Randomized, double-blind, placebo-controlled study of the tolerability and pharmacokinetics of ascending single (TDU6964) and 14-day repeated (TDR6966) oral doses of SAR501788 and pilot food variability evaluation (FED6965) in healthy young male subjects - Tolerability and pharmacokinetics of 14-day repeated oral doses of SAR501788 in healthy elderly male and female subjects (TDR6967)

The drug to be given is a new, investigational compound that may eventually be
used for the treatment of diabetic and anticancer drug induced-neuropathies.
SAR501788 is a novel drug that selectively binds to a specific receptor in
nerves; peripheral benzodiazepine receptor (PBR). In laboratory and animal
studies SAR501788 has shown to help slow down the development of nerve damage
caused by diabetes (diabetic peripheral neuropathy) and to protect certain
nerves from damage by some particular anti-cancer drugs. SAR501788 therefore,
is expected to may help treating neuropathies (damage to nerves) caused by
diabetes or anti-cancer drugs.
This study consists of 4 parts. Part 1 is a single rising dose part, in Part 2
the effect of food in combination with the drug will be investigated. In Part 3
and 4 the effects of the drug when taken in 14-day repeated ascending doses
will be investigated. Part 3 is in younger men and Part 4 in elderly men and
women.

to assess the tolerability and safety after single oral ascending doses of
SAR501788 in healthy young male subjects (Part 1)
to assess the tolerability and safety after repeated oral ascending doses of
SAR501788 in healthy young male subjects (Part 3)
to assess the pharmacokinetic parameters after single (Part 1) and repeated
oral ascending doses of SAR501788 (Part 3) in healthy young male subjects
to assess the tolerability and safety after repeated oral ascending doses of
SAR501788 in healthy elderly male and female subjects (Part 4)
to asses the pharmacokinetic (PK) parameters after repeated oral ascending
doses of SAR501788 in healthy elderly male and female subjects (Part 4)
to obtain preliminary information on the effect of a high fat meal on the
pharmacokinetics of SAR501788 in healthy young male subjects (Part 2)
to provide preliminary information regarding the potential renal excretion of
the compound
(Parts 1, 3 and 4)
to evaluate the potential of SAR501788 1) to induce CYP3A4, 2) to interact with
the Renin Angiotensin Aldosterone System, 3) to alter steroid hormone levels
(Parts 3 and 4)

Part 1 (TDU6964)
Design :
a double-blind, randomized, placebo-controlled, sequential single ascending
dose part with seven cohorts of eight subjects each receiving a single oral
dose of SAR501788 or placebo (six verum and two placebo)

Procedures and assessments
Screening and follow-up :
clinical laboratory (including INR and aPTT), physical examination, vital signs
(supine and standing), oral body temperature, body weight, 12-lead ECG; at
eligibility screening: height, medical history, alcohol and drug screen, HBsAg,
anti HCV, anti-HIV 1/2; physical examination, body weight, alcohol and drug
screen, vital signs (supine and standing), oral body temperature, 12-lead ECG
and clinical laboratory (including INR and aPTT) to be repeated upon admission

Observation period :
one period in clinic from -24 h up to 48 h after drug administration

Blood sampling :
for pharmacokinetics of SAR501788: 0.5 h pre-dose and 0.5, 1, 2, 3, 4, 6, 8,
10, 12, 16, 24, 36 and 48 h post-dose
for genotyping and archival blood sampling: 0.5 h pre-dose

Urine sampling :
for pharmacokinetics of SAR501788: pre-dose and intervals 0-24 h and 24-48 h
post-dose

Safety assessments :
adverse events: throughout the study; physical examination: 48 h post-dose;
vital signs (supine and standing): 0.5 h pre-dose and 1, 2, 3, 4, 6, 8, 12, 24,
36 and 48 h post-dose; oral body temperature: 0.5 h pre-dose and 24 h
post-dose; 12-lead ECG: 0.5 h pre-dose (in triplicate) and 1, 2, 3, 4, 6, 8,
12, 24, 36 and 48 h post-dose; clinical laboratory (including INR and aPTT): 24
and 48 h post-dose; telemetry: from 24 h pre-dose until 12 h post-dose

Bioanalysis :
analysis of plasma and urine SAR501788 samples using validated methods by
Sponsor

Part 2 (FED6965)
Design :
an open label, randomized, two-way crossover part in eight healthy male
subjects receiving a single oral dose of SAR501788 in the fed state in one
period and a single oral dose of SAR501788 in the fasted state in the other
period; a washout of seven days between dosing

Procedures and assessments
Screening and follow-up :
clinical laboratory (including INR and aPTT), physical examination, vital signs
(supine and standing), oral body temperature, body weight, 12-lead ECG; at
eligibility screening: height, medical history, alcohol and drug screen, HBsAg,
anti HCV, anti-HIV 1/2; physical examination, body weight, alcohol and drug
screen, vital signs (supine and standing), oral body temperature, 12-lead ECG
and clinical laboratory (including INR and aPTT) to be repeated upon each
admission

Observation period :
2 periods, each period in clinic from -24 h up to 48 h after drug administration

Blood sampling :
for pharmacokinetics of SAR501788: 0.5 h pre-dose and 0.5, 1, 2, 3, 4, 6, 8,
10, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 h post-dose
for genotyping and archival blood sampling: 0.5 h pre-dose (period 1 only)

