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

描述（由申请人提供）：琥珀酸半醛脱氢酶（SSADH）缺乏症仍然是GABA（4-氨基丁酸）代谢最普遍和不可治疗的疾病。基于相应小鼠模型的临床前疗效发现，提出了SGS742 （GABA(B)受体拮抗剂）在SSADH缺陷患者中的安慰剂对照II期试验，该试验将评估治疗组与安慰剂组的安全性、耐受性以及SSADH严重程度相关指标的变化。将采用交叉设计，将患者随机分为SGS742和安慰剂的初始6个月试验。我们项目的创新之处在于在aldh5a1-/-小鼠的临床前疗效研究的基础上，采用合理的干预措施，在这种疾病中实施了第一个安慰剂对照、盲法试验。我们的单一正式假设是，在经颅磁刺激量化的SGS742干预期间，ssadh缺陷患者的皮质沉默期（CSP）将向正常值延长，并恢复长间隔皮质内抑制（LICI）。其次，探索性结果包括脑脊液中的代谢生物标志物（GABA， GHB），神经心理学评估和安全性。Aim 1将比较SGS742和PBO对TMS水平的影响作为主要结局，依赖于SGS742和PBO组之间TMS差异的大小，以及等效的配对t检验来评估统计显著性水平。Aim 2采用了相同的程序，评估SGS742对生物标志物水平的影响，包括GABA和GHB，以及SGS742对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，以比较相对于PBO， SGS742患者报告的不良和严重不良事件发生的几率。适当的生物标志物结果，具有在该患者队列中进行牛磺酸类似试验经验的调查团队，经过验证的实用试验设计和广泛的可招募队列

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.