Efficacy and safety trial with S 44819 after recent ischemic cerebral Event
ID
Source
Brief title
RESTORE BRAIN
Condition
- Other condition
Synonym
Health condition
Cerebrovascular accidents
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study is to demonstrate the superiority of at lest
one of the two doses of S44819 versus placebo on functional recovery from
ischaemic stroke measured with the mRS after 90 days of treatment.
Secondary outcome
The secondary objectives are:
- to assess the efficacy of two doses of S44819 in stroke recovery using
neurological evaluations (NIHSS), activities of daily living test (BI) and
cognitive performance tests (Moca, TMT)
- to assess the safety and tolerability of S44819.
Background summary
Stroke is the leading cause of acquired handicap in adult live. Ischemic stroke
(cerebral infarction) accounts for more than 80% of stroke in industrialized
countries.
Currently available evidence based treatments act either in the acute phase of
ischemic stroke, or on primary and secondary prevention.
GABA is the main inhibitory transmitter in the human brain. It is known from
preclinical and clinical studies that an acute cerebral infarction is followed
by an increased activity of GABAergic neurons. In the acute phase of such an
event, this is thought to be a defense mechanism to prevent excitotoxicity by
protecting cerebral neurons threatened from impaired oxygen and energy supply.
However, in the post-acute phase after a cerebral infarction, this increased
GABAergic activity has a negative effect on neuroplasticity, and studies in
animals and in humans have shown that sustained increased activity of the
GABAergic system is associated with worse functional outcome.
S 44819 is a competitive antagonist of the GABAA-*5 receptor and has shown to
enhance cognitive and motor recovery in several preclinical stroke models.
Study objective
Efficacy and safety trial with S 44819 after recent ischemic cerebral Event
Study design
This study is a phase II, international, multi-centre, randomized,
placebo-controlled, double-blind study with a 90 days double-blind treatment
period followed by a 15 days period with no treatment.
The study is divided into a selection period, a double-blind treatment period
of 90 days and a follow-up period of 15 days.
Intervention
The study treatment period is divided into 3 arms: a first one receives placebo
wheras the second arm will be given 300 mg S44819 twice daily. The third arm
will be allocated to 150 mg S44819 twice daily.
Study burden and risks
7 study visits are planned in this study, and one phone contact with the
investigator.
For inclusion, an MRI is mandatory.
At 6 study visits, an ECG will be taken.
At selection, D30, D60, D90 and D105 bloodsamples are planned.
At D5 it is planned to take pharmacokinetics samples at 3 timepoints, whereas
this is planned at D30, D60 and D90 only once.
The patient can optionally consent to give a bloodsample for pharmacogenomics
analysis.
At selection, women of childbearing potential will be tested for pregnancy with
a urinary or blood pregnancy test.
At D30, D60, D90 and D105, the patient will be questioned for quality of live
using a visual analogue scale. At these visits, a CSSRS will also be
performed.
The effect of the study medication will be evaluated by the investigator by
means of the mRS, and the NIHSS at D0 D5 D30, D60 and D90 and by the Barthell
Index at D30, D60 and D90 .
At D30 and D90 the MoCA will be done and at D90 the trail making test A&B
will be done.
This study is a phase II trial and possibly not all side effects of the product
are known. Headache is currently the most frequently reported side effect.
The patient has the chance of 2 out of 3 to be randomised to the active
medication and could in this case potentially benefit from the study. On the
other hand, the patient enables the further development of the product which in
turn could result in other patients benefitting from the treatment. During the
study the patient can benefit from an extended medical follow-up.
Rue Carnot 50
SURESNES CEDEX 92284
FR
Rue Carnot 50
SURESNES CEDEX 92284
FR
Listed location countries
Age
Inclusion criteria
- Patients aged between 18 and 80 years (both inclusive),
- Acute ischemic stroke (IS) that occurred at least 48 hours (2 days) and less than 144 hours (6 days) (both inclusive) before selection. If the exact stroke onset time is unknown, by convention it will be defined as the moment the patient was seen well for the last time. Those patients can be included if the time interval between last seen well and stroke discovery is less than 12 hours,
- No previous disability (neither physical nor cognitive pre-stroke impairment),
- NIHSS 7-20 (both inclusive),
- Patient clinically stable according to the investigator's judgement.
- Inclusion done between 72 hours (3 days) and 144 hours (6 days) (both inclusive) after IS onset,
- Brain MRI results available with at least DWI, T2*, FLAIR,
- Brain MRI showing an acute supratentorial cortical ischemic stroke responsible for the clinical picture of the patient.
Exclusion criteria
- Impossibility to undertake an adequate rehabilitation in a specialised centre, and / or ambulatory rehabilitation services
- Stroke due to cerebral venous thrombosis,
- Vascular surgery or endovascular treatment likely to be required during the next 3 months
- Severe co-morbid medical conditions with a life expectancy <12 months or any other disease or condition which would place a patient at undue risk by being included in the study or likely to interfere significantly with the evaluation criteria of the study (according to the investigator's opinion)
- Class III or class IV Heart failure according to the New York Heart Association (NYHA) classification,
- Chronic alcohol abuse1 or drug abuse or addiction, as judged by the investigator (excluding nicotine).
- Pre-existing psychiatric disease likely to impact the clinical evaluation during the study,
- Epileptic seizure during the last 2 years or treatment for epilepsy during the last 12 months,
- Known positive HIV serology, unresolved hepatitis B and/or C infection,
- Pre-stroke known clinically significant cognitive impairment (i.e with impact on daily activities) or known dementia,
- Known severe renal impairment:
- Severe hepatic impairment or known liver enzymes abnormalities
- Contraindication or unable to perform a MRI
- Long-term prescription of benzodiazepine (BZD) that cannot be stopped without exposing the patient to safety risk
- Pregnancy, breastfeeding or possibility of becoming pregnant during the study
- Female patients with child bearing potential and procreative male patients not willing to use effective contraception methods throughout the treatment period and at least 15 days post last treatment intake.
- Brain MRI showing
o a severe microangiopathy,
o an acute haemorrhagic stroke or an important haemorrhagic transformation of the brain infarct ,
o an acute ischemic or haemorrhagic lesion in brain stem or cerebellum likely to contribute significantly to the clinical picture of the patient,
o acute lacunar infarction in the territory of a deep perforating artery likely to contribute significantly to the clinical picture of the patient,
o signs of a pre-existing severe cerebrovascular disease
- Follow-up showing symptomatic haemorrhagic transformation of the cerebral infarction (Symptomatic defined clinically as a worsening of at least 4 points on the NIHSS),
- Repeated demonstration of ECG QTcf > 480ms (at least 2 ECGs out of 3 with a QTcf > 480ms),
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 | EUCTR2016-001005-16-NL |
| CCMO | NL57643.078.16 |