The Efficacy and Safety of a Selective Estrogen Receptor Beta Agonist (LY500307) for Negative Symptoms and Cognitive Impairment Associated With Schizophrenia
| Status: | Recruiting |
|---|---|
| Conditions: | Cognitive Studies, Schizophrenia |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 10/13/2017 |
| Start Date: | June 2013 |
| End Date: | June 2018 |
| Contact: | Nikki Mehdiyoun, MA |
| Email: | iupdp@iupui.edu |
| Phone: | 317-8941-4287 |
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.
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.
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.
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.
Inclusion Criteria:
- 18 to 65 years of age at study entry
- Male
- DSM IV-TR diagnosis of schizophrenia as confirmed by Structured Clinical Interview for
DSM-IV-TR (SCID)
- Outpatient or inpatient status
- Mild to moderate overall disease severity as defined by a CGI-S score of less than or
equal to 4 (moderately ill) at randomization
- Moderate levels of negative symptoms as defined by a PANSS negative symptom sub-score
greater than or equal to 11.
- Clinical stability as defined by:
1. No exacerbation of illness leading to an intensification of treatment in the
opinion of the investigator within four weeks prior to randomization, and
2. No change in antipsychotic medication for at least four weeks prior to
randomization
Exclusion Criteria:
- Subjects with current acute, serious, or unstable medical conditions, including, but
not limited to: inadequately controlled diabetes, asthma, COPD, severe
hypertriglyceridemia, recent cerebrovascular accidents, acute systemic infection or
immunologic disease, unstable cardiovascular disorders, malnutrition, or hepatic,
renal gastroenterologic, respiratory, endocrinologic, neurologic, hematologic, or
infectious diseases
- Known or suspected history of prostate cancer, breast cancer, or other clinically
significant neoplastic disease (other than squamous cell or basal cell carcinoma of
skin)
- Known or suspected history of deep venous thrombosis, stroke, venous thromboembolism,
pulmonary embolism, paresis or paralysis that may be thrombogenic in origin
- Subjects currently receiving testosterone replacement therapy or drugs that influence
the hypothalamus-pituitary-gonadal axis.
- Subjects who have clinically significant extrapyramidal signs (EPS) as defined by a
score of >20 on the Simpson-Angus Scale (SAS)
- Clinically significant electrocardiogram (ECG) abnormality, including, but not limited
to, a corrected QT interval (Bazett's; QTcB) >450 msec. Repeat ECGs may be conducted
at the discretion of the principal investigator.
- Subjects with known medical history of Human Immunodeficiency Virus positive (HIV+)
status
- Subjects with an active seizure disorder
- Subjects with implanted pacemaker, medication pump, vagal stimulator, deep brain
stimulator, TENS unit, ventriculoperitoneal shunt, or other contraindication to
undergoing an MRI scan
- Known IQ less than 70 based on medical history
- Current DSM IV-TR diagnosis of substance dependence (excluding caffeine and nicotine)
- Subjects who test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B
surface antigen (HBsAg) with or without positive Hepatitis B core total antibody
- Subjects with moderate to severe renal impairment as defined by creatinine clearance
(CrCl) < 60 ml/min (measured by the Cockcroft-Gault equation) at screening. Repeat
evaluation may be conducted at the discretion of the Principal Investigator.
- Subjects with hepatic impairment as defined by liver transaminases or total bilirubin
> 3 × upper limit of normal (ULN). Repeat evaluation may be conducted at the
discretion of the Principal Investigator.
- Subjects considered a high risk for suicidal acts - active suicidal ideation as
determined by clinical interview OR any suicide attempt in 30 days prior to screening
- Subjects who have participated in a clinical trial with any pharmacological treatment
intervention for which they received study-related medication in the four weeks prior
to randomization OR subjects currently receiving treatment (within 1 dosing interval
plus four weeks) with an investigational depot formulation of an antipsychotic
medication
- Subjects who demonstrate overtly aggressive behavior or who are deemed to pose a
substantial risk of danger in the Investigator's opinion
We found this trial at
4
sites
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Indianapolis, Indiana 46222
Principal Investigator: Alan Breier, MD
Phone: 317-941-4287
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