Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial
S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety...
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| Veröffentlicht in: | Lancet neurology 2020-03, Vol.19 (3), p.226-233 |
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| creator | Chabriat, Hugues Bassetti, Claudio L Marx, Ute Audoli-Inthavong, Marie-Laure Sors, Aurore Lambert, Estelle Wattez, Marine Hermann, Dirk M ALTHAUS, Katharina AMARO, Sergi BAE, Hee-Joon BAK, Zbigniew BARBARINI, Leonardo BASSI, Pietro BAZAN, Rodrigo BERECZKI, Daniel BERKOWICZ, Tomasz BERROUSCHOT, Joerg BLACQUIERE, Dylan BROLA, Waldemar BUTCHER, Kenneth CARDONA, Pere CHA, Jae-Kwan CLOUD, Geoffrey COHEN, David CORDONNIER, Charlotte CSANYI, Attila CZLONKOWSKA, Anna DAVIS, Stephen DAWSON, Jesse DE KLIPPEL, Nina DENIER, Christian DESFONTAINES, Philippe DIENER, Hans-Christoph DIOSZEGHY, Peter DIPPEL, Diederik Willem DORADO, Laura FOLYOVICH, Andras FREITAS, Gabriel Rodriguez FRIEDRICH, Mauricio Andre FRYZE, Waldemar GAGLIARDI, Rubens Jose GOTTSCHAL, Marianna GRIMLEY, Rohan GROND, Martin GRÖSCHEL, Klaus HOSSEINI, Hassan HWANG, Yangha KALLMUENZER, Bernd KHAN, Usman KLEINIG, Tim KOVES, Agnes LAGO MARTIN, Aida LASEK-BAL, Anetta LEMBO, Giuseppe LEMMENS, Robin LINDERT, Ralf PORCELLO MARRONE, Luiz Carlos MARTINEZ ZABALETA, Maite MAS, Jean-Louis MASJUAN VALLEJO, Jaime MAZIGHI, Mikael MINELLI, Cesar MISTRI, Amit MOLINA, Carlos MONICHE ALVAREZ, Francisco CABRAL MORO, Carla Heloisa MULLENERS, Wim NABAVI, Darius NEAU, Jean-Philippe O'BRIEN, Bill OVARY, Csaba PANCZEL, Gyula PARK, Man Seok PHAN, Thanh RAGAB, Suzanne REJDAK, Konrad RODRIGUEZ DE FREITAS, Gabriel ROFFE, Christine ROQUER GONZALEZ, Jaume ROVER, Luisa SAMPAIO SILVA, Gisele SCHELLINGER, Peter SEGURA MARTIN, Tomas SHAW, Louise SIBON, Igor SKODA, Ondrej SMADJA, Didier SOBOLEWSKI, Piotr SODA, Hassan SPRIGG, Nikola SWIAT, Maciej SZAPARY, Laszlo SZEGEDI, Norbert TONI, Danilo VALIKOVICS, Attila VECSEI, Laszlo WEIN, Theodore WONG, Andrew XIMENEZ CARRILLO, Alvaro |
| description | S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke.
RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one d |
| doi_str_mv | 10.1016/S1474-4422(20)30004-1 |
| format | Article |
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Bassetti, Claudio L ; Marx, Ute ; Audoli-Inthavong, Marie-Laure ; Sors, Aurore ; Lambert, Estelle ; Wattez, Marine ; Hermann, Dirk M ; ALTHAUS, Katharina ; AMARO, Sergi ; BAE, Hee-Joon ; BAK, Zbigniew ; BARBARINI, Leonardo ; BASSI, Pietro ; BAZAN, Rodrigo ; BERECZKI, Daniel ; BERKOWICZ, Tomasz ; BERROUSCHOT, Joerg ; BLACQUIERE, Dylan ; BROLA, Waldemar ; BUTCHER, Kenneth ; CARDONA, Pere ; CHA, Jae-Kwan ; CLOUD, Geoffrey ; COHEN, David ; CORDONNIER, Charlotte ; CSANYI, Attila ; CZLONKOWSKA, Anna ; DAVIS, Stephen ; DAWSON, Jesse ; DE KLIPPEL, Nina ; DENIER, Christian ; DESFONTAINES, Philippe ; DIENER, Hans-Christoph ; DIOSZEGHY, Peter ; DIPPEL, Diederik Willem ; DORADO, Laura ; FOLYOVICH, Andras ; FREITAS, Gabriel Rodriguez ; FRIEDRICH, Mauricio Andre ; FRYZE, Waldemar ; GAGLIARDI, Rubens Jose ; GOTTSCHAL, Marianna ; GRIMLEY, Rohan ; GROND, Martin ; GRÖSCHEL, Klaus ; HOSSEINI, Hassan ; HWANG, Yangha ; KALLMUENZER, Bernd ; KHAN, Usman ; KLEINIG, Tim ; KOVES, Agnes ; LAGO MARTIN, Aida ; LASEK-BAL, Anetta ; LEMBO, Giuseppe ; LEMMENS, Robin ; LINDERT, Ralf ; PORCELLO MARRONE, Luiz Carlos ; MARTINEZ ZABALETA, Maite ; MAS, Jean-Louis ; MASJUAN VALLEJO, Jaime ; MAZIGHI, Mikael ; MINELLI, Cesar ; MISTRI, Amit ; MOLINA, Carlos ; MONICHE ALVAREZ, Francisco ; CABRAL MORO, Carla Heloisa ; MULLENERS, Wim ; NABAVI, Darius ; NEAU, Jean-Philippe ; O'BRIEN, Bill ; OVARY, Csaba ; PANCZEL, Gyula ; PARK, Man Seok ; PHAN, Thanh ; RAGAB, Suzanne ; REJDAK, Konrad ; RODRIGUEZ DE FREITAS, Gabriel ; ROFFE, Christine ; ROQUER GONZALEZ, Jaume ; ROVER, Luisa ; SAMPAIO SILVA, Gisele ; SCHELLINGER, Peter ; SEGURA MARTIN, Tomas ; SHAW, Louise ; SIBON, Igor ; SKODA, Ondrej ; SMADJA, Didier ; SOBOLEWSKI, Piotr ; SODA, Hassan ; SPRIGG, Nikola ; SWIAT, Maciej ; SZAPARY, Laszlo ; SZEGEDI, Norbert ; TONI, Danilo ; VALIKOVICS, Attila ; VECSEI, Laszlo ; WEIN, Theodore ; WONG, Andrew ; XIMENEZ CARRILLO, Alvaro</creator><creatorcontrib>Chabriat, Hugues ; Bassetti, Claudio L ; Marx, Ute ; Audoli-Inthavong, Marie-Laure ; Sors, Aurore ; Lambert, Estelle ; Wattez, Marine ; Hermann, Dirk M ; ALTHAUS, Katharina ; AMARO, Sergi ; BAE, Hee-Joon ; BAK, Zbigniew ; BARBARINI, Leonardo ; BASSI, Pietro ; BAZAN, Rodrigo ; BERECZKI, Daniel ; BERKOWICZ, Tomasz ; BERROUSCHOT, Joerg ; BLACQUIERE, Dylan ; BROLA, Waldemar ; BUTCHER, Kenneth ; CARDONA, Pere ; CHA, Jae-Kwan ; CLOUD, Geoffrey ; COHEN, David ; CORDONNIER, Charlotte ; CSANYI, Attila ; CZLONKOWSKA, Anna ; DAVIS, Stephen ; DAWSON, Jesse ; DE KLIPPEL, Nina ; DENIER, Christian ; DESFONTAINES, Philippe ; DIENER, Hans-Christoph ; DIOSZEGHY, Peter ; DIPPEL, Diederik Willem ; DORADO, Laura ; FOLYOVICH, Andras ; FREITAS, Gabriel Rodriguez ; FRIEDRICH, Mauricio Andre ; FRYZE, Waldemar ; GAGLIARDI, Rubens Jose ; GOTTSCHAL, Marianna ; GRIMLEY, Rohan ; GROND, Martin ; GRÖSCHEL, Klaus ; HOSSEINI, Hassan ; HWANG, Yangha ; KALLMUENZER, Bernd ; KHAN, Usman ; KLEINIG, Tim ; KOVES, Agnes ; LAGO MARTIN, Aida ; LASEK-BAL, Anetta ; LEMBO, Giuseppe ; LEMMENS, Robin ; LINDERT, Ralf ; PORCELLO MARRONE, Luiz Carlos ; MARTINEZ ZABALETA, Maite ; MAS, Jean-Louis ; MASJUAN VALLEJO, Jaime ; MAZIGHI, Mikael ; MINELLI, Cesar ; MISTRI, Amit ; MOLINA, Carlos ; MONICHE