Conditions: Schizophrenia
Keywords: schizophrenia Estrogen receptor agonist cognitive impairment negative symptoms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 95
Healthy volunteers: no

Brief 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 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.

Detailed description:

Arms:
arm 1: LY500307 150mg arm 2: placebo 6 pills of inactive drug arm 3: LY500307 75mg arm 4: LY500307 25mg

Interventions: intervention 1: LY500307 150mg intervention 2: LY500307 75mg intervention 3: Placebo intervention 4: LY500307 25mg
Intervention descriptions: intervention 1: LY500307 150mg daily dose (6 capsules of 25mg) for 8 weeks intervention 2: LY500307 75mg daily dose (3 capsules of 25mg and 3 capsules of placebo) for 8 weeks intervention 3: 6 placebo capsules daily for 8 weeks intervention 4: LY500307 25mg daily dose (1 capsules of 25mg and 5 capsules of placebo) for 8 weeks

Protocol document:
Prot_SAP_000.pdf: 
LY500307: Schizophrenia 
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Page 1 of 36 
 
 
 
 
 
 
 
 
The Efficacy and Safety of a Selective Estrogen Receptor Beta agonist 
(LY500307) for Negative Symptoms and Cognitive Impairment Associated 
with Schizophrenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator:  
Alan Breier, MD 
Department of Psychiatry 
IU School of Medicine 
NCT01874756 
 
 
 
 


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Table of Contents: 
 
1.0 
Background and Rationale 
2.0 
Preliminary Studies 
3.0 
Specific Aims 
4.0 
Study Design/Investigational Plan 
5.0 
Study Population (Inclusion/Exclusion Criteria)  
6.0 
Subject Recruitment 
7.0 
Study Procedures 
8.0 
Clinical Assessments and Procedures 
9.0 
Safety Assessments and Procedures 
10.0 Criteria for Repeat Assessments, Rescreening, and Discontinuation 
11.0 Laboratory Assessments 
12.0 Study Medication  
13.0 Concomitant Medication 
14.0 Adverse Events 
15.0 Steering Committee and Data Safety Monitoring Board  
16.0 Statistical Methods 
17.0 Privacy/Confidentiality Issues 
18.0 Record Retention 
 
Attachments 
A. 
Study Procedures Table 
B. 
Concomitant Medications 
C. 
References 


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1. 
Background and Rationale 
 
Schizophrenia is a devastating mental illness affecting approximately one percent of the world’s 
population (1).  It is ranked by the World Health Organization as one of the 10 leading causes of disability 
worldwide (2).  The unmet medical need associated with this illness is significant.  Unemployment, lack 
of independent living and relative social isolation are experienced by the vast majority of schizophrenic 
patients.  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 
significantly contribute to the functional disability associated with this illness (3).  Both of these symptom 
domains are relatively unresponsive to approved treatments for schizophrenia, the first and second 
generation antipsychotic drugs, which has prompted a substantial focus on identifying new targets and 
developing novel therapeutic agents for these symptom complexes (4).  A treatment that improves 
negative symptoms and/or cognitive impairment would have a major impact on the clinical landscape of 
schizophrenia by increasing the likelihood that patients with this illness would obtain higher levels of 
functioning and achieve an overall enhanced quality of life. 
 
Estrogen’s CNS Effects 
 
Estrogen has well documented CNS effects that include neuroprotection, plasticity and improved 
cognitive performance (5, 6).  The cognitive effects include improvement in working and verbal memory, 
(5) which is affected in schizophrenia (7-9).  In fMRI studies, estrogen plasma levels have been correlated 
with cortical activation patterns produced by cognitive tasks in healthy females (10).  Several 
neuroimaging studies have shown that treatment with estradiol in healthy women resulted in greater 
prefrontal activation during a working memory task compared to placebo (11-13).  Similarly, 
neuroimaging studies in schizophrenic populations have demonstrated heightened task-related cortical 
activation associated with estrogen levels.  For example, during a spatial rotation task, a positive 
correlation was found between cortical activation and estrogen levels in schizophrenic women (14).   
 
The above clinical trial results of estrogen and its effects on brain systems described support the potential 
therapeutic role of estrogen for negative and cognitive symptoms associated with schizophrenia.  
However, estrogen has had limited therapeutic application for male and premenopausal female patients 
with schizophrenia because of safety concerns including uterine cancer, heart disease, and feminization in 
men. 
 
Estrogen’s Therapeutic Effects in Schizophrenia   
 
Several lines of investigation have supported the potential therapeutic effects of estrogen for the negative 
and cognitive symptoms of schizophrenia.  Women with schizophrenia have a later age of onset and less 
severe course of illness with fewer negative symptoms compared to males, which has led to the 
hypothesis that estrogen may have a neuroprotective effect for schizophrenia (15).  Symptoms of 
schizophrenia are exacerbated during menopause and periods of the menstrual cycle when estrogen is low 
suggesting estrogen may have an “antipsychotic” effect (16).  Additionally, low levels of estrogen have 
also been associated with more severe negative symptoms and cognitive deficits, including working and 
verbal memory impairments, in females with schizophrenia (16, 17).  In a recent meta-analysis (18), 
estrogen therapy was shown to be effective in female patients with schizophrenia for both overall and 
negative symptoms (four randomized clinical trials, N=214 patients).  In a separate analysis of trials 
assessing the efficacy of estradiol (three randomized clinical trials, N=170 female patients), even larger 


LY500307: Schizophrenia 
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Page 4 of 36 
effect sizes were found for overall and negative symptoms (18).  In addition, clinical trials have shown 
that estradiol, as compared to placebo, improves cognition in females with schizophrenia (19, 20).   
 
Rationale for Estrogen Receptor Beta as a Therapeutic Target for Schizophrenia   
 
The effects of estrogen are mediated through two estrogen receptors – ER-alpha (ERα) and ER-beta 
(ERβ) which was discovered in 1996 (21-23).  ERα is the primary receptor for estrogen’s effects in 
reproductive systems.  Unlike ERα, ERβ is essentially absent from adult pituitary and endometrium so 
agonists for this receptor subtype would not be associated with risks for chemical castration, feminization 
effects in men and uterine cancer (24).  There is substantially greater ERβ than ERα receptor densities in 
the cerebral cortex and hippocampus (25), two brain regions implicated in the cognitive impairment and 
negative symptoms of schizophrenia (26).  The hybridization signal for ERα mRNA in cerebral cortex 
and hippocampus is very weak while ERβ mRNA signal is robust in those regions (25).  ERβ has been 
shown to mediate the cognitive-enhancing effects of estradiol on hippocampal-dependent spatial working 
memory tasks and, similarly, selective ERβ agonists improved spatial working memory and promoted 
hippocampal synaptic plasticity in wild-type but not ERβ null mutant mice (27).  Cognitive deficits have 
been demonstrated in ERβ knock out studies and cognitive enhancement in preclinical studies of selective 
ERβ agonists (22, 28).  ERβ mRNA is related to oxytocin and arginine vasopressin mRNAs in mice bred 
for extremes in social behavior (29) suggesting a possible role for ERβ in mediating negative symptoms.  
Selective ERβ agonists increase cortical GABA synthesis and increase removal of synaptic glutamate by 
astrocytes (21) which are plausible mechanisms to explain ERβ mediated therapeutic effects on cognitive 
and negative symptoms in schizophrenia.  Indeed, decreased cortical GABA-ergic tone and altered 
cortical glutamatergic neurotransmission are among the most prominent pathophysiological hypotheses to 
account for the negative and cognitive symptoms of this illness (30-33).  Because of ERβ’s unique CNS 
properties, it has been proposed that ligands for this site be developed as potential therapeutics for CNS 
disorders including schizophrenia (23, 24). 
 
LY500307, a selective ERβ agonist, as a potential therapeutic for schizophrenia 
 
LY500307: Eli Lilly and Company (Lilly) has established research programs to synthesize and develop 
selective agonists for ERβ.  Its lead compound is LY500307 which is a selective ERβ agonist with an 
excellent preclinical and Phase 1 profile (see below).  Lilly’s initial indication was for benign prostatic 
hypertrophy (BPH).  ERβ is the predominate estrogen receptor subtype in prostate (34).  In a BPH mouse 
model, orally administered LY500307 significantly reduced prostate weight without affecting circulating 
testosterone levels and it did not affect prostate weight in ERβ knock out animals.  A large, multi-site 
Phase 2 study (N=441) of LY500307 failed to achieve its primary endpoint of improvement in the 
International Prostate Symptom Score.  It was, however, safe and well tolerated with a paucity of adverse 
events and no clinical signs of ERα engagement such as suppression of testosterone levels. 
 
 
2. 
Preliminary Studies  
 
LY500307 Preclinical Development   
 
All of the LY500307 data presented in the application was obtained from Lilly data files (investigator 
brochures, study protocols, study summaries).  LY500307 is an orally active, small molecule that was 
synthesized by Lilly to maximize binding to the ERβ receptor and minimize binding to the estrogen ERα 
receptor.  LY500307 is highly potent and selective for ERβ.  In competitive binding assays, its affinity for 
ERα is 2.04 nM, while its affinity for ERβ is 0.16 nM, representing an approximately 12-fold selectivity 
towards ERβ.  LY500307 has negligible off target (non-estrogen receptor) binding.     


LY500307: Schizophrenia 
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Nonclinical pharmacokinetic studies in multiple species indicated that peak plasma concentrations 
(Cmax) of parent were observed from 0.5 to 8 hours after oral dosing.  Following Cmax, plasma 
concentrations declined with elimination half-life values ranging between 3.3 and 7.8 hours for parent and 
between 5.9 and 21.4 hours for metabolites after oral administration.  LY500307 was rapidly metabolized 
and the resulting metabolites were eliminated at a slower rate compared to the parent compound.  
LY500307 is highly bound (97.2% to 99.5%) to plasma proteins from mice, rats, monkeys and humans.  
The degree of plasma protein binding was independent of concentration over the ranges tested for all 
species.  It is highly lipophilic and readily enters the CNS compartment with quantifiable levels of C-14-
LY500307 in cerebrum, cerebellum, medulla and olfactory bulb.  Direct glucoronidation and/or sulfation 
were the primary metabolic routes identified in mice, rats and monkeys. 
 
