Schizophrenia Clinical Trial
Official title:
The Efficacy and Safety of a Selective Estrogen Receptor Beta Agonist (LY500307) for Negative Symptoms and Cognitive Impairment Associated With Schizophrenia
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 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 ERβ and engagement of ERα,
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.
n/a
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