ALVAREZ, Francisco ; CABRAL MORO, Carla Heloisa ; MULLENERS, Wim ; NABAVI, Darius ; NEAU, Jean-Philippe ; O'BRIEN, Bill ; OVARY, Csaba ; PANCZEL, Gyula ; PARK, Man Seok ; PHAN, Thanh ; RAGAB, Suzanne ; REJDAK, Konrad ; RODRIGUEZ DE FREITAS, Gabriel ; ROFFE, Christine ; ROQUER GONZALEZ, Jaume ; ROVER, Luisa ; SAMPAIO SILVA, Gisele ; SCHELLINGER, Peter ; SEGURA MARTIN, Tomas ; SHAW, Louise ; SIBON, Igor ; SKODA, Ondrej ; SMADJA, Didier ; SOBOLEWSKI, Piotr ; SODA, Hassan ; SPRIGG, Nikola ; SWIAT, Maciej ; SZAPARY, Laszlo ; SZEGEDI, Norbert ; TONI, Danilo ; VALIKOVICS, Attila ; VECSEI, Laszlo ; WEIN, Theodore ; WONG, Andrew ; XIMENEZ CARRILLO, Alvaro ; RESTORE BRAIN study investigators</creatorcontrib><description>S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke.
RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov, NCT02877615.
Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64–1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81–1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0–2 vs 3–6 or mRS 0–1 vs 2–6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2–8] in 150 mg S44819 group, 4 [2–7] in 300 mg S44819 group, and 4 [2–6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0–26·0] in 150 mg S44819 group, 23·0 [19·0–26·5] in 300 mg S44819 group, and 22·0 [17·0–26·0] in placebo group), time needed to complete parts A (50 s [IQR 42–68] in 150 mg S44819 group, 49 s [36–63] in 300 mg S44819 group, and 50 s [38–68] in placebo group) and B (107 s [81–144] in 150 mg S44819 group, 121 s [76–159] in 300 mg S44819 group, and 130 s [86–175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60–100] in 150 mg S44819 group, 90 [70–100] in 300 mg S44819 group, and 90 [70–100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths.
There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans.
Servier.</description><identifier>ISSN: 1474-4422</identifier><identifier>EISSN: 1474-4465</identifier><identifier>DOI: 10.1016/S1474-4422(20)30004-1</identifier><language>eng</language><publisher>Elsevier Ltd</publisher><ispartof>Lancet neurology, 2020-03, Vol.19 (3), p.226-233</ispartof><rights>2020 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3041-c2594810d729737d1a463a48d3462ee01ee243f6c18633bca3282541fd679b433</citedby><cites>FETCH-LOGICAL-c3041-c2594810d729737d1a463a48d3462ee01ee243f6c18633bca3282541fd679b433</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S1474-4422(20)30004-1$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3554,27933,27934,46004,64396</link.rule.ids></links><search><creatorcontrib>Chabriat, Hugues</creatorcontrib><creatorcontrib>Bassetti, Claudio L</creatorcontrib><creatorcontrib>Marx, Ute</creatorcontrib><creatorcontrib>Audoli-Inthavong, Marie-Laure</creatorcontrib><creatorcontrib>Sors, Aurore</creatorcontrib><creatorcontrib>Lambert, Estelle</creatorcontrib><creatorcontrib>Wattez, Marine</creatorcontrib><creatorcontrib>Hermann, Dirk