The results of nonclinical safety, pharmacology and toxicology studies demonstrated an acceptable 
safety profile.  Non-clinical toxicology studies support 24-week exposures in humans.  No CNS, 
respiratory, or cardiovascular risks were identified at doses as high as 30 mg/kg in rats and mice and 1500 
mg/kg in monkeys.   LY500307 has weak effects at hERG (IC-50 >1mM).  In rat and monkey 1-, 6-, and 
9-month toxicity studies, the NOEL-defining toxicity was consistent with the pharmacology of an 
estrogen agonist and is considered to be non-life-threatening, able to be monitored, and generally 
reversible.  The NOEL was determined to be 1.0 mg/kg/day in the male rat and 1.5 mg/kg/day in the male 
monkey following 9 months of daily dosing.  
 
Phase 1 Studies  
 
In a single dose escalating study (SDES) (BPAC), healthy men (N=30, mean age: 44.3 years, age range: 
23-60 years) were assigned to placebo and one of the following oral LY500307 dosing arms:  0.5, 5, 25, 
125, 250, and 500 mg.  In a multiple dose escalating study (MDES) (BPAD), healthy men (N=34, mean 
age: 49.5 years, age range: 21-62 years) were randomized to a 2-week treatment course of placebo and the 
following oral LY500307 dosing arms: 0.5, 5, 25, and 100 mg/day.  
 
The pharmacokinetic concentration-time profiles of LY500307 post -single and -multiple oral doses 
indicates fast absorption, based on C-max within one hour following a single dose or multiple doses of 
LY500307 in most subjects, followed by a biexponential decline with a well-defined terminal elimination 
phase (Figure 1).  The terminal t1/2 of LY500307 is approximately 15 hours.  At steady state, the Cmax 
and daily exposure (area under the concentration versus time curve over the dosing interval) increased 
approximately 50% compared with those from a single dose or the first dose. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LY500307: Schizophrenia 
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Safety in Phase 1 was assessed in the SDES (BPAC) and MDES (BPAD) described above as well as a 
single dose (25 mg) 14-C-LY500307 distribution study (N=6 healthy male subjects) (BPAF).  Overall, 
LY500307 was well tolerated and associated with a paucity of adverse events (AEs).  There were no 
serious AEs reported and no clinically significant safety concerns encountered in any of the three studies.  
All AEs reported in these studies were mild to moderate in severity and all were self-limiting without 
discontinuation of LY500307 dosing.  Table 1 summarizes the AEs considered possibly/probably related 
to LY500307 from these studies.  In addition, LY500307 produced no statistically significant changes in 
plasma cortisol, estradiol, thyroid-stimulating hormone (TSH) or prolactin.  No significant effects were 
noted on vital signs, body weight or ECG recordings.  
 
 
 
 
 
 
 
 
 
 
Figure 1. Pharmacokinetic concentration-time profiles of LY500307 post -single and -multiple oral doses 


LY500307: Schizophrenia 
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Page 7 of 36 
Table 1. Summary of Adverse Events Possibly/Probably Related to LY500307 Treatment 
 
 
    Abbreviation: ID = identification; BM = bowel movement. 
    Data Source: Clinical Study Report for I1A-MC-BPAC; Clinical Study Report for I1A-MC-BPAD; Clinical Study 
    Report for I1A-MC-BPAF; bpag_v1_tfls_01dec201 
 
ERβ Selectivity and Effects on Testosterone:  Non-selective estrogenic ligands (e.g., estrogen, estradiol, 
selective estrogen receptor modulators, SERMs) suppress the hypothalamus-pituitary-gonadal axis, 
resulting in decreases in testosterone and other reproductive hormone plasma levels (35, 36).  The ERα, 
but not ERβ, receptor mediates the suppressing effects of these hormones (35, 36).  Because testosterone 
suppression is mediated by ERα and it is associated with less intra-subject variability than other 
reproductive hormones (e.g., luteinizing hormone), plasma total testosterone levels have been used as a 
biomarker of central ERβ selectivity in clinical trials.  Preclinical studies demonstrated dose-dependent 
effects of LY500307 on plasma total testosterone concentrations with engagement of ERα at the higher 
doses tested.  In the SDES, plasma total testosterone levels demonstrated significant dose-dependent 
decreases at doses at 25 mg and above (i.e., 125 mg, 250 mg and 500 mg).  Effects at 25 mg were small 
(12% change from baseline).  Testosterone suppression was reversible in all cases.  In the 14-day MDES, 
testosterone suppression did not occur at any dose including the highest dose tested which was 100 
mg/day.  The mean change from baseline in plasma total testosterone levels (nmol/dL) between the 100 
mg/day assigned group (N=6) and placebo assigned group (N=8) across all time points ranged from a 
difference of -2.50 (p=0.205) to 0.99 (p=0.621).  In the Phase 2 BPH study (see below), there were no 
effects observed on total testosterone or other reproductive hormones at any dose including 25 mg/day 
which was the highest dose tested.  These data suggest that 25 mg is an ERβ selective dose.  The MDES 
provide support for ERβ selectivity at doses up to 100 mg/day.    
 
Drug-drug interaction:  Based on data from definitive in vitro studies that assess cytochrome P450 (CYP) 
- mediated drug interactions and plasma concentrations of LY500307 from Phase 1 and Phase 2 trials, the 
risk for LY500307 to inhibit or induce major CYP isoform is low.  No mechanism-based inactivation of 
any of the CYPs tested by LY500307 was found.  These data suggest that LY500307 co-administration 
with most second generation antipsychotic medications and mood stabilizers (commonly metabolized by 
CYP3A4,5,6, CYP2C9,CYP1A, CYP2C19, or CYP2D6) is unlikely to lead to CYP-mediated DDI.   
 
 


LY500307: Schizophrenia 
Version: 05.01.17 (Amendment L) 
Page 8 of 36 
Phase 2 Study of BPH   
 
LY500307 was tested as a potential treatment for BPH in an outpatient, multisite 24-week, randomized, 
placebo-controlled Phase 2 dose finding study in men 45 years and older (median ages for the treatment 
groups ranged from 63.55 to 67.47 years) with lower urinary tract symptoms and enlarged prostates 
secondary to BPH.  Four hundred and forty one male subjects were enrolled and randomized to placebo or 
one of the following LY500307 treatment arms: 1, 3, 10, or 25 mg doses of LY500307.  LY500307 failed 
to achieve its primary endpoint of improvement in the International Prostate Symptom Score.  It was, 
however, well tolerated with a paucity of adverse events.  The incidence rates of serious adverse events 
(SAEs), total AEs, and early terminations due to AEs were low and comparable between placebo and all 
LY500307 treatment arms.  There was no evidence of effects on plasma total testosterone in any dosage 
arm.  Total testosterone data are shown for all dosage arms at baseline (week 0), week 12 and week 24 in 
Table 2.  Two consecutive post randomization plasma total testosterone values below 300 ng/dL, which is 
the lower limit of the normal range, was an a priori determined criterion for treatment discontinuation.  
Few subjects met this criterion and there was no relationship to study dose (placebo N=5, 1 mg N=3, 3 
mg N=0, 10 mg N=2, and 25 mg N=4).  There were no alterations in lipid levels or routine blood counts 
and no changes in weight and vital signs in subjects randomized to any LY500307 treatment dose.  In 
addition, LY500307 had no effects on reported sexual function.  The PK profile of LY500307 in BPH 
patients was similar to the PK profile in healthy men in the Phase 1 trials.  
 
 
 
                                                                                                                 
                                                                                                                 
While preclinical models provided compelling support for LY500307’s efficacy for BPH, it is unclear 
why the Phase 2 study failed to meet its primary efficacy endpoint.  It was speculated that the study’s 
highest dose of 25 mg/per day may have been too low and/or the advanced age of the BPH subjects may 
have contributed to the failure to demonstrate efficacy for BPH.  It is well known that as men age, the 
hypothalamus-pituitary-gonadal sensitivity to estrogen suppression decreases (37). 
 
Phase 1b/2a clinical trial in schizophrenia (blinded data) 
 
The Phase 1b/2a clinical trial in schizophrenia is ongoing. Thirty of the thirty subjects have completed the 
trial. Investigators are blind to study drug assignment; however there have been no serious adverse events, 
no evidence of total testosterone suppression (as defined by a 50% reduction since the Visit 2 value) (see 
Table 3), no evidence of QTcB prolongations (see Table 4), and no adverse events (AEs) considered 


LY500307: Schizophrenia 
Version: 05.01.17 (Amendment L) 
Page 9 of 36 
“probably related” to study drug. There have been eight AEs determined to be “possibly related” to study 
drug as indicated in Table 5 below.  
 
