Phase II Trial of SGS-742 in Succinic Semialdehyde Dehydrogenase Deficiency

描述（由申请方提供）：琥珀酸半醛脱氢酶（SSADH）缺乏症仍然是最普遍且无法治疗的GABA（4-氨基丁酸）代谢疾病。根据相应鼠模型的临床前疗效结果，拟定在SSADH缺陷患者中开展SGS 742（GABA（B）受体拮抗剂）的安慰剂对照II期试验，该试验将评价治疗组与安慰剂组的安全性、耐受性和SSADH严重程度相关指标的变化。将采用交叉设计，其中患者被随机分配到初始6个月的SGS 742与安慰剂试验中。我们项目的创新在于实施了第一个安慰剂对照的盲法试验，在这种疾病中使用基于aldh 5a 1-/-小鼠临床前疗效研究的合理干预。我们唯一的正式假设是，SSADH缺陷患者将有延长向正常值的皮层沉默期（CSP），并返回长间期皮质内抑制（LICI），在SGS 742干预量化经颅磁刺激。次要探索性结局包括脑脊液中的代谢生物标志物（GABA、GHB）、神经心理学评价和安全性。目标1将比较SGS 742与PBO对TMS水平的影响作为主要结局，这依赖于SGS 742和PBO组之间TMS差异的幅度，以及配对t检验的等效性，以评估统计学显著性水平。在目标2中采用了相同的程序，其评估了SGS 742对生物标志物水平（包括GABA和GHB）的影响，以及对开启与关闭SGS 742的神经心理学评估的评分。在目标3中，我们转向安全性评估。当我们评估不良或毒性事件的频率时，我们的分析框架将包括多个逻辑回归模型，以比较离散事件的发生率，例如相对于PBO，SGS 742组报告的不良和严重不良事件。适当的生物标志物结局，具有在该患者队列中进行牛磺酸类似试验经验的研究团队，经过验证的实用试验设计，以及广泛的可招募队列 主题是强调我们成功潜力的特征。短期而言，我们会就SGS 742的进一步临床开发作出“进行或不进行”的决定。该项目的长期意义集中在确定SSADH缺乏症和相关疾病的有效治疗方法，其中神经认知功能障碍与GABA能系统相关。

DESCRIPTION (provided by applicant): Succinic semialdehyde dehydrogenase (SSADH) deficiency remains the most prevalent and untreatable disorder of GABA (4-aminobutyrate) metabolism. A placebo-controlled phase II trial of SGS742 (GABA(B) receptor antagonist) in SSADH-deficient patients is proposed, based upon preclinical efficacy findings in the corresponding murine model, which will evaluate safety, tolerability, and change in relevant indicators of SSADH severity in treatment vs. placebo groups. A crossover design will be employed where patients are randomized into an initial six month trial of SGS742 versus placebo. Our project's innovation resides in implementing the first placebo-controlled, blinded trial in this disorder using a rational intervention based upon preclinical efficacy studies in aldh5a1-/- mice. Our single formal hypothesis is that SSADH-deficient patients will have lengthening toward normal values of the cortical silent period (CSP), and return of long interval intracortical inhibition (LICI), during SGS742 intervention as quantified by transcranial magnetic stimulation. Secondary, exploratory outcomes include metabolic biomarkers in cerebrospinal fluid (GABA, GHB), neuropsychological evaluation, and safety. Aim 1 will compare the effect of SGS742 v. PBO on TMS levels as the primary outcome, relying both on the magnitude of the difference in TMS between the SGS742 and PBO group, as well as the equivalent of a paired t-test to assess the statistical significance level. The same procedure is employed in Aim 2 which evaluates SGS742 effects on biomarker levels, including GABA and GHB, as well as scores on neuropsychological assessments on vs. off SGS742. In Aim 3, we shift to the evaluation of safety. When we evaluate the frequency of adverse or toxic events, our analysis framework will comprise multiple logistic regression models to compare the odds of discrete occurrences such as reported adverse and serious adverse events in those on SGS742 relative to PBO. Appropriate biomarker outcomes, an investigative team with experience in a similar trial of taurine in this patient cohort, a proven, practical trial design, and a broad cohort of recruitable subjects are features that underscore our potential for success. In the short term, we will formulate a "go/no-go" decision regarding further clinical development of SGS742. The project's long term significance centers on identification of effective treatment for SSADH deficiency and related disorders in which neurocognitive dysfunction correlates with GABAergic systems.