M</creatorcontrib><creatorcontrib>ALTHAUS, Katharina</creatorcontrib><creatorcontrib>AMARO, Sergi</creatorcontrib><creatorcontrib>BAE, Hee-Joon</creatorcontrib><creatorcontrib>BAK, Zbigniew</creatorcontrib><creatorcontrib>BARBARINI, Leonardo</creatorcontrib><creatorcontrib>BASSI, Pietro</creatorcontrib><creatorcontrib>BAZAN, Rodrigo</creatorcontrib><creatorcontrib>BERECZKI, Daniel</creatorcontrib><creatorcontrib>BERKOWICZ, Tomasz</creatorcontrib><creatorcontrib>BERROUSCHOT, Joerg</creatorcontrib><creatorcontrib>BLACQUIERE, Dylan</creatorcontrib><creatorcontrib>BROLA, Waldemar</creatorcontrib><creatorcontrib>BUTCHER, Kenneth</creatorcontrib><creatorcontrib>CARDONA, Pere</creatorcontrib><creatorcontrib>CHA, Jae-Kwan</creatorcontrib><creatorcontrib>CLOUD, Geoffrey</creatorcontrib><creatorcontrib>COHEN, David</creatorcontrib><creatorcontrib>CORDONNIER, Charlotte</creatorcontrib><creatorcontrib>CSANYI, Attila</creatorcontrib><creatorcontrib>CZLONKOWSKA, Anna</creatorcontrib><creatorcontrib>DAVIS, Stephen</creatorcontrib><creatorcontrib>DAWSON, Jesse</creatorcontrib><creatorcontrib>DE KLIPPEL, Nina</creatorcontrib><creatorcontrib>DENIER, Christian</creatorcontrib><creatorcontrib>DESFONTAINES, Philippe</creatorcontrib><creatorcontrib>DIENER, Hans-Christoph</creatorcontrib><creatorcontrib>DIOSZEGHY, Peter</creatorcontrib><creatorcontrib>DIPPEL, Diederik Willem</creatorcontrib><creatorcontrib>DORADO, Laura</creatorcontrib><creatorcontrib>FOLYOVICH, Andras</creatorcontrib><creatorcontrib>FREITAS, Gabriel Rodriguez</creatorcontrib><creatorcontrib>FRIEDRICH, Mauricio Andre</creatorcontrib><creatorcontrib>FRYZE, Waldemar</creatorcontrib><creatorcontrib>GAGLIARDI, Rubens Jose</creatorcontrib><creatorcontrib>GOTTSCHAL, Marianna</creatorcontrib><creatorcontrib>GRIMLEY, Rohan</creatorcontrib><creatorcontrib>GROND, Martin</creatorcontrib><creatorcontrib>GRÖSCHEL, Klaus</creatorcontrib><creatorcontrib>HOSSEINI, Hassan</creatorcontrib><creatorcontrib>HWANG, Yangha</creatorcontrib><creatorcontrib>KALLMUENZER, Bernd</creatorcontrib><creatorcontrib>KHAN, Usman</creatorcontrib><creatorcontrib>KLEINIG, Tim</creatorcontrib><creatorcontrib>KOVES, Agnes</creatorcontrib><creatorcontrib>LAGO MARTIN, Aida</creatorcontrib><creatorcontrib>LASEK-BAL, Anetta</creatorcontrib><creatorcontrib>LEMBO, Giuseppe</creatorcontrib><creatorcontrib>LEMMENS, Robin</creatorcontrib><creatorcontrib>LINDERT, Ralf</creatorcontrib><creatorcontrib>PORCELLO MARRONE, Luiz Carlos</creatorcontrib><creatorcontrib>MARTINEZ ZABALETA, Maite</creatorcontrib><creatorcontrib>MAS, Jean-Louis</creatorcontrib><creatorcontrib>MASJUAN VALLEJO, Jaime</creatorcontrib><creatorcontrib>MAZIGHI, Mikael</creatorcontrib><creatorcontrib>MINELLI, Cesar</creatorcontrib><creatorcontrib>MISTRI, Amit</creatorcontrib><creatorcontrib>MOLINA, Carlos</creatorcontrib><creatorcontrib>MONICHE ALVAREZ, Francisco</creatorcontrib><creatorcontrib>CABRAL MORO, Carla Heloisa</creatorcontrib><creatorcontrib>MULLENERS, Wim</creatorcontrib><creatorcontrib>NABAVI, Darius</creatorcontrib><creatorcontrib>NEAU, Jean-Philippe</creatorcontrib><creatorcontrib>O'BRIEN, Bill</creatorcontrib><creatorcontrib>OVARY, Csaba</creatorcontrib><creatorcontrib>PANCZEL, Gyula</creatorcontrib><creatorcontrib>PARK, Man Seok</creatorcontrib><creatorcontrib>PHAN, Thanh</creatorcontrib><creatorcontrib>RAGAB, Suzanne</creatorcontrib><creatorcontrib>REJDAK, Konrad</creatorcontrib><creatorcontrib>RODRIGUEZ DE FREITAS, Gabriel</creatorcontrib><creatorcontrib>ROFFE, Christine</creatorcontrib><creatorcontrib>ROQUER GONZALEZ, Jaume</creatorcontrib><creatorcontrib>ROVER, Luisa</creatorcontrib><creatorcontrib>SAMPAIO SILVA, Gisele</creatorcontrib><creatorcontrib>SCHELLINGER, Peter</creatorcontrib><creatorcontrib>SEGURA