The Efficacy and Safety of a Selective Estrogen Receptor Beta agonist (LY500307)

描述（由申请人提供）：精神分裂症是一种毁灭性的精神疾病，影响了大约1%的世界人口，并与大量未满足的医疗需求有关。消极症状（如情绪表达和社会行为受限）和认知障碍（如工作记忆和言语记忆）是精神分裂症的核心临床特征，并在很大程度上导致与该疾病相关的功能残疾。这两种症状域对已批准的精神分裂症治疗相对无反应，这促使人们将重点放在确定新靶点和开发针对这些症状复合物的新疗法上。几项研究支持雌激素对精神分裂症阴性症状和认知症状的潜在治疗作用。然而，雌激素对男性和绝经前精神分裂症患者的治疗应用有限，因为其耐受性问题包括子宫癌的易损性、心脏病和男性女性化的影响。选择性雌激素受体受体激动剂（ER β）是一类新的治疗方法，它相对没有雌激素的主要副作用，但已证明在大脑中具有雌激素样作用，包括改善认知能力和与极端社会行为有关。因此，这些药物可能对精神分裂症的认知和阴性症状有治疗作用。本应用的主要目的是确定选择性ER β激动剂LY500307是否能显著改善精神分裂症患者的阴性症状和认知症状。次要目的包括通过fMRI评估LY500307对工作和情景记忆任务时脑血流量的影响，以及听觉感觉加工和工作记忆的电生理指标。单一无缝1b/2a期自适应设计将用于在试验的第一阶段（申请的第1年）评估两种LY500307剂量（25mg /天和75mg /天），以确定哪种剂量应该提前到第二阶段（申请的第2年和第3年），或者是否应该停止试验。Go/No Go标准

DESCRIPTION (provided by applicant): Schizophrenia is a devastating mental illness affecting approximately one percent of the world's population and is associated with substantial unmet medical need. Negative symptoms (e.g., constricted emotional expression and social behavior) and cognitive impairment (e.g., working and verbal memory) are core clinical features of schizophrenia and substantially contribute to the functional disability associated with this illness. Both of these symptom domains are relatively unresponsive to approved treatments for schizophrenia which has prompted a substantial focus on identifying new targets and developing novel therapeutics for these symptom complexes. Several lines of investigation have supported the potential therapeutic effects of estrogen for negative and cognitive symptoms in schizophrenia. However, estrogen has had limited therapeutic application for male and premenopausal patients with schizophrenia because of tolerability concerns including uterine cancer liability, and heart disease and feminization effects in men. Selective Estrogen Receptor Beta (ER beta) agonists are a new class of treatments that are relatively free of estrogen's primary side effects and yet have demonstrated estrogen-like effects in brain including improvement in cognitive performance and an association to extremes in social behavior. Thus, these agents may have a therapeutic role for cognitive and negative symptoms in schizophrenia. The primary objectives of this application are to determine if the selective ER beta agonist LY500307 significantly improves negative and cognitive symptoms in patients with schizophrenia. Secondary aims include assessing LY500307 effects on cerebral blood flow during working and episodic memory tasks with fMRI, and electrophysiological indices of auditory sensory processing and working memory. A single seamless phase 1b/2a adaptive design will be used to evaluate two LY500307 doses (25 mg/day and 75 mg/day) in the first stage of the trial (year 1 of the application) to determine which dose should be advanced to stage 2 (years 2and 3 of the application) or if the trial should be discontinued. Go/No Go criteria to determine advancement to stage 2 are: 1) positive signal detection in at least one of three cognitive and negative symptom primary endpoints, and 2) failure to decrease testosterone levels from baseline which is reflective of maintaining selectivity for ER beta. In stage 1, 30 patients with schizophrenia will be randomized (1:1:1) to one of the two doses of LY500307 or placebo to an 8-week add-on to antipsychotic medication trial. Providing go/no go criteria are met, 60 patients will be randomized (1:1) in stage 2 of the trial to the "winning" LY500307 dose or placebo. At this time, only male schizophrenic patients will be studied because of the extensive safety data base in males (>400 males treated for 6 months) obtained by Eli Lilly demonstrating favorable safety and tolerability. Results of this study will determine if LY500307 should be advanced for further testing in schizophrenia.