Data Sheet 1_Acute effects of partial positive allosteric GABAA receptor modulation by GT-002 on psychophysiological and cognitive measures: protocol for the TOTEMS phase II trial targeting cognitive impairment associated with schizophrenia.pdf

BackgroundCognitive impairment remains a critical unmet treatment need in schizophrenia spectrum disorders (SSD). Disruption of cortical excitation/inhibition balance, involving dysfunction of the gamma-aminobutyric acid (GABA) system, leads to aberrant gamma oscillations and impaired brain network function. This disruption may manifest as hypofrontality, which is associated with deficits in basic information processing thought to underlie the cognitive impairments observed in SSD. GT-002 is a novel GABAA receptor partial positive allosteric modulator. Preclinical rodent studies have demonstrated GT-002’s potential to reduce hypofrontality, while three Phase I trials have established its safety and tolerability in healthy participants.
AimThe TOTEMS Phase II trial examines acute effects of a single oral dose of GT-002 on psychophysiological measures of early information processing, including event-related electroencephalography (EEG), electromyography, and resting-state EEG in SSD patients.
MethodsA single-center, double-blind, placebo- and active comparator-controlled, randomized, four-way crossover challenge trial. We will recruit 20 clinically stable patients with SSD and 30 healthy controls. Participants will receive a single dose of GT-002 (1 mg and 2 mg, developed by Gabather AB), oxazepam (15 mg), and placebo across four study drug exposure days, separated by a washout period ≥7 days. Psychophysiological measures and cognitive assessments, including the Trail Making Test and selected subtests from the Brief Assessment of Cognition in Schizophrenia and Cambridge Neuropsychological Test Automated Battery, will be conducted following each administration.
Anticipated resultsWe hypothesize that GT-002 will improve prepulse inhibition of the startle reflex in patients relative to placebo and oxazepam, reflecting improved sensorimotor gating. Secondary hypotheses include improved mismatch negativity, selective attention, 40-Hz auditory steady-state response, and normalized resting-state EEG in SSD patients following GT-002. Exploratory endpoints include safety and tolerability of GT-002 as well as differential effects on cognition compared to oxazepam, particularly in processing speed, attention, reaction time, and working memory.
PerspectivesTOTEMS is the first trial to investigate acute effects of GABAA receptor modulation by GT-002 on early information processing in SSD. If successful, it will support further clinical trials of longer-term GT-002 treatment as a novel pharmacological approach to target impairments in information processing in SSD, potentially ameliorating cognitive impairments.
Clinical trial registrationEU CT number 2024-519389-28-00.

背景：精神分裂症谱系障碍（schizophrenia spectrum disorders, SSD）患者的认知损害仍是一项亟待满足的关键临床治疗需求。皮层兴奋/抑制平衡紊乱（累及γ-氨基丁酸（gamma-aminobutyric acid, GABA）系统功能异常）可导致γ振荡异常及脑网络功能受损，该紊乱可表现为前额叶低活动（hypofrontality），而前额叶低活动与基础信息加工缺陷相关，此类缺陷被认为是SSD患者认知损害的潜在病理基础。GT-002是一种新型GABAA受体部分正变构调节剂（GABAA receptor partial positive allosteric modulator）。临床前啮齿类动物研究已证实GT-002可改善前额叶低活动，而三项I期临床试验则明确了其在健康受试者中的安全性与耐受性。
研究目的：本TOTEMS II期临床试验旨在评估单次口服GT-002对SSD患者早期信息加工相关心理生理学指标的急性影响，检测指标包括事件相关脑电图（event-related electroencephalography, EEG）、肌电图（electromyography, EMG）及静息态脑电图。
研究方法：本试验为单中心、双盲、安慰剂与活性对照随机四交叉挑战试验。研究将纳入20名临床病情稳定的SSD患者及30名健康对照受试者。所有受试者将在4个给药日分别单次口服GT-002（1mg、2mg，由Gabather AB公司研发）、奥沙西泮（oxazepam，15mg）及安慰剂，各给药日之间设置≥7天的洗脱期。每次给药后均将开展心理生理学指标检测与认知评估，认知评估工具包括连线测验（Trail Making Test）、精神分裂症认知简明评估量表（Brief Assessment of Cognition in Schizophrenia, BACS）的指定分测验，以及剑桥神经心理自动化成套测验（Cambridge Neuropsychological Test Automated Battery, CANTAB）。
预期结果：本研究假设，与安慰剂及奥沙西泮相比，GT-002可改善SSD患者的惊反射前脉冲抑制（prepulse inhibition of the startle reflex, PPI），提示感觉运动门控（sensorimotor gating）功能得到改善。次要研究假设包括：GT-002可改善SSD患者的失匹配负波（mismatch negativity, MMN）、选择性注意、40Hz听觉稳态反应（40-Hz auditory steady-state response, ASSR），并使静息态脑电图恢复正常。探索性终点包括GT-002的安全性与耐受性，以及相较于奥沙西泮对认知功能的差异化影响，尤其体现在加工速度、注意力、反应时与工作记忆方面。
研究展望：TOTEMS是首项探讨GT-002通过调控GABAA受体对SSD患者早期信息加工产生急性影响的临床试验。若试验成功，将支持开展更长疗程的GT-002治疗临床试验，为靶向SSD患者信息加工缺陷的新型药理学干预手段提供依据，有望改善患者的认知损害。
临床试验注册：欧盟临床试验编号（EU CT number）2024-519389-28-00。