Safety assessments :
adverse events: throughout the study; physical examination: 24 and 48 h
post-dose; vital signs (supine and standing): 0.5 h pre-dose and 1, 2, 3, 4, 6,
8, 12, 24, 36 and 48 h post-dose; oral body temperature: 48 h post-dose;
12-lead ECG: 0.5 h pre-dose (in triplicate) and 1, 2, 3, 4, 6, 8, 12, 24, 36
and 48 h post-dose; clinical laboratory: 24 and 48 h post-dose; telemetry: from
24 h pre-dose until 12 h post-dose

Bioanalysis :
analysis of plasma and urine SAR501788 samples using validated methods by
Sponsor


Parts 3 (TDR6966) and 4 (TDR6967)
Design :

Part 3: a double-blind, randomized, placebo-controlled, sequential fourteen day
repeated ascending dose part with three cohorts of twelve healthy male subjects
each receiving oral doses of SAR501788 or placebo (nine verum and three
placebo) for fourteen days

Part 4: a double-blind, randomized, placebo-controlled, sequential fourteen day
repeated ascending dose part with two cohorts of twelve healthy elderly male
and female subjects each (at least five of each gender in each dose group)
receiving oral doses of SAR501788 or placebo (nine verum and three placebo) for
fourteen days
Procedures and assessments

Screening and follow-up :
clinical laboratory (including INR and aPTT), physical examination, vital
signs, oral body temperature, body weight, 12-lead ECG; at eligibility
screening: height, medical history, alcohol and drug screen, HBsAg, anti HCV,
anti-HIV 1/2; physical examination, body weight, alcohol and drug screen, vital
signs (supine and standing), oral body temperature, 12-lead ECG and clinical
laboratory (including INR and aPTT) to be repeated upon admission

Observation period :one period in clinic from -41 h before drug administration
on Day 1 up to 48 h after drug administration on Day 14

Blood sampling :
for pharmacokinetics of SAR501788: 0.5 h pre-dose and 0.5, 1, 2, 3, 4, 6, 8,
10, 12 and 16 h post-dose on Day 1, pre-dose on Days 2, 3, 4, 7, 8, 11 and 13
and pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120,
144 and 168 h post-dose on Day 14
for pharmacodynamics of plasma pregnenolone, pregnenolone sulphate,
testosterone, DHEA, DHEA sulphate and serum prolactin and plasma renin, AcSDKP
and aldosterone: 22, 20 and 16 h pre-dose and pre-dose and 2, 4 and 8 h
post-dose on Day 1, pre-dose on Day 2 and pre-dose and 2, 4, 8 and 24 h
post-dose on Day 14

for genotyping and archival blood sampling: pre-dose on Day 1

Urine sampling :
for pharmacokinetics of SAR501788: pre-dose on Day 1 and pre-dose until 24 h
post-dose on Day 14
for 6-beta-OH cortisol and cortisol: from 24 h pre-dose until pre-dose on Day 1
and from pre-dose until 24 h post-dose on Day 14

Safety assessments :
adverse events: throughout the study; physical examination: pre-dose on Days 2
and 7 and 0.5 h pre-dose and 48 h post-dose on Day 14; vital signs: pre-dose
and 1, 2, 3, 4, 6, 8 and 12 h post-dose on Day 1, pre-dose and 2 h post-dose on
Days 2-13, 0.5 h pre-dose and 1, 2, 3, 4, 6, 8, 12, 24 and 48 h post-dose on
Day 14; oral body temperature: 0.5 h pre-dose and 4 and 8 h post-dose on Day 1,
pre-dose on Days 2 and 7 and 0.5 h pre-dose and 4, 8 and 48 h post-dose on Day
14; 12-lead ECG: pre-dose (in triplicate) and 1, 2, 3, 4, 6, 8 and 12 h
post-dose on Day 1, pre-dose and 2 h post-dose on Day 2, pre-dose on Days 4, 7,
11 and 0.5 h pre-dose and 1, 2, 3, 4, 6, 8, 12, 24 and 48 h post-dose on Day 14
(all time points on Days 14 and 15 in triplicate); clinical laboratory:
pre-dose on Days 2, 4, 7 and 11 and 0.5 h pre-dose and 24 h post-dose on Day
14; telemetry: from 24 h pre-dose until 12 h post-dose on Day 1 and from
pre-dose until 12 h post-dose on Day 14

Bioanalysis :
analysis of plasma and urine SAR501788 samples using validated methods by
Sponsor
analysis of urine 6-beta-OH cortisol and cortisol using a validated method by
Sponsor
analysis of plasma pregnenolone, pregnenolone sulphate, DHEA, DHEA sulphate and
plasma renin, AcSDKP and aldosterone using validated methods by Sponsor
analysis of serum prolactin and plasma testosterone using clinical laboratory
methods by Sponsor

Procedures: pain, light bleeding, haematoma.

As SAR501788 will be administered to man for the first time in this study,
adverse effects in man have not been reported up to now. In animal studies, in
which SAR501788 was administered daily in (very) high doses,no target organ
toxicity was induced by SAR501788 following repeated administrations at doses
of up to 2000mg/kg/day in rat, monkey or dog for up to 1 month. Apart from
white material in the feces (consistent with unabsorbed compound) in all
species, the only other effect seen was slight transient weight loss in monkeys
during the first week of the 1 month study.