The Efficacy and Safety of a Selective Estrogen Receptor Beta Agonist (LY500307) for Negative Symptoms and Cognitive Impairment Associated With Schizophrenia

Study Summary

The primary objectives of this application are to determine if the selective ERβ agonist LY500307, when added to antipsychotic medications, improves negative and/or cognitive symptoms in patients with schizophrenia. The specific hypotheses to be tested are to determine if LY500307 is safe and well tolerated in this population and whether it elicits a sufficient efficacy signal to be advanced for further testing in schizophrenia. A two-stage Phase 1b/Phase 2a adaptive ("drop the inferior dose") experimental design is ongoing that combines three studies (clinical dose optimization, cortical target engagement confirmation and efficacy and safety assessment) into a single clinical trial. Stage 1 was conducted in year 1 and Stage 2 will be conducted in years 2 and 3. The goal of Stage 1 was to identify and advance the highest dose that did not demonstrate a safety signal and had target selectivity as determined by lack of TT suppression. This criteria was fulfilled at both doses, the larger of the two (75 mg/day dose) was advanced to Stage 2. Furthermore, there was no suggestion of ERα receptor activation (i.e., no pattern of TT decreases or feminization AEs) at either dose (25 mg/day and 75 mg/day). A third arm of 150 mg/day was added to Stage 2 for evaluation. Stage 2 results in the following three arms: placebo, 75 mg/day and 150 mg/day. The goals of Stage 2 are to further assess LY500307 doses for safety and target selectivity, confirm cortical target engagement and assess efficacy. Primary Aim 1: To determine if LY500307 demonstrates cortical target engagement as assessed by fMRI/N-back in frontal-parietal regions. Secondary measures of target engagement are fMRI episodic memory, Pseudo-Continuous Arterial Spin Labeling, Mismatch Negativity/evoked response potentials, Auditory Steady State Response, Auditory P300 and Quantitative EEG (QEEG). Primary Aim 2: To determine if LY500307 is superior to placebo for one or more of the primary efficacy endpoints: negative

Primary Outcome

The Negative Symptom Assessment Scale - 16-item (NSA-16) is used to help clinicians rate behaviors (not psychopathology) commonly associated with negative symptoms of schizophrenia. The scale rates subjects on 16 "anchors," is a semi-structured, clinical interview, and each item is rated from 1 to 6. The total score is the sum of the 16 specific items and ranges from 16 to 96; a higher score indicates greater severity of illness. In addition, there is a global rating that represents the overall

Interventions

• DRUG Placebo
• DRUG LY500307 150mg
• DRUG LY500307 75mg
• DRUG LY500307 25mg