MARTIN, Tomas</creatorcontrib><creatorcontrib>SHAW, Louise</creatorcontrib><creatorcontrib>SIBON, Igor</creatorcontrib><creatorcontrib>SKODA, Ondrej</creatorcontrib><creatorcontrib>SMADJA, Didier</creatorcontrib><creatorcontrib>SOBOLEWSKI, Piotr</creatorcontrib><creatorcontrib>SODA, Hassan</creatorcontrib><creatorcontrib>SPRIGG, Nikola</creatorcontrib><creatorcontrib>SWIAT, Maciej</creatorcontrib><creatorcontrib>SZAPARY, Laszlo</creatorcontrib><creatorcontrib>SZEGEDI, Norbert</creatorcontrib><creatorcontrib>TONI, Danilo</creatorcontrib><creatorcontrib>VALIKOVICS, Attila</creatorcontrib><creatorcontrib>VECSEI, Laszlo</creatorcontrib><creatorcontrib>WEIN, Theodore</creatorcontrib><creatorcontrib>WONG, Andrew</creatorcontrib><creatorcontrib>XIMENEZ CARRILLO, Alvaro</creatorcontrib><creatorcontrib>RESTORE BRAIN study investigators</creatorcontrib><title>Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial</title><title>Lancet neurology</title><description>S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke.
RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov, NCT02877615.
Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64–1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81–1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0–2 vs 3–6 or mRS 0–1 vs 2–6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2–8] in 150 mg S44819 group, 4 [2–7] in 300 mg S44819 group, and 4 [2–6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0–26·0] in 150 mg S44819 group, 23·0 [19·0–26·5] in 300 mg S44819 group, and 22·0 [17·0–26·0] in placebo group), time needed to complete parts A (50 s [IQR 42–68] in 150 mg S44819 group, 49 s [36–63] in 300 mg S44819 group, and 50 s [38–68] in placebo group) and B (107 s [81–144] in 150 mg S44819 group, 121 s [76–159] in 300 mg S44819 group, and 130 s [86–175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60–100] in 150 mg S44819 group, 90 [70–100] in 300 mg S44819 group, and 90 [70–100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths.
There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans.
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Alvaro</creatorcontrib><creatorcontrib>RESTORE BRAIN study investigators</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Lancet neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chabriat, Hugues</au><au>Bassetti, Claudio L</au><au>Marx, Ute</au><au>Audoli-Inthavong, Marie-Laure</au><au>Sors, Aurore</au><au>Lambert, Estelle</au><au>Wattez, Marine</au><au>Hermann, Dirk M</au><au>ALTHAUS, Katharina</au><au>AMARO, Sergi</au><au>BAE, Hee-Joon</au><au>BAK, Zbigniew</au><au>BARBARINI, Leonardo</au><au>BASSI, Pietro</au><au>BAZAN, Rodrigo</au><au>BERECZKI, Daniel</au><au>BERKOWICZ, Tomasz</au><au>BERROUSCHOT, Joerg</au><au>BLACQUIERE, Dylan</au><au>BROLA, Waldemar</au><au>BUTCHER, Kenneth</au><au>CARDONA, Pere</au><au>CHA, Jae-Kwan</au><au>CLOUD, Geoffrey</au><au>COHEN, David</au><au>CORDONNIER, Charlotte</au><au>CSANYI, Attila</au><au>CZLONKOWSKA, Anna</au><au>DAVIS, Stephen</au><au>DAWSON, Jesse</au><au>DE KLIPPEL, Nina</au><au>DENIER, Christian</au><au>DESFONTAINES, Philippe</au><au>DIENER, Hans-Christoph</au><au>DIOSZEGHY, Peter</au><au>DIPPEL, Diederik Willem</au><au>DORADO, Laura</au><au>FOLYOVICH, Andras</au><au>FREITAS, Gabriel Rodriguez</au><au>FRIEDRICH, Mauricio Andre</au><au>FRYZE, Waldemar</au><au>GAGLIARDI, Rubens