Table 3. Total Testosterone Levels (ng/dL) and Percent Changes in Testosterone from Baseline 
Subject Number Age
V1 (Screening)
V2 (Baseline)
Value (ng/dL)
Value (ng/dL)
Value (ng/dL)
% Change
Value (ng/dL)
% Change
Value (ng/dL)
% Change
B4001
25
659
450
524
(+)16.4
764
(+)69.8
497
(+)10.4
B4002
22
449
569
516
(-)9.3
581
(+)2.1
606
(+)6.5
B4004
47
545
530
465
(-)12.3
505
(-)4.7
587
(+)10.8
B4006
51
912
736
770
(+)4.6
828
(+)12.5
616
(-)16.3
B4007
36
472
377
513
(+)36.1
436
(+)15.6
426
(+)13.0
B4009
35
512
423
506
(+)19.6
370
(-)12.5
481
(+)13.7
B4010
23
516
585
572
(-)2.2
553
(-)5.5
516
(-)11.8
B4012
24
780
796
900
(+)13.1
844
(+)6.0
882
(+)10.8
B4015
19
323
334
342a
(+)2.4
329
(-)1.5
436
(+)30.5
B4016
50
379
412
416
(+)1.0
398
(-)3.4
479
(+)16.3
B4017
53
449
435
457
(+)5.1
416
(-)4.4
421
(-)3.2
B4019
53
416
563
Not Assessedb
N/A
487
(-)13.5
536
(-)4.8
B4021
27
707
675
825
(+)22.2
756
(+)12.0
749
(+)11.0
B4022
26
570
575
682
(+)18.6
704
(+)22.4
660
(+)14.8
B4023
36
543
344
561
(+)63.1
396
(+)15.1
356
(+)3.5
B4024
30
486
530
643
(+)21.3
410
(-)22.6
606
(+)14.3
B4025
23
398
497
429
(-)13.7
643
(+)29.4
545
(+)9.7
B4026
55
753
855
779
(-)8.9
546
(-)36.1
546
(-)36.1
B4027
21
438
492
477
(-)3.0
446
(-)9.3
414
(-)15.9
B4028
28
430
175h
394
(+)125.1
243g
(+)38.9
357
(+)104.0
B4030
40
419
444
525
(+)18.2
514
(+)15.8
517
(+)16.4
B4031
33
348
400
496
(+)24.0
401
(+)0.3
492
(+)23.0
B4032
47
398
349
350
(+)0.3
382
(+)9.5
414
(+)18.6
B4033
37
351c
242h
300d
(+)24.0
317f
(+)31.0
326
(+)34.7
B4034
32
326
311
383
(+)23.2
312
(+)0.3
345
(+)10.9
B4035
25
312
397
522
(+)31.5
541
(+)36.3
495
(+)24.7
B4036
36
385
340
471
(+)38.5
362
(+)6.5
322
(-)5.3
B4039
19
628
710
671
(-)5.5
667
(-)6.1
654
(-)7.9
B4041
21
503
439
570
(+)29.8
559
(+)27.3
535
(+)21.9
B4042
30
337e
357
335
(-)6.2
432
(+)21.0
393
(+)10.1
V3 (2 weeks)
V4 (4 weeks)
V6 (8 weeks)
 
b=Evaluation of testosterone on 11.13.13 was cancelled by the lab due to lab accident. Testosterone sample was drawn and assessed within normal range with a value of 487 ng/dL at 
subsequent visit on 11.25.13.  Therefore V3 testosterone was not assessed.
c=Visit 1 occurred on 02.10.14 and sample was drawn at 09:30 AM.  Result was reported on 02.12.14 with a value of 302 ng/dL.  Subject returned to clinic on 02.13.14 and testosterone was 
redrawn at 07:55 AM.  Result was reported on 02.14.14 with a value of 351 ng/dL, within normal limits. 
a=Visit 3 occurred on 10.18.13 and sample was drawn at 09:10AM.  Result was reported on 10.21.13 with a flagged value of 247 ng/dL.  Subject returned to clinic on 10.22.13 and testosterone 
was redrawn at 07:37AM.  Result was reported on 10.23.13 with a value of 342 ng/dL, within normal limits.  Subject did not meet discontinuation criteria as retest value was above 300 ng/dL.
h=Study inclusion is based on Visit 1 values because the result of Visit 2 values are received after study medication initiation/randomization.
g=Visit  4 occurred on 04.03.14 and sample was drawn at 07:13 AM.  Result was reported on 04.04.14 with a value of 259 ng/dL.  Subject returned to clinic on 04.09.14 and testosterone was 
redrawn at 08:26 AM.  Result was reported on 04.10.14 with a value of 243 ng/dL.  
f=Visit  4 occurred on 03.27.14 and sample was drawn at 07:42 AM.  Result was reported on 03.28.14 with a value of 285 ng/dL.  Subject returned to clinic on 04.03.14 and testosterone was 
redrawn at 07:27 AM.  Result was reported on 04.04.14 with a value of 317 ng/dL, within normal limits.  Subject did not meet discontinuation criteria as retest value was above 300 ng/dL.
d=Visit 3 occurred on 03.13.14 and sample was drawn at 08:14 AM.  Result was reported on 03.14.14 with a flagged value of 240 ng/dL.  Subject returned to clinic on 03.19.14 and 
testosterone was redrawn at 07:40 AM.  Result was reported on 03.20.14 with a value of 300 ng/dL, within normal limits.  Subject did not meet discontinuation criteria as retest value was 
above 300 ng/dL.
e=Visit 1 occurred on 03.17.14 and sample was drawn at 09:29 AM.  Result was reported on 03.18.14 with a value of 299 ng/dL.  Subject returned to clinic on 03.19.14 and testosterone was 
redrawn at 08:38 AM.  Result was reported on 03.20.14 with a value of 337 ng/dL, within normal limits.  Subject did not meet discontinuation criteria as retest value was above 300 ng/dL.
 
 
 
 
 
 
 
 
 


LY500307: Schizophrenia 
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Table 4. ECG QTcB's Values and Value Changes from  
Baseline 
 
ECG QTcB's Values and Value Chages from Baseline in Schizophrenia Patients Studied in Estrogen Receptor Beta Prot
Subject Number
Value (ms)
Value Change 
Since Baseline
Value (ms)
Value Change 
Since Baseline
B4001
396
(-)5
390
(-)11
B4002
390
(-)26
391
(-)25
B4004
404
(+)9
408
(+)13
B4006
403
(+)6
380
(-)17
B4007
444
(+)4
405
(-)35
B4009
394
(-)3
417
(+)20
B4010
389
(-)8
401
(+)4
B4012
393
(+)4
419
(+)30
B4015
378
(-)1
420
(+)41
B4016
438
(-)9
456a
(+)9
B4017
419
(+)2
412
(-)5
B4019
398
(-)4
414
(+)12
B4021
408
0
402
(-)6
B4022
414
(+)9
408
(+)3
B4023
421
(-)12
429
(-)4
B4024
412
(+)5
404
(-)3
B4025
403
(-)3
402
(-)4
B4026
403
(+)7
396
0
B4027
390
(-)12
404
(+)2
B4028
386
(-)4
383
(-)7
B4030
410
(+)11
405
(+)6
B4031
409
(-)21
405
(-)25
B4032
404
(-)5
404
(-)5
B4033
418
(-)22
412
(-)28
B4034
410
(+)4
413
(+)7
B4035
402
(+)5
405
(+)8
B4036
438
(+)18
405
(-)15
B4039
402
(-)6
416
(+)8
B4041
397
(+)27
378
(+)8
B4042
408
(-)41
412
(-)37
a= Average of 3 QTcB's was 447ms
406
401
416
370
430
449
408
395
397
440
396
405
389
397
397
379
406
407
397
420
390
V6
402
399
409
440
V1 (Baseline)
V4
Value (ms)
408
402
417
447
433
 
 
 
 
 
 
 
 
 
 
 
 


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Table 5. Phase 1b/2a Clinical Trial Adverse Events “Possibly Related” to Study Drug (blinded data) 
 
System 
Specific AE 
Start Date 
Stop Date 
Mild 
Moderate 
Severe 
Neuropsychiatric 
Somnolence 
31-Mar-2014 
a 
 
Xd 
 
 
Head “tightness” 
25-Dec-2013 
a 
X 
 
 
 
Insomnia 
27-Feb-2014 
a 
X 
 
 
Dermatologic 
Rash, nonpruritic 
06-Jan-2014 
16-Jan-2014 
X 
 
 
Endocrine 
Unilateral breast 
tenderness b,c 
04-Oct-2013 
31-Oct-2013 
X 
 
 
Gastrointestinal 
Increased appetite 
28-Feb-2014 
a 
X 
 
 
Genitourinary 
Urinary frequency 
02-Mar-2014 
a 
 
X 
 
 
Delayed ejaculation 
03-Sep-2013 
14-Sep-2013 
X 
 
 
a. Ongoing at the end of the end of the trial 
b. This event occurred in the absence of decreases in total testosterone and at a time when a new antipsychotic medication was   
    initiated 
c. Prolactin values are as follows: 22-Aug-2013 = 25.7 ng/mL, on 20-Sept-2013 = 49.5 ng/mL, and on 17-Oct-2013 = 14.6  
    ng/mL.  
d. Initially assessed as “mild” in severity on 28-Feb-2014, but increased to “moderate” in severity on 31-Mar-2014 
 
 
 
3. 
Specific Aims 
 
Several lines of investigation have demonstrated that estrogen is an effective treatment for the negative 
and cognitive symptoms of schizophrenia.  However, estrogen treatment itself is prohibitive for male and 
pre-menopausal female patients because of safety concerns that include uterine cancer, heart disease and 
feminization effects in men.  The effects of estrogen are mediated through two estrogen receptors – ER-
alpha (ERα) and ER-beta (ERβ) (24).  Data suggest that selective estrogen receptor β (ERβ) agonists may 
be an effective treatment for the cognitive impairment and negative symptoms of schizophrenia without 
the major safety risks of estrogen therapy.  The primary objectives of this application are to select the 
LY500307 dose that provides the best opportunity to assess full cortical target engagement and to assess 
efficacy of this dose for negative and/or cognitive symptoms in patients with schizophrenia.  The aims 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 single seamless, two-staged, Phase 
1b/2a adaptive design will be used.  The purpose of Stage 1 is to evaluate two LY500307 doses (25 
mg/day and 75 mg/day) to determine which dose should be advanced to Stage 2 for continued dose 
assessment, cortical target engagement, and efficacy assessments.  
 
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. 


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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.   
 
