Last updated on February 2018

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

Brief description of study

The primary objectives of this application are to determine if the selective ER 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 ER 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 symptoms (Negative Symptom Assessment Scale - 16-item total score), working memory (the composite score for the Letter Number Sequencing and Spatial Span tests) and verbal memory (Hopkins Verbal Learning Test).

Primary Aim 3: To determine if LY500307 reduces total testosterone (TT) plasma concentrations, which is indicative of loss of selectivity for ER and engagement of ER, using the following criteria: Decrease in TT plasma concentrations of 50% from baseline in 50% of subjects per arm treated for two consecutive post-randomization values with LY500307 in Stage 1 and Stage 2 of the trial.

Primary Aim 4: To assess the safety of LY500307 by determining if there are SAEs, AEs "probably related to study drug," QTc prolongation, TT suppression (50% reduction from baseline) and to evaluate for other safety signals.

Secondary aims are to assess LY500307 effects on regional brain activation and connectivity during working (2-Back visual-verbal working memory task) and episodic (scene encoding and recognition)and memory tasks, and to evaluate electrophysiological indices of auditory sensory processing and working memory (auditory steady state responses, mismatch negativity (MMN) and auditory P300). It is predicted that LY500307 will produce greater increases than placebo in brain activity in prefrontal cortex and hippocampus during the working memory and episodic memory tasks, respectively, connectivity during resting fMRI, as well as increases in power of the auditory steady state response, MMN amplitude and P300 amplitude. The fMRI and electrophysiological measures will provide evidence of target engagement of LY500307 in schizophrenia and will be assessed as potential biomarkers for future clinical trials. Additional secondary aims will include assessing the effects of LY500307 on safety, positive symptoms, depression, social functioning and quality of life.

Clinical Study Identifier: NCT01874756

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Recruitment Status: Open

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