A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy

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A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy

Montagnese, Sara (författare): University of Padova, Padova, Italy,Univ Padua, Padua, Italy.

Lauridsen, Mette (författare): Hospital of South West Jutland, Esbjerg, Denmark,Hosp South West Jutland, Esbjerg, Denmark.

Vilstrup, Hendrik (författare): Aarhus University, Aarhus, Denmark,Aarhus Univ, Aarhus, Denmark.

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Zarantonello, Lisa (författare): University of Padova, Padova, Italy,Univ Padua, Padua, Italy.

Lakner, Géza (författare): CRU Hungary Kft., Miskolc, Hungary

Fitilev, Sergey (författare): State Budgetary Healthcare Institution “City Polyclinic №2”, Moscow, Russian Federation,State Budgetary Healthcare Inst City Polyclin 2, Moscow, Russia.

Zupanets, Igor (författare): Clinical and Diagnostics Center, National University of Pharmacy, Kharkiv, Ukraine,Natl Univ Pharm, Clin & Diagnost Ctr, Kharkiv, Ukraine.

Kozlova, Irina (författare): State Healthcare Institution “Saratov Clinical Hospital #5”, Saratov, Russian Federation,Saratov Clin Hosp 5, State Healthcare Inst, Saratov, Russia.

Bunkova, Elena (författare): Medical University “Reaviz”, Samara, Russian Federation,Med Univ Reaviz, Samara, Russia.

Tomasiewicz, Krzysztof (författare): Department of Infectious Diseases and Hepatology, Medical University of Lublin, Poland,Med Univ Lublin, Dept Infect Dis & Hepatol, Lublin, Poland.

Berglund, Jan Erik (författare): CTC Clinical Trial Consultants AB, Uppsala, Sweden,CTC Clin Trial Consultants AB, Uppsala, Sweden.

Rorsman, Fredrik, Docent, 1960- (författare): Uppsala universitet,Gastroenterologi/hepatologi

Hagström, Hannes (författare): Karolinska Institutet,Karolinska Univ Hosp, Dept Upper GI Dis, Unit Hepatol, Stockholm, Sweden.

Kechagias, Stergios (författare): Linköpings universitet,Avdelningen för diagnostik och specialistmedicin,Medicinska fakulteten,Region Östergötland, Mag- tarmmedicinska kliniken,Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden.

Ocklind, Carin Edmark (författare): Dept of Gastroenterology, Västerås Hospital, Sweden,Västerås Hosp, Dept Gastroenterol, Västerås, Sweden.

Mauney, Joe (författare): Array Biostatistics, NC, Wilmington, United States,Array Biostat, Wilmington, NC USA.

Thunarf, Fredrik (författare): LINK Medical Research AB, Uppsala, Sweden,LINK Med Res AB, Uppsala, Sweden.

Mokhatarani, Masoud (författare): Karolinska Institutet,Umecrine Cognit AB, Stockholm, Sweden.

Bäckström, Torbjörn (författare): Umeå universitet,Obstetrik och gynekologi,Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.;Umeå Univ, Dept Clin Sci Obstet & Gynecol, SE-90187 Umeå, Sweden.

Doverskog, Magnus (författare): Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.

Lins, Lars-Erik (författare): Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.

Månsson, Maria (författare): Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.

Samuelson, Per (författare): Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.

Nilsson, Dag (författare): Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.

Schalling, Martin (författare): Umecrine Cognition AB, Stockholm, Sweden; Department of Molecular Medicine and Surgery and the Center for Molecular Medicine at Karolinska Institutet., Sweden,Umecrine Cognit AB, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.;Karolinska Inst, Ctr Mol Med, Solna, Sweden.

Johansson, Inga-Maj (författare): Umeå universitet,Obstetrik och gynekologi,Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.;Umeå Univ, Dept Clin Sci Obstet & Gynecol, SE-90187 Umeå, Sweden.

Arlander, Eva (författare): Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.

Scharschmidt, Bruce F. (författare): Umecrine Cognition AB, Stockholm, Sweden,Umecrine Cognit AB, Stockholm, Sweden.

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University of Padova, Padova, Italy Univ Padua, Padua, Italy (creator_code:org_t)

Elsevier, 2021
2021
Engelska.
Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:1, s. 98-107

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Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis.Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks’ dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days.Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well.Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone.Lay summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug.Clinical trial registration number: EudraCT 2016-003651-30.

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Av lärosätet: Umeå universitet; Karolinska Institutet; Linköpings universitet; Uppsala universitet

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A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy

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