 
4. 
Study Design/Investigational Plan 
 
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 Stage1 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.  If these criteria were fulfilled at both doses, the larger of the 
two (75 mg/day dose) would be advanced to Stage 2. Furthermore, if 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 would be added to Stage 2 for evaluation.  This scenario then results 
in the following three arms in Stage 2: 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. 
 
In evaluating Stage 1 blinded safety and target selectivity (i.e., TT effects) data, the pattern of results 
(Tables 3, 4, and 5 above) suggest that both the 25 mg/day and 75 mg/day doses are safe and free of ERα 
receptor effects and would result in advancing the 75 mg/day dose to Stage 2.  It should be noted that 
inspection of the blinded TT data from 30 completed subjects reveals that the TT suppression Go/No Go 
criterion, which requires five of 10 subjects per arm to demonstrate at least a 50% decrease in TT from 
baseline for “No Go,” has been fulfilled as there has been no evidence of TT suppression.     
 
The trial will be run “seamlessly” which means that the transition from Stage 1 to Stage 2 will be 
conducted without significant interruption and without breaking the study blind.  The advantages of the 
two-stage seamless adaptive design are the efficient use of subjects, increased statistical power for final 
analysis and more rapid completion of the trial by minimizing  the time between the end of Stage 1 and 
commencement of Stage 2.  All data from the Stage 1 will be combined with Stage 2 data for the final 
analyses after the completion of Stage 2.  In Stage 1, there are 10 subjects per arm (a total of 30 subjects).   
 
Stage 2-Three Arm Dosing (Placebo, 75 mg/day, and 150 mg/day): During Stage 2 an additional 70 
subjects will be randomized in a 1:1:1.5 ratio, with 20 assigned to placebo, 20 assigned to 75 mg/day and 
30 assigned to 150 mg/day. Thus, a total of 100 subjects (30 subjects in Stage 1 plus 70 subjects in Stage 
2) are required for this study.  The final target engagement, efficacy, and safety analyses will include data 
from all 100 subjects and a dose-concentration-response analytic strategy that is highly sensitive to signal 
detection will be used.   
 
Rationale for Stage 1 Doses 
 
The selection of LY500307 25 mg/day dose for assessment in Stage 1 was based on the extensive 
preclinical, Phase 1 and Phase 2 BPH trial data sets.  This dose was safe, well tolerated and selective for 
ERβ receptors without engagement of ERα receptors as demonstrated by the lack of effects on total 
testosterone levels (Table 3).  The 75 mg/day dose was selected based on the Phase 1a multiple dose 
escalating study (MDES) that demonstrated 100 mg/day was safe, well tolerated and failed to affect 


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plasma testosterone levels.  Safety including potential changes in testosterone levels was carefully 
monitored throughout the trial.  If testosterone levels dropped below the normal lower limit of 300 ng/dL, 
a repeat value was assessed.  If the retest value was also below 300 ng/dL, the subject met discontinuation 
criteria.    
 
Rationale for Stage 2 Doses 
 
The rationale for selecting 150 mg/day as the higher dose option is based on data from Lilly’s Phase 1 14-
day multi-dose escalating study (MDES) of LY500307 in healthy male volunteers.  This study revealed 
that no dose, including the highest dose tested at 100 mg/day, suppressed testosterone or was associated 
with concerning adverse events.  Lilly’s Phase 1single dosing studies (BPAC and BPAF) reveal no AEs 
deemed to be “possibly/probably related” to LY500307 at 125 mg/day or 250 mg/day and only one AE 
(headache) at 500 mg/day (see Table 1 above). In addition to enhancing target engagement in the current 
Phase 1b/2a study, the 150 mg/day dose will allow for robust dose-concentration-response analyses of 
biomarker and efficacy endpoints across all arms tested (i.e., placebo, 25 mg/day, 75 mg/day, and 150 
mg/day) (see Section 16 below). 
 
Addressing Safety in Stage 2 
 
Escalating doses of selective ERβ agonists have the potential for losing ERβ selectivity and commence 
the engagement of ERα receptors which may produce “estrogen-like” effects including adverse events 
associated with estrogen therapy.  One such event is potential thromboembolic events (e.g., deep vein 
thrombosis, stroke, cardiovascular events).  However, the overall rate of thromboembolic events 
associated with estrogen therapy is relatively low and risk factors for these events include past history of 
thromboembolic events, advanced age, greater duration of exposure and higher dose estrogen preparations 
(35, 38-41).  We anticipate the risk to be somewhat reduced based on our study sample; the study sample 
is predominately young-to-middle aged (Stage 1 mean age of 33.9 years old) whereas advanced age is a 
risk factor for thromboembolic events during estrogen therapy.   
 
A comprehensive safety plan is included in protocol (see Section 9 below) to ensure the safety of subjects 
participating in Stage 2 and that the risk for “estrogen-like” adverse events including thromboembolic 
events is mitigated.  It has been demonstrated in Lilly’s Single Dose Escalating Study (BPAC) that 
LY500307 related TT suppression occurs relatively rapidly.  Therefore, potential cases of TT suppression 
in this study will be likely detected at week 1 (Visit 2.5), the first post-randomization TT assessment 
point.  Importantly, this relatively short exposure interval and close monitoring of ERα engagement 
greatly reduces the possibility of experiencing adverse events, particularly an estrogen-like induced 
thromboembolic event.  Moreover, related to the risk that higher dose estrogen preparations have greater 
thrombogenic potential than lower doses, this risk factor is addressed in the current protocol by purposely 
dosing LY500307 to avoid ERα receptor binding and thus negating the effects of full estrogen-like 
receptor activation that occurs with high dose estrogen preparations.  In addition, ERα engagement is 
closely monitored with serial TT sampling.  TT and safety will be assessed at screening, baseline, and 
weeks 1, 2, 4 and 8 during the treatment phase of the study.  
Rationale for Primary Endpoints 
 
Primary Aim 1:  fMRI/N-back was selected as the primary biomarker of cortical target engagement 
because it has been shown to be sensitive to estrogen (11) and numerous studies have consistently 
demonstrated that this paradigm demonstrates abnormal frontal and parietal activation in 
schizophrenia.(42-45) 
 


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Primary Aim 2:  The Negative Symptom Assessment Scale – 16-item (NSA-16) is a commonly used, 
validated instrument for assessing negative symptoms in schizophrenia clinical trials (46).  The three 
cognitive tests were chosen because 1) the literature indicates they are sensitive to estrogen (5), 2) they 
reflect core cognitive impairment in schizophrenia (47) and 3) they are contained in the Measurement and 
Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery 
(MCCB) which has been validated for schizophrenia treatment trials and endorsed by NIMH and FDA for 
studies of cognitive impairment associated with this illness (48).  The Hopkins Verbal Learning Test has 
6 alternative forms to mitigate practice effects and the Letter Number Sequencing and Spatial Span tests 
have minimal practice effects after the first follow up testing session.   
 
Primary Aim 3:  Both estrogen therapy and ERα agonists, but not selective ERβ agonists, robustly 
suppress plasma testosterone levels (35, 36).  Thus, decreases in plasma testosterone concentrations from 
baseline levels in the LY500307 arms would reflect ERα engagement.  Although schizophrenia and 
antipsychotic drugs are not directly associated with altered testosterone levels (49), antipsychotics may 
increase plasma prolactin levels which could secondarily reduce plasma testosterone levels (50). In 
addition, other factors such as smoking status, age and obesity may influence testosterone concentrations 
(51).  Thus each subject will be used as his own control in assessing LY500307 potential effects on this 
hormone to address the effects of potential confounds.   
 
NIMH Research Domain Criteria (RDoC) Initiative:  The NIMH RDoC initiative, which is a component 
of the NIMH strategic plan, encourages the assessment of dimensions of observable behaviors and brain 
functions that may cut across traditional diagnostic categories (see NIMH/RDoC web page).  RDoC 
principles have informed multiple aspects of the study design.  While the DSM diagnosis of 
schizophrenia will be used for entry into the protocol, this heterogeneous disorder will also be 
characterized by dimensional measures of symptoms, cognitive processes and neurobiological function.  
This will enable the evaluation in secondary analyses whether these dimensional measures predict 
treatment response.  Second, working memory and episodic memory outcomes will be evaluated across 
units of analysis, including behavioral, fMRI and ERPs.  Three working memory paradigms 
recommended by the RDoC Working Memory Workshop were selected: N-back (which is coupled with 
fMRI), Letter Number Sequencing and Spatial Span.  The ERP paradigms, P300 and MMN, both 
exemplify the construct of “Change Detection Tasks.”  Thus, the findings from this study will likely assist 
in the validation of the sensitivity of several key RDoC constructs to estrogen modulation across multiple 
levels of analysis. 
 
Clinical Research Site  
 
The IU Psychotic Disorders Program (IUPDP), which is directed by the PI (Breier) and part of the IU 
Department of Psychiatry, is located in Indianapolis, Indiana.  IUPDP research personnel will manage the 
day-to-day activities of conducting the trial, including subject recruitment, consenting and screening 
subjects, conducting study visits, performing assessments, and study medication management.  The 
IUPDP has three research psychiatrists, a fully dedicated study coordinator, two fully dedicated clinical 
research specialists, two fully dedicated subject recruiters, three fully dedicated research technicians, a 
data manager and three raters (1 PhD, 2 Masters level) who have been trained and have extensive 
experience in conducting the assessments in this application including the NSA-16 (46) and the cognitive 
tests used as primary outcome measures. 
 