Jose</au><au>GOTTSCHAL, Marianna</au><au>GRIMLEY, Rohan</au><au>GROND, Martin</au><au>GRÖSCHEL, Klaus</au><au>HOSSEINI, Hassan</au><au>HWANG, Yangha</au><au>KALLMUENZER, Bernd</au><au>KHAN, Usman</au><au>KLEINIG, Tim</au><au>KOVES, Agnes</au><au>LAGO MARTIN, Aida</au><au>LASEK-BAL, Anetta</au><au>LEMBO, Giuseppe</au><au>LEMMENS, Robin</au><au>LINDERT, Ralf</au><au>PORCELLO MARRONE, Luiz Carlos</au><au>MARTINEZ ZABALETA, Maite</au><au>MAS, Jean-Louis</au><au>MASJUAN VALLEJO, Jaime</au><au>MAZIGHI, Mikael</au><au>MINELLI, Cesar</au><au>MISTRI, Amit</au><au>MOLINA, Carlos</au><au>MONICHE ALVAREZ, Francisco</au><au>CABRAL MORO, Carla Heloisa</au><au>MULLENERS, Wim</au><au>NABAVI, Darius</au><au>NEAU, Jean-Philippe</au><au>O'BRIEN, Bill</au><au>OVARY, Csaba</au><au>PANCZEL, Gyula</au><au>PARK, Man Seok</au><au>PHAN, Thanh</au><au>RAGAB, Suzanne</au><au>REJDAK, Konrad</au><au>RODRIGUEZ DE FREITAS, Gabriel</au><au>ROFFE, Christine</au><au>ROQUER GONZALEZ, Jaume</au><au>ROVER, Luisa</au><au>SAMPAIO SILVA, Gisele</au><au>SCHELLINGER, Peter</au><au>SEGURA MARTIN, Tomas</au><au>SHAW, Louise</au><au>SIBON, Igor</au><au>SKODA, Ondrej</au><au>SMADJA, Didier</au><au>SOBOLEWSKI, Piotr</au><au>SODA, Hassan</au><au>SPRIGG, Nikola</au><au>SWIAT, Maciej</au><au>SZAPARY, Laszlo</au><au>SZEGEDI, Norbert</au><au>TONI, Danilo</au><au>VALIKOVICS, Attila</au><au>VECSEI, Laszlo</au><au>WEIN, Theodore</au><au>WONG, Andrew</au><au>XIMENEZ CARRILLO, Alvaro</au><aucorp>RESTORE BRAIN study investigators</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial</atitle><jtitle>Lancet neurology</jtitle><date>2020-03</date><risdate>2020</risdate><volume>19</volume><issue>3</issue><spage>226</spage><epage>233</epage><pages>226-233</pages><issn>1474-4422</issn><eissn>1474-4465</eissn><abstract>S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke.
RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov, NCT02877615.
Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64–1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81–1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0–2 vs 3–6 or mRS 0–1 vs 2–6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2–8] in 150 mg S44819 group, 4 [2–7] in 300 mg S44819 group, and 4 [2–6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0–26·0] in 150 mg S44819 group, 23·0 [19·0–26·5] in 300 mg S44819 group, and 22·0 [17·0–26·0] in placebo group), time needed to complete parts A (50 s [IQR 42–68] in 150 mg S44819 group, 49 s [36–63] in 300 mg S44819 group, and 50 s [38–68] in placebo group) and B (107 s [81–144] in 150 mg S44819 group, 121 s [76–159] in 300 mg S44819 group, and 130 s [86–175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60–100] in 150 mg S44819 group, 90 [70–100] in 300 mg S44819 group, and 90 [70–100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths.
There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans.
Servier.</abstract><pub>Elsevier Ltd</pub><doi>10.1016/S1474-4422(20)30004-1</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1474-4422 |
| ispartof | Lancet neurology, 2020-03, Vol.19 (3), p.226-233 |
| issn | 1474-4422 1474-4465 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2362081851 |
| source | Access via ScienceDirect (Elsevier); ProQuest Central UK/Ireland |
| title | Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial |
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