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

SGS-742 治疗琥珀酸半醛脱氢酶缺乏症的 II 期试验

• 批准号: 8479999
• 负责人: K Michael GIBSON
• 金额: $ 18.61万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8479999
• 关键词: 4-Aminobutyrate aminotransferase; Agonist; Basic Science; Biological Markers; Blinded; Cerebrospinal Fluid; Child; Clinical; Clinical Data; Clinical Pharmacology; Clinical Research; Clinical Trials Design; Collaborations; Crossover Design; Data; Defect; Development; Disease; District of Columbia; Dose; Drug Compounding; Environment; Epilepsy; Evaluation; Event; Extramural Activities; Family; Frequencies; Functional disorder; GABA-B Receptor; Genetic Crossing Over; Goals; Grant; Information Systems; Intellectual functioning disability; Intervention; Intervention Studies; Lead; Logistic Regressions; Measures; Medical center; Metabolic; Metabolic Diseases; Metabolism; Modeling; Multi-Institutional Clinical Trial; Mus; National Institute of Neurological Disorders and Stroke; Neurocognitive; Normal Range; Outcome; Outcome Measure; Participant; Patients; Pediatric Hospitals; Phase; Phase II Clinical Trials; Phenotype; Physicians; Placebo Control; Placebos; Practical trial; Procedures; Publications; Quality of life; Randomized; Relative (related person); Reporting; Research; Research Personnel; SGS-742; Safety; Sample Size; Serious Adverse Event; Severities; Site; Source; Succinate-semialdehyde dehydrogenase; Succinate-semialdehyde dehydrogenase deficiency; System; Taurine; Testing; Time; Transcranial magnetic stimulation; United States National Institutes of Health; Universities; Washington; active method; aldehyde dehydrogenases; aminobutyrate; arm; autism spectrum disorder; base; cohort; cost; design; effective therapy; efficacy trial; experience; gamma-Aminobutyric Acid; innovation; neuropsychological; open label; preclinical efficacy; primary outcome; public health relevance; receptor; success

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.

描述（由申请人提供）：琥珀酸半甲醛脱氢酶（SSADH）缺乏症仍然是GABA（4-氨基丁酸）代谢的最普遍，最不可治疗的疾病。基于相应的鼠模型中的临床前疗效发现，提出了SGS742（GABA（B）受体拮抗剂）的安慰剂对照II期试验，提出了SSADH缺陷患者的一项试验，该发现将评估安全性，耐受性和相关指标的治疗vs. vs. vs. blosbo组的相关指标的变化。将采用跨界设计，将患者随机分为SGS742对安慰剂的最初六个月试验。我们的项目的创新属于该疾病中的第一个安慰剂对照，盲目试验，利用基于AldH5A1 - / - 小鼠的临床前疗效研究的理性干预措施。我们的单一形式假设是，在SGS742通过经颅磁刺激量化的SGS742干预期间，缺乏SSADH缺乏的患者将朝着皮质静默期（CSP）的正常值延长，并返回长期间隔内抑制（LICI）。次要的探索结果包括脑脊液（GABA，GHB）中的代谢生物标志物，神经心理学评估和安全性。 AIM 1将将SGS742v。PBO对TMS水平的影响与主要结果进行比较，这既取决于SGS742和PBO组之间TMS差异的幅度，又依赖于配对T检验的等效量来评估统计学意义水平。 AIM 2中采用了相同的程序，该程序评估了SGS742对包括GABA和GHB在内的生物标志物水平的影响，以及对SGS742的神经心理学评估的评分。在AIM 3中，我们转向对安全的评估。当我们评估不良事件或有毒事件的频率时，我们的分析框架将包含多个逻辑回归模型，以比较SGS742上相对于PBO的离散事件的几率，例如报告的不良事件和严重的不良事件。适当的生物标志物结果，一个在此患者队列中具有类似牛磺酸试验的调查团队 受试者是强调我们成功潜力的功能。在短期内，我们将对SGS742的进一步临床发展制定“ GO/No-Go”决定。该项目的长期意义集中在鉴定SSADH缺乏症和相关疾病的有效治疗中，其中神经认知功能障碍与GABA能系统相关。