Sample Size Determination   
 
Thirty subjects will be randomly assigned to three arms (1:1:1) in Stage 1.  In Stage 2, 70 additional 
subjects will be randomized to placebo, the selected LY500307 arm from Stage 1, or the 150 mg/day 
arm.  Thus a total of 100 subjects will be randomized for the study.  In a study of chronic schizophrenia, 


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Shekhar et al (52) reported significant effects of the mixed M1/M4 agonist xanomeline (N=20) on verbal 
and working memory (p<0.05) and trend effects of negative symptoms (p=0.08) with effect sizes up to 
0.9 (52).  Based on the estimates from a cross-over study of a nicotinic agonist in patients with 
schizophrenia (53), it is reasonable to expect an improvement in the working memory score with a mean 
of 4.5 and a standard deviation of 7.3 using data from the less effective of two doses in that study.  Thus 
for this study, we assume a treatment effect size of 0.61 between the placebo group and the LY500307 
treated group.  The power estimate based on the variance of the change is conservative for the proposed 
analyses that actually use baseline outcome values as covariates.  We will test the treatment effects on the 
three primary efficacy measures (negative symptoms, working memory and verbal episodic memory) at 
the end of Stage 2 with one-tailed tests at an overall alpha=0.1 (see Stage 2 Efficacy Analysis in Section 
16.0).  Adjusting for multiple comparisons, the test for each of the three individual efficacy outcomes will 
be performed at alpha=0.0333.  The fMRI data will be tested at alpha=0.05.  With 30 subjects each in the 
placebo, 75mg and 150 mg groups across the entire study, 10 subjects assigned to 25 mg/day from Stage 
1, and the employment of the dose-concentration-response analytic strategy, we will have >80% power to 
detect a beneficial treatment effect on each outcome for any effect size >0.61 (measured in SD of the 
change). 
 
 
5. 
Study Population (Inclusion/Exclusion Criteria) 
 
Medically stable male subjects with a confirmed diagnosis of schizophrenia as determined by the 
Structured Clinical Interview for DSM-IV-TR (SCID) (54) interview will be enrolled in the trial.  The 
rationale for including only males is based on the lack of data on females in the Lilly LY500307 Phase 1 
and 2 data sets.  If the results of the current proposal are positive, Phase 1 studies in females with 
schizophrenia could be rapidly conducted and females could then be potentially included in future Phase 
2 and 3 trials.  
 
Clinical trial guidelines established by the NIMH sponsored MATRICS initiative (55) was used for the 
proposed trial.  As recommended by MATRICS, subjects will meet DSM IV-TR diagnostic criteria for 
schizophrenia and will be clinically stable prior to enrollment.  Enrolling stable subjects will help to 
isolate changes in cognitive and negative symptoms apart from changes in other symptoms and clinical 
features.  Extrapyramidal signs may confound interpretation of therapeutic effects on cognition and 
negative symptoms so only subjects without significant EPS will be enrolled.  Treatments with 
anticholinergic properties will be monitored throughout the trial using the Anticholinergic Cognitive 
Burden Scale (ABS) (56). Guidelines developed for assessing the efficacy of agents for cognitive 
impairment associated with schizophrenia do not recommend excluding patients based on their 
cholinergic medication scores.  The 1:1:1.5 randomization used in this study will mitigate the preferential 
effects of medication properties on the experimental arm.  Analyses are based on change from baseline 
cognitive testing which will mitigate preferential effects of medication properties on the experimental 
arm.  Previously reported studies demonstrating positive effects of agents on cognition in schizophrenia 
did not screen out patients based on ABS scores.  Therefore, the ABS will be used to monitor 
psychotropic medications based on their anticholinergic effects and not used to determine 
inclusion/exclusion.  MATRICS recommends adding the investigational compound to a stable regimen of 
antipsychotic drug therapy to further minimize the likelihood that changes in psychosis and other clinical 
features of schizophrenia during the study will compromise the interpretation of primary drug effects on 
cognition.  The MATRICS guidelines do not recommend requiring minimum cut off scores on cognitive 
tests as inclusion criteria.  However, a minimum level of negative symptoms will be required for inclusion 
in the current study.   
 
Inclusion Criteria: 


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1. 18 to 65 years of age at study entry 
2. Male 
3. DSM IV-TR diagnosis of schizophrenia as confirmed by Structured Clinical Interview for DSM-
IV-TR (SCID) 
4. Outpatient or inpatient status 
5. Mild to moderate overall disease severity as defined by a CGI-S score of less than or equal to 4 
(moderately ill) at randomization 
6. Moderate levels of negative symptoms as defined by a PANSS negative symptom sub-score > 11.  
7. Clinical stability as defined by: 
a. No exacerbation of illness leading to an intensification of treatment in the opinion of the 
investigator within four weeks prior to randomization 
 
Exclusion Criteria: 
1. 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 
2. 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)  
3. Known or suspected history of thromboembolic events including deep venous thrombosis, stroke, 
venous thromboembolism, pulmonary embolism, paresis or paralysis that may be thrombogenic 
in origin.  
4. Subjects currently receiving testosterone replacement therapy or drugs that influence the 
hypothalamus-pituitary-gonadal axis.   
5. Subjects who have clinically significant extrapyramidal signs (EPS) as defined by a score of >20 
on the Simpson-Angus Scale (SAS) (57) 
6. 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. 
7. Subjects with known medical history of Human Immunodeficiency Virus positive (HIV+) status  
8. Subjects with an active seizure disorder  
9. Subjects with implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, 
TENS unit, ventriculoperitoneal shunt, or other contraindication to undergoing an MRI scan 
10. Known IQ less than 70 based on medical history 
11. Current DSM IV-TR diagnosis of substance dependence (excluding caffeine and nicotine)  
12. 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  
13. 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. 
14. 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. 
15. 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 
16. 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 
17. Subjects who demonstrate overtly aggressive behavior or who are deemed to pose a substantial 
risk of danger in the Investigator’s opinion 


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6.  
Subject Recruitment 
 
Subjects will be recruited through referring community mental health centers, treatment providers, invited 
to participate if they are included in our registry, and self-referrals through advertisement and word-of-
mouth.  
 
 
7.  
Study Procedures 
 
The following assessments and procedures will be administered according to the study procedures table 
(Attachment A).  All assessments will be completed by study personnel trained to administer the 
instruments and will be based on interviews with the subject or questionnaires completed by the subject.  
 
 
8.  
Clinical Assessments and Procedures 
 
Primary Efficacy Outcome Measures:  
 
Negative Symptom Assessment Scale – 16-item (NSA-16), a primary outcome measure, 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 which represents the 
overall assessment of a subject’s negative symptoms. The rating should not be an average of any 
particular behavior, but a gestalt of everything observed in the interview (58). 
 
Hopkins Verbal Learning Test-Revised, Wechsler Memory Scale-Third Ed, Spatial Span, and 
Letter-Number Sequencing are cognitive tests for verbal memory (Hopkins) and working memory 
(Spatial Span and Letter-Number Sequencing combined as a single composite score).  These tests are part 
of the MCCB (48) which has proven reliability for clinical trials of cognitive impairment associated with 
schizophrenia.  For each cognitive test, a multi-item score will be derived based on the raw item values 
according to the MCCB scoring manual.  Each of the individual item raw scores is standardized to age- 
and gender-corrected t-scores (mean=50, standard deviation=10).  Each working memory test will be 
converted in to a single domain score. 
 
Secondary Outcome Measures: 
 
MATRICS Consensus Cognitive Battery (MCCB) will be administered in its entirety at baseline, Visit 
4, and the end of study.  It is a reliable cognitive battery (test-retest reliability ~0.7 for most tests, (48).  
Small but statistically significant practice effects have been noted with speed of processing and problem-
solving subtests (1/5th of standard deviation).  To overcome these practice effects, alternate forms of 
MCCB will be implemented in this study.  The total average administration time of MCCB is 
approximately 75 minutes.  MCCB is comprised of seven cognitive domains and 10 related tests (Trail 
Making Test: Part A; Brief Assessment in Cognition in Schizophrenia: Symbol Coding; Hopkins Verbal 
Learning Test-Revised; Wechsler Memory Scale-Third Ed: Spatial Span; Letter-Number Sequencing; 
Neuropsychological Assessment Battery: Mazes; Brief Visuospatial Memory Test-Revised; Category 
Fluency: Animal Naming; Mayer-Salovey-Caruso Emotional Intelligence Test: Managing Emotions; and 
Continuous Performance Test-Identical Pairs).  For each cognitive test, a multi-item score will be derived 
based on the raw item values according to the MCCB scoring manual.  Each of the individual item raw 
scores is standardized to age- and gender-corrected t-scores (mean=50, standard deviation=10).  Each test 


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will be converted in to a domain score, with Working Memory and Speed of Processing domains 
consisting of 2 and 3 tests, respectively.  
Note: At day 14 and 42 only the Hopkins Verbal Learning Test-Revised, Wechsler Memory Scale-Third 
Ed: Spatial Span, and Letter-Number Sequencing will be administered.  At day 0, 28, and 56, the entire 
MCCB will be administered and the 3 tests that constitute primary outcome measures will be 
administered prior to the administration of the remainder of the MCCB so test administration order is 
maintained throughout the trial for the cognitive primary outcome measures.   
 
Clinical Global Impression Severity Scale (CGI-S) (59) will be used for repeated evaluations of global 
psychopathology. The CGI-S scale is widely used in schizophrenia research and is a single 7-point Likert 
scale rating severity of psychopathology on a scale of 1 (normal, not ill) to 7 (very severely ill). 
 
Clinical Global Impression Change Scale (CGI-I) (59) is used to assess the clinical change as 
compared to symptoms at baseline using a 7-point Likert scale, ranging from very much improved (1) to 
very much worse (7). 
 
The Positive and Negative Syndrome Scale (PANSS) (60) is an assessment instrument for general 
psychopathology and positive symptoms.   The PANSS contains 30 items that assess symptoms of 
psychotic disorders including positive, negative and general psychopathology.  The PANSS was chosen 
because of its widespread use in clinical studies of psychosis, and its demonstrated reliability in assessing 
psychopathology across diverse patient populations.  
 
