Een enkelvoudig geblindeerd, gerandomiseerd onderzoek met meervoudig opklimmende doseringen (deel1) en een onderzoek met 7 periodes naar de biologische beschikbaarheid (deel 2) van LT-NS001 en NAPROXEN met gezonde vrijwilligers

Part 1: Single-blind, randomized, placebo-controlled, escalating multiple dose
(MD) study in 30 healthy male subjects (4 sequential groups, Groups 1-4) who
will receive either 500 mg b.i.d. NAPROSYN for 7 days with a final dose in the
morning of Day 8 (Group 1, 6 subjects); or 800, 1000 or 1200 mg b.i.d. LT NS001
suspension or placebo for 7 days with a final dose in the morning of Day 8
(Groups 2-4, 8 subjects per group; 6 subjects on active drug and 2 on placebo).

Part 2: open-label, single dose 7-treatment, crossover bioavailability (BA)
study in 3 healthy male subjects and 3 healthy postmenopausal female subjects
(one group of subjects, 7 periods, Group 5) involving administration of single
doses of 1000 mg LT-NS001 tablet formulation A, B and C, 500 mg NAPROSYN, 1000
mg of LT NS001 suspension, 500 mg EC Naprosyn, 500 mg NAPROSYN and 800 or 1200
mg LT NS001 tablet formulation A, B or C (best option from the first three
periods) in a fixed sequence.

Primary :
To determine the safety and tolerability of multiple doses of LT-NS001 given
twice daily as a suspension for 7.5 days in healthy male subjects

Secondary:
To determine the plasma pharmacokinetics of LT-NS001 suspension and naproxen
tablet (NAPROSYN®) when given twice daily for 7.5 days in healthy male subjects
To determine an optimal dose-level range for Phase 2 dosing, i.e. the dose at
which AUC and Cpre for b.i.d. LT-NS001 are comparable to 500 mg b.i.d. NAPROSYN
To compare the pharmacokinetics of three different tablet formulations of
LT-NS001 with LT-NS001 oral suspension and NAPROSYN tablet given as a single
oral dose to healthy subjects

Screening and follow-up:Clinical laboratory, height, weight, full physical
examination, vital signs (including temperature), and ECG; at eligibility
screening: medical and medication history, HBsAg, anti-HCV, anti HIV 1/2, and
drug screen; clinical chemistry and drug screen will be repeated upon admission
in Part 1; drug screen will be repeated upon each admission in Part 2.

Observation period :
Part 1: in clinic from 17 h prior to first dosing up to 24 h after drug
administration on Day 8, with ambulant visits 48 and 72 h after drug
administration on Day 8
Part 2: in clinic from 17 h prior to each dosing up to 24 h after drug
administration, with ambulant visits 48 and 72 h after each drug administration

Blood sampling :for LT-NS001 and naproxen pharmacokinetics
Part 1: Day 1: pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 8, 12 (pre-dose), 24
(pre-dose), 48 (predose), and 72 h
(pre-dose); Day 8: pre-dose, and 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 24, 48 and 72
h after drug administration
Part 2: pre-dose and 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 16, 24, 48 and 72 h
after drug administration

Safety assessments :
Part 1:adverse events and concomitant medication: throughout the study
vital signs: pre-dose and 1, 4, 8 h post-dose on Days 1 and 8
clinical laboratory: predose on Days 1 and 8
ECG: pre-dose, 0.5, 1 and 4 h post dose on Days 1 and 8
Part 2:adverse events and concomitant medication: throughout the study
vital signs: pre-dose and 1, 4, 8 and 24, 48 and 72 h post-dose
ECG: pre-dose, and 0.5, 1 and 4 h post dose

Bioanalysis :Analysis of LT-NS001 and naproxen in human plasma by HPLC by PRA
International.

Active substance :LT-NS001 Activity : prodrug of naproxen, non-selective COX inhibitor Indication : acute, sub-acute and chronic musculoskeletal inflammatory diseases Strength : see Dosage Forms Dosage form :Part 1, Groups 2-4; Part 2, Group 5: 800, 1000 or 1200 mg LT-NS001 / 50 mL, mixed with corn starch, in oral suspension Part 2, Group 5: 3 different tbd-mg LT-NS001 tablet formulations (A, B and C) Reference medication Name : NAPROSYN® Active substance :naproxen free acid Activity : non-selective COX inhibitor Indication : acute, sub-acute and chronic musculoskeletal inflammatory diseases Strength : 500 mg (free acid) Dosage form :Part 1, Group 1 and Part 2, Group 5: 500 mg NAPROSYN EU equivalent dosage form Reference medication Name : NAPROSYN® EC Active substance :naproxen free acid Activity : non-selective COX inhibitor Indication : acute, sub-acute and chronic musculoskeletal inflammatory diseases Strength : 500 mg (free acid) Dosage form : Part 2, Group 5: 500 mg NAPROSYN EC Placebo Oral suspension visually matching LT-NS001 oral suspension

LT-NS001 was previously administered to 47 healthy male volunteers at doses,
ranging from 30 to 600 mg per day. In this earlier study, a number of Adverse
Events (AEs; adverse side effects) were noted among subjects treated with
either LT-NS001 or an inactive placebo., In the single rising dose part of the
study, there was no relationship observed between dose level and number AEs or
number of subjects reporting AEs.
All AEs were of mild intensity. In the multiple risng dose part of the study,
AEs increased slightly with increasing doses All AEs were of mild intensity
except for elevated liver enzymes, which were of moderate intensity and were
reported by 3 subjects. One subject reported pain of moderate intensity at a
venipuncture site pain. Overall, the most frequently reported AEs were upper
abdominal discomfort and distension, abnormal liver function tests and change
in urinary frequency. These most frequently reported AEs were mainly reported
by subjects of the multiple dose group. There were no deaths or serious AEs.
Except for elevated liver function test values reported by subjects receiving
multiple doses of LT-NS001, no clinically relevant abnormalities in laboratory
measurements were observed. None of the increases in liver function tests
exceeded 3-times the upper limit of the normal range for the test. All of the
increases in liver function tests resolved spontaneously before or after
cessation of the study medication. According to the package inserts for
marketed forms of NAPROSYN, as many as 15% of subjects taking this drug report
mild increases in liver function tests similar in magnitude to those observed
in the prior study of LT-NS001
The doses of LT-NS001 to evaluate in this study are not anticipated to cause
any serious adverse effects. However, there is a possibility that any of the
above-mentioned side effects or other adverse effects may occur.