients with known hypersensitivity to soy,
17. Known intolerance/hypersensitivity to Investigational Medicinal Product (IMP: LT-02 or mesalamine),
18. Treatment with steroids (oral, inhalative, or intravenous [IV]), cyclosporine or tacrolimus within last 4 weeks prior to randomization,
19. Treatment with methotrexate within last 6 weeks prior to randomization,
20. Treatment with TNF-alpha-antagonists, azathioprine, 6-mercaptopurine, or anti-integrin therapy within last 8 weeks prior to randomization,
21. Treatment with rectal mesalamine or corticosteroid formulations within last 2 weeks prior to randomization,
22. Treatment with other investigational drug within last 12 weeks prior to randomization except LT-02,
23. Concomitant treatment with coumarins (e.g., phenprocoumon),
24. Unwillingness to undergo endoscopy with biopsy sampling at end of treatment (EOT)/withdrawal visit of this study,
25. Clinical suspicion of addiction to alcohol or drugs,
26. Existing or intended pregnancy or breast-feeding,
27. Subjects deemed by the investigator to be unlikely to comply with the protocol requirements, instructions and study-related restrictions; e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study,
28. Participation in another clinical trial within the last 30 days prior to baseline visit (except for the Phase III study PCG-2/UCA), simultaneous participation in another clinical trial, or previous participation in this trial and having received IMP.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001205-84-NL |
| CCMO | NL52721.091.15 |