Personal and Social Performance Scale (PSP) (61) is a 100-point, single item, clinician rated scale to 
assess 4 domains of functioning, including personal and social relationships, socially useful activities, 
self-care and disturbing and aggressive behaviors.  
 
Quality of Life Scale (QLS) (62) assesses multiple dimensions of quality of life.  It was developed 
specifically for schizophrenia populations and is commonly employed in clinical trials. 
 
Barnes Akathisia Scale (BARS) (63) is used to rate drug-induced akathisia.  Symptoms are rated on a 4-
point scale, with 0 being no akathisia and 3 being severe akathisia.  A global clinical assessment of 
akathisia is then scored on a 6-point scale, with 0 being no evidence of akathisia and 5 being severe 
akathisia. 
 
Simpson Angus Scale (SAS) (57) is a 10-item scale used to evaluate the presence and severity of drug 
induced Parkinsonism.  Each item is rated from 0 to 4. 
 
Calgary Depression Scale for Schizophrenia (CDSS) (64) is a nine-itemed structured interview 
specifically developed for assessment of depression in patients with schizophrenia.  Items are scored from 
0 (absent) to 3 (severe). 
 
Columbia Suicide Severity Rating Scale (C-SSRS) (65) captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviors during the assessment period.  The definition of 
behavioral suicidal events used in this scale is based on those used in the Columbia Suicide History Form 
(66).  During the baseline assessment, questions are in relation to lifetime experiences and all subsequent 
questioning is in relation to the last assessment.  
 
Anticholinergic Cognitive Burden Scale (ABS) (56) was developed by an interdisciplinary group of 
pharmacy and medical professionals using a systematic review identifying drugs with anticholinergic 
activity established in the literature.  Drugs are categorized based on their clinically relevant cognitive 


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C  Q  Z  G  C  R  D  C  G  S  J  F  C  H  P  T
0 back (target=C)
B  X  X A  G  G L  F  G  N  N T  C  P  P H
1 back
K  S  B  S  Q  M  M G  M  R  C  J  C  F  Q  F
2 back
N-Back Task
Scene Encoding Task
Figure 2. N-Back Task 
Figure 3. Scene Encoding 
effects. Summed scores reflect the total clinically relevant anticholinergic effects on cognition of all 
medications in a subject's drug regimen, with higher scores denoting higher burden. 
 
 
MRI Methods  
 
MRIs will be performed at the IU Center for Neuroimaging 
using an integrated 90-minute exam including structural 
and functional MRI (fMRI).  All scans will be completed 
on a newly installed (June 2012) research-dedicated 
Siemens MAGNETOM Skyra 3T 70cm bore whole body 
scanner using a 32-channel head coil.  Scans will include 
structural series for registration with functional tasks, to 
examine white matter integrity, and to rule out incidental 
findings, and fMRI and MR perfusion measures.  FMRI 
tasks will focus on episodic and working memory.   
Positioning and motion: Subjects are instructed to 
remain still during scanning and deformable foam cushioning is used to stabilize the head.  Real time 
image reconstruction and processing are used for quality assurance at the time of scanning.  If there is any 
problem the scan is repeated.  For fMRI, minor subvoxel-level translation or rotation is adjusted during 
post-processing.  Noise: Noise-attenuating headphones and ear stopples provide excellent noise reduction 
and permit adequate auditory perception. Longitudinal repositioning:  We will employ Siemens 
AutoAlign scanner software to help ensure maximum reproducibility. AutoAlign, which uses a 3D atlas 
for automated slice positioning, appears robust and to yield repeatable and accurate repositioning (67).  
Structural Imaging Sequences include: (1) Sagittal survey 3-plane localizer (2) Sagittal T1-weighted 
MP-RAGE 3D anatomical volume (3) 3D fluid attenuated inversion recovery (FLAIR) and (4) Diffusion 
tensor imaging (DTI).  Functional MRI Sequences include:  Echo-planar functional MRI and GRE Field 
map. 
 
fMRI activation tasks:  fMRI activation tasks will include Visual-Verbal 2-Back, Scene Encoding and 
Recognition, and Resting Connectivity paradigms, shown by our group and others to demonstrate reliable 
activation for the cognitive functions and brain regions of interest (68-78).  We have successfully 
implemented all tasks in multiple studies of patients with psychosis and other clinical populations, as well 
as in pharmacological imaging studies, and have detected task-related activation in expected brain 
regions. 
 
2-Back Visual-Verbal working memory task: Verbal working memory has been widely studied in 
terms of cognitive components and models (79-83), neural circuitry of the frontal lobes and basal 
ganglia (84), and its disruption in brain disorders such as schizophrenia (45, 85), MS (78, 86), and 
MTBI (70, 71), as well as in relation to estrogen status (11, 12, 87, 88).  Subjects view a string of 
consonant letters (except L, W, and Y).  The working memory load is varied parametrically via 
three task conditions: 0-back, 1-back, and 2-back (Figure 2).  The 0-back control condition has a 
minimal working memory load; subjects are asked to decide if the current letter matches a single 
target letter that is specified before the epoch begins. In the 1-back condition, they are asked to 
decide if the current letter matches the previous one.  During the 2-back condition, the task is to 
decide whether the letter currently presented matches the letter that has been presented two back 
in the sequence.  In our previous studies, this task has been highly robust in producing bilateral 
frontal and parietal activation in healthy 
young and elderly controls and sensitive 
to differences in patient groups (70, 71, 
77, 78).  Task length 6:09. 
 


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Scene Encoding and Recognition tasks: These tasks utilize stimuli and a task design modified 
from that used by Detre et al. in episodic memory studies in temporal lobe epilepsy (68, 69, 74).  
In their published studies and Drs. Saykin and McDonalds’ initial work, these tasks elicit reliable 
bilateral MTL activation in healthy children, adolescents, and adults, with a slight right 
hemisphere predominance.  During the blocked-design encoding trial subjects attempt to encode 
complex scenes for later recognition (Figure 3).   
The control condition consists of repetition of a single degraded version of one of the encoding 
stimuli.  During the event-related recognition trial the subject views target scenes intermixed with 
foils, and is asked to decide which were presented during the encoding trial. Task length for each 
trial is 5:15. 
 
Pseudo-Continuous Arterial Spin Labeling (pCASL) perfusion images will also be acquired to quantify 
any drug related changes in cerebral blood flow.  Subjects are asked to lie still and keep their eyes closed.  
Task length 5:14. 
 
Functional Imaging Stimulation and Physiological Monitoring Procedures:  All stimuli are presented 
through an MR-safe and compatible headphone and projector system (Psychology Software Tools, Inc.).  
Experimental tasks are presented by PC interface and are programmed using the Presentation software 
package. Responses are recorded electronically through an MRI compatible fiber optic button response 
system (Current Designs, Inc.).  This custom device is also connected to the sync pulse output of the 
scanner’s gradient amplifier and sends a TTL signal to the PC marking the time each volume is acquired 
for synchronization between scans, event-related fMRI stimuli, and button responses.  A comprehensive 
physiological monitoring system will be used with synchronized digital recording including pulse 
oximeter, respiratory belt, HR and BP measures, which will be available for analysis in relation to BOLD 
fMRI and PASL time series. 
 
Event Related Potentials (ERP) Methods   
 
Electroencephalography (EEG) will be recorded from a 32 channel, silver/silver-chloride scalp electrode 
montage using Neuroscan Inc. SYNAMPS-2 bioamplifier with a bandpass of .1 to 200 Hz (24 dB/octave 
roll off).  Electrode impedance will be maintained below 5 kOhms. EEG will be recorded continuously 
during the stimulus paradigms.  Three minute periods of resting EEG will be recorded for eyes open and 
eyes closed prior to the ERP paradigms.  All three ERP measures are highly sensitive to schizophrenia, 
with an effect sizes (d) > 0.7 (7, 89).  Auditory Steady State Response (ASSR) which synchronizes to 
the frequency and phase of periodic auditory stimuli, will be used to test auditory pathway integrity and 
possible ERβ modulation of glutamate and GABA transmission (90, 91).  ASSR power in the gamma 
range (40 to 59 Hz) is usually reduced in schizophrenia (d > .8; 10). Gamma frequency entrainment will 
be obtained to a series of 100 click trains (40 Hz; 1000 ms duration; 500 ms ISI; 90 dB).  After digital 
filtering (.1 to 55 Hz), ocularcorrection and artifact rejection, averaging (100 ms baseline and 1000 ms 
post-stimulus epoch) and baseline correction, we will measure event-related spectral perturbation (ERSP; 
mean power relative to baseline) at Fz to 40 click train stimulation (92), and predict larger ERSP values in 
treated patients.  Phase locking factor (inter-trial coherence) will also be measured, since this measure of 
synchrony is often affected in schizophrenia as well (7).  In addition, we will obtain QEEG recordings 
during the same ERP/MMN testing sessions.  This measure is one of the most commonly used indices to 
confirm CNS penetrance and cortical activity in early stage CNS drug development.  Increased average 
alpha power (8 to 13 Hz) across the set of electrode sites determined by QEEG in LY500307 treated 
subjects compared to placebo treated subjects will be the measure of activity utilized in this study.  
Mismatch Negativity (MMN) is an ERP component elicited by a deviant tone interpolated in a series of 
standard tones which indexes pre-attentive sensory memory, and is generated by the auditory and frontal 
cortices (89).  MMN amplitude is reduced in schizophrenia and has been correlated with level of 
psychosocial function in schizophrenia and degree of grey matter loss in frontal cortex and Heschl’s gyrus 


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(93).  MMN will be recorded to infrequent 1.2 kHz tones (0.05 probability, 50 ms duration) amid frequent 
1.0 kHz tones, with a 300 ms ISI and total of 1,600 tone presentations.  After digital filtering (.01 to 24 
Hz), ocular correction and artifact rejection, averaging by condition (100 ms baseline and 300 ms post-
stimulus epoch) and baseline correction, the standard ERP will be subtracted from the deviant ERP.  
MMN will be measured as the most negative sample in the difference waveform between 100 and 300 ms 
period at Fz, and it is predicted that MMN will be increased in treated subjects.  Auditory P300 
component  indexes working memory during stimulus discrimination and is decreased in schizophrenia 
with an effect size of about 0.9 (89).  ERPs will be elicited by infrequent target tone-pips of 40-ms 
duration presented pseudo-randomly, interspersed among frequent low-pitched tones (1000 Hz, 90 dB) 
with 1 s ISIs and 600 trials.  Subjects will respond to infrequent target tones using a button press.  Target 
ERP trials will be processed off line, using digital filtering with a low pass of 24 Hz, ocular correction, 
and artifact rejection for trials with data points exceeding + 100 microvolts prior to averaging trials within 
each condition.   After averaging using the epoch -100 to 600 ms after stimulus onset, P300 latency will 
be measured at the largest positive voltage sample between 280 and 600 ms at the Pz electrode site of the 
target ERP relative to baseline.  Peak amplitude will be measured as the mean voltage between + 20 ms 
about the peak latency at the Pz electrode site.  It is predicted that P300 peak voltage will be greater, and 
P300 latency shorter in treated subjects.  Total ERP testing time: about one hour. 
 
 
9.  
Safety Assessments and Procedures 
 
Vital Signs: Vital signs will be assessed at study visits per Study Procedures Table (Attachment A).  
Blood pressure, heart rate, and oxygen saturation will be taken in a seated position or supine position after 
a rest period of five minutes.   
 
Medical History: The subject’s lifetime medical history will be taken during the screening period. 
Medical history includes previous and current diseases.  
 
Physical Examination: A physical examination including a neurological examination, an assessment for 
breast tenderness and gynecomastia, thrombosis (e.g., calf tenderness, shortness of breath), and sexual 
dysfunction. 
 
Electrocardiograph (ECG): A supine, 12 lead ECG will be performed according to the Study 
Procedures Table (Attachment A). Potentially clinically significant ECG abnormalities will be interpreted 
by a local cardiologist at the discretion of the Principal Investigator 
 
 
10. 
Criteria for Repeat Assessments, Rescreening, and Discontinuation 
 
Repeat Assessments 
 
Screening Window 
-Screening assessments can be repeated within the screening window under the same screening 
number with the exception of eligibility criteria related rating scales/questionnaires. Subject 
diagnosis confirmation will not be repeated.  
 
-Morning (6am-12pm) Total Testosterone (TT) Plasma Levels:  As noted, TT will be assessed 
during screening.   
 
 


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Post Randomization 
-Morning (6am-12pm) Total Testosterone (TT) Plasma Levels:  See Section 12, Stage 2 Dosing 
Downward Titration 
 
Rescreening 
Subjects who screen fail may be rescreened one time, under a new screening number. If a subject is 
rescreened, all screening assessments (with the exception of the diagnosis confirmation) must be repeated 
and the stability criteria timelines must be met.  
 
Discontinuation  
Subjects will be discontinued under the following circumstances: 
 
ECG: Any subject with an absolute QTc of 450 msec or greater or a change from baseline of 60 
msec or greater during the active treatment phases  
 
Total Testosterone Suppression:  Subjects with a 50% reduction from baseline post dosing 
downward titration (See Section 12) will have values reassessed within one week of receipt. If the 
retest value is also a 50% reduction from baseline, the subject will be discontinued.  
 
Study Medication Non-Compliance: Significant noncompliance is defined as missing > 7 
consecutive days of study medication or > 20 cumulative doses during the entire study.  
 
If a subject discontinues from the study, discontinuation assessments will be at the discretion of the 
principal investigator. 
 
A subject may withdraw from the study medication at any time at his own request, or may be withdrawn 
at any time at the discretion of the principal investigator for safety, behavioral, or administrative reasons.  
 
 
11. 
Laboratory Assessments 
 
Laboratory assessments (blood and urine) will be collected at time points specified in Study Procedures 
Table (Attachment A) and analyzed by a local laboratory with the exception of the urine dipstick 
assessments which will be collected and analyzed onsite. 
 
A total of 26 mL of blood will be collected at Visit 1, 14 mL at Visit 2, 10 mL of blood at Visits 2.5 and 
3, 17 mL at Visit 4 and 23 mL of blood at Visit 6.  
 
Laboratory assessments to be completed:  
 
complete blood count with differential (CBC w/diff) 
comprehensive metabolic panel (CMP) 
hepatitis panel 
hemoglobin A1c (HgbA1c) 
lipid panel 
testosterone plasma levels (Free and Total) 
thyroid stimulating hormone level (TSH) 
urine toxicology screen 
Luteinizing Hormone 
Prolactin 
 


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Pharmacokinetics (PK):  Pharmacokinetic (PK) blood samples to determine LY500307 plasma 
concentration will be obtained according to the Attachment A.  The exact time of the blood draws and 
dosing will be recorded.   
 
 
12. 
Study Medication 
Study medication will be taken by mouth once daily.  During Stage 1 doses will consist of 25 mg, 75 mg, 
and placebo.  During Stage 2, placebo, LY500307 75 mg/day, and LY500307 150 mg/day will be 
administered as six blinded study drug pills per day.  LY500307 and matched placebo will be supplied by 
Lilly for the study.  Placebo capsules will look like LY5000307, with matching shape, taste, and color.  
All study medication supplies will be labeled, stored, reconciled, and destroyed according to applicable 
regulatory requirements.  A Certificate of Analysis, the expiry date, and a statement of GMP compliance 
will be supplied by Lilly. 
 
Stage 2 Dosing Downward Titration 
 
If total testosterone suppression is confirmed during the study (a 50% reduction from baseline post 
randomization), subjects will be blindly switched to the next lowest dosing arm for the remainder of the 
trial.  Thus, a subject randomized to 150 mg/day will be titrated down to 75 mg/day, and those 
randomized to 75 mg/day will be titrated down to placebo, and those randomized to placebo will continue 
on placebo.  
 
Stage 2 Continued Dose Assessment 
 
The first 10 subjects randomized to 150 mg/day will be reviewed by the Data Safety Monitoring Board 
(Section 15 below) to determine the safety of further randomizations at this dose. If five or more of 10 
subjects randomized to 150 mg/day meet the TT suppression criteria as described in Section 12 above, 
that dose will be dropped from Stage 2 and all future newly randomized subjects will be randomized to 
placebo and 75 mg/day in a 1:1 fashion. (Note: ERα receptor engagement by LY500307 insures full 
engagement of ERβ receptors.  Thus, if 150 mg/day proves to be a TT suppressing dose, these data 
provide support that the 75 mg/day dose is fully activating ERβ receptors and therefore increases 
confidence that the primary aim of this study [i.e., assessing the ERβ receptor as a target for innovative 
therapeutics for schizophrenia] will be achieved).  
 
 
Treatment Compliance 
 
Compliance with medications will be assessed at each study visit by direct questioning and study 
medication count of unused study medication and packaging to be returned at each visit.  Study 
medication dispensing records will be obtained.   
 
 
13. 
Concomitant Medication 
  See Attachment B. 
 
 
14. 
Adverse Events 
 
Adverse events (AEs), especially those for which the relationship to study medication is not “unrelated,” 
will be followed up until they have returned to baseline status or stabilized at the discretion of the 


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principal investigator. If after the follow-up period, return to baseline or stabilization cannot be 
established an explanation will be recorded in the source documentation. 
 
 
15. 
Steering Committee and Data Safety  
 
Monitoring Board 
 
The Steering Committee will serve as the operational governing board for the project.  The Steering 
Committee will monitor and review reports from the Data Safety Monitoring Board (described below) 
and any serious AEs.  It will oversee the conduct of the trial and progress towards meeting study 
milestones.  It will meet following an award notice and quarterly during the conduct of the trial.  The 
Steering Committee will be chaired by the study PI and will include the CTSI Director, senior statistician, 
senior pharmacologist, Lilly representative ex officio, NIH Project Scientist, NIH Program Officer, and 
two external scientists with expertise in early stage clinical trials and statistics.  The Steering Committee 
will be charged with the review of all relevant data at the end of Stage 1 with the purpose of determining 
if Go/No go criteria has been met.  The relevant data include adverse events considered “probably” and 
“possibly” related to study drug or study procedure, QTcB values, and TT levels.  
 
Steering Committee, Eli Lilly scientists and NIH scientists and program officers determined that the Stage 
1 sample size (10 subjects per arm) was too small to draw conclusions about cortical target engagement 
and efficacy and therefore these related endpoints will not be considered in the Go/No Go decision.  
The IU Adult Psychiatry Data Safety Monitoring Board (DSMB) will be responsible for data and safety 
monitoring.  DSMB is responsible for reviewing study procedures, AEs, safety mailings (if applicable), 
enrollment, active subject progress, drop-out rates, and ongoing conduct of the research.  The DSMB 
members can ask questions and make comments and/or recommendations to the investigators.  The IRB 
is notified of significant findings by way of the DSMB meeting minutes at the time of continuing review.  
DSMB members consist of Department of Psychiatry faculty members who are not investigators on this 
trial.  Data on the number of subjects enrolled and the number of AEs will be reviewed by the Board at 
least quarterly and more frequently if needed.  The resulting report will be issued to the IU IRB at least at 
the time of continuing review or more frequently by request.  Any unanticipated events will be 
immediately directed to the PI who will follow the IRB reporting procedures.  
 
The DSMB will be responsible for reviewing all safety and testosterone data for the first 10 subjects 
treated with 150 mg/day in Stage 2 to determine if it is safe to further randomize subjects to this dose (as 
described in Section 12 above).  
 
 
16. 
Statistical Methods 
 
Data Management   
 
Data management will be performed by the Indiana CTSI Design and Biostatistics Program under the 
direction of Dr. Lourens.  The study database will be set up in OnCore clinical trial software system for 
data acquisition and management, including establishing a trial eCRF, procedures for randomization and 
biomarker acquisition and tracking.  All procedures will conform to FDA GCP requirements.  Data will 
be quality checked and entered into data analytic programs on a continual basis throughout the conduct of 
the study to be certain analyses of all relevant variables are available on the established timeline for the 
ADC to make the Go/No go decision at the end of Stage 1.  
 


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Stage 1 Dose Selection Analyses 
 
Go/No go criteria:  At the end of Stage 1, relevant data will be provided to the Steering Committee to 
make the Go/No go decision.  Two LY500307 doses (25 mg/day or 75 mg/day) will be evaluated in Stage 
1 to determine which dose will be advanced to Stage 2 for continued dose assessment, cortical target 
engagement and efficacy assessment analyses. Advancement to Stage 2 will be determined according to 
the following Go/No go criteria: 1) Lack of a safety signal as defined by SAEs, concerning AEs deemed 
to be probably related to study medication, absolute QTcB of 450 msec or greater or a change from 
baseline of 60 msec or greater during the active treatment phases, and  2) lack of TT suppression as 
determined by a decrease in total testosterone plasma concentrations from baseline levels of at least 50% 
in at least 5 of 10 subjects per LY500307 dosing arm for two of three consecutive post-randomization 
values.  Testosterone suppression reflects ERα engagement and lack of ERβ selectivity.   
 
Stage 2 Continued Dose Assessment, Cortical Target Engagement, and Efficacy Assessment Analyses 
 
Data collected from both stages will be combined for a final analysis. Providing the 150 mg/day dose is 
not dropped from Stage 2 because of TT suppression, a dose-concentration-response analysis will be used 
as the primary analytic approach with a secondary approach being based on intent-to-treat principles. If 
the 150 mg/day dose is dropped from the Stage 2 of the trial, intent-to-treat will be the primary analytic 
approach used and dose-concentration-response will be the secondary approach.  Both methods are 
described subsequently:  
 
Dose-Concentration-Response Analyses:  A simultaneous Pharmacokinetic (PK)/Pharmacodynamic (PD) 
modeling approach will be employed. Each subject’s LY500307 blood concentration measurements will 
be utilized in conjunction with a population PK model that was previously developed for this compound 
internally at Lilly.  This PK model, based on assumptions derived from thermodynamic laws, will be used 
to generate individual-specific exposures, specifically the area under the concentration time curve 
generated from empirical Bayes estimates for PK parameters for each subject conditional on their 
concentration measurement.  The subject-specific exposure estimate from the model will then be 
compared to the observed responses at the 8 week time point to construct a dose-concentration-response 
model.  The use of individualized concentration exposure values will increase the range of observations 
utilized in comparison to a strict dose-response analysis.  The dose-response analysis is limited to four 
points (placebo (i.e., zero dose), 25 mg/day, 75 mg/day and 150 mg/day) to define the relationship with 
response.   
 
It is anticipated that at any given dose there will be variability in the observed individual concentration 
exposures.  The dose-concentration-response analysis will provide additional “points” that will be shared 
across subjects to assist in defining the nature of the concentration response relationship.  This will be 
particularly important if the relationship has an emax or sigmoid emax shape with multiple parameters to 
be identified. The four concentration response relationship types will be explored; linear, exponential, 
emax and sigmoid emax, and the models will be implemented using a linear or nonlinear mixed effects 
modeling framework in NONMEM VII to facilitate sharing of data across subjects while preserving 
within-subject correlation.   
 
There will be two tiers to the examination of whether there is a concentration effect related signal.  The 
first “test” is based on the change in the objective function value when a concentration factor is included 
in the model as either a linear or exponential effect.  That is, is there any detectable effect of incorporating 
the individualized concentration (we will use the area under the curve derived from the Empirical Bayes 
Estimates of the PK parameters for each subject).  An alpha level for significance of 0.05 will be used.  If 
there is a significant difference in the evaluation at test 1, the additional model structures will be 


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evaluated to determine what “shape” appears to best describe the relationship between concentration and 
response.   
 
As stated above, four concentration response relationship types will be compared (linear, exponential, 
emax, sigmoid emax).  These are standard PD relationships and, in particular, the emax and sigmoid emax 
models are based on assumptions that derive from receptor occupancy theory and thermodynamic laws 
similar to the PK model.  These models will be constructed and tested utilizing a linear/nonlinear mixed 
effects modeling approach.  Objective function value differences, information criteria (e.g. AIC) and 
simulation based model performance evaluation techniques such as visual predictive checks will be 
utilized to evaluate model performance and guide model selection for the concentration effect 
relationship.  Once a model is selected, the responses for a particular dosage can be simulated, 
incorporating between subject variability as well as parameter uncertainty identified using the modeling 
approach described above.  These simulations will generate a distribution of predicted responses for 
dosages of interest (including placebo as the zero dose condition).  The simulated/predicted responses can 
be examined to evaluate whether or not there is overlap in the distributions by percentile and provide an 
answer as to whether or not a particular dosage administered to subjects results in a distinguishable 
difference in response from placebo.  In addition, the model can be used to examine the effect of 
increasing the numbers of subjects to distinguish drug effect from placebo at any number of dosages 
under different trial conditions. 
 
Intent-to–Treat Analyses:   Point estimates and the corresponding confidence intervals for the primary 
study endpoints (biomarkers and efficacy measures) at week 8 will be obtained.  Statistical tests will be 
performed based on one-sided test at the 10% level of significance with an adjustment for multiple 
comparisons for the 3 primary efficacy outcome measures with each primary measure tested at an alpha 
threshold of p<0.0333 as noted above.  One-tailed tests are planned because the main interest of this study 
is to determine if LY500307 is superior to placebo and thus has produced a sufficient efficacy signal in 
one or more of the three primary efficacy outcome measures to warrant further assessment in subsequent 
larger, confirmatory trials.  It is therefore a priority of this data analytic plan to avoid a “false negative” 
(i.e., falsely concluding LY500307 lacks efficacy) that may lead to prematurely terminating further 
development of the compound.   
 
A “per protocol” analysis will restrict the analysis to subjects who receive minimal exposure to the 
intervention, have a minimal number of longitudinal evaluations, and/or are free of major protocol 
violations.  A “completer” analysis will only include subjects who completed treatment without exiting or 
prematurely terminating from their assigned treatment.  Because subjects may be removed differentially 
across the treatment arms in these analyses, both approaches are vulnerable to differential selection bias 
and will be interpreted cautiously. 
 
Repeated Measures Analyses:  Most of the study outcomes are observed repeatedly at well-defined time-
points post-randomization, so the primary analyses are based on mixed models for repeated measurements 
(MMRM).  This includes the mixed effects models for continuous outcomes (normally transformed if 
necessary) as implemented in PROC MIXED in SAS in which subjects are included as random effects.  
The fixed-effects predictors include the overall mean, the treatment effect, the time effect, the treatment × 
time interaction plus selected covariates.  Initially, time will be treated as a categorical variable to avoid 
arbitrary assumptions on the nature of the trend over time.  Hypotheses will be tested by deriving 
contrasts among the model parameters, including between-group differences at the end of study, and the 
effect size of treatment will be estimated accordingly.  This primary analysis will be applied to each of the 
primary and secondary outcomes. 
 
Covariates in Regression Models:  The baseline value of the outcome, centered about its sample mean, 
will be included in each analysis.  The baseline value tends to correlate with post-randomization 


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outcomes, and this maneuver reduces residual variance, thus increasing statistical power and the precision 
of the estimated treatment effect.  Otherwise, only a small number of prognostic factors, e.g. age, found to 
be imbalanced at baseline, will also be entered into the model. 
 
Missing Data: For this study, missing data falls in to one of two general categories:  The first is data that 
is missing because of missed visits or early termination.  The second is related to incomplete data.  The 
former will not affect the results of the mixed-effects model, which is unbiased if missing-at-random 
assumptions are met; sensitivity analyses will also be performed as described below.  The problem of 
incomplete data in composite measures will be addressed in the case of the cognitive measures by 
following MATRICS Neurocognition Committee guidelines for imputation (94).  For other instruments, 
total and subscale scores will be imputed using the average of the available items as long as 80% or more 
of the individual items are available.  A low dropout rate is anticipated because subjects will have met a 
priori clinical stability criteria before randomization and those agents will not be altered throughout the 
course of the active treatment phase.  For drop-outs, sensitivity analyses will be performed using a variety 
of imputed values, including best-case and worst-case scenarios, as well as multiple imputations if drop-
out is higher than expected.   
 
Other Confounders Arising Post-Randomization:  Analyses will be conducted to investigate: (a) 
adherence to the assigned study medication, (b) co-administration of psychotropic medications, and (c) 
discontinuation from the study intervention, and logistic regression analysis will be applied to investigate 
these factors.  First, it will determine whether these effects occur differentially across the treatment arms 
suggesting that a differential selection bias may have influenced the results.  Then, whether baseline 
characteristics are predictive of any behavior will be evaluated.  This will include demographic 
characteristics, initial severity as measured by the baseline values of the outcome variables, and clinical 
characteristics such as diagnoses and medications taken at baseline.  Finally, these confounding factors 
will be included as covariates in the primary analyses to investigate whether the conclusions on treatment 
effects are altered. 
 
Pharmacokinetics (PK):  These data will be used in post hoc analyses to potentially explain inter-subject 
variability and toxicity. 
 
Brain Imaging Analyses  
 
Quality control, preprocessing and statistical analyses for all scans (see "MRI Methods") will follow 
established protocols as in our previous publications (e.g., working memory (95-97), episodic memory 
(98), Resting DMN connectivity (99), PASL perfusion (100), DTI (101, 102), structural MRI (103-105)).  
Region of interest (ROI) predictions for LY500307 treated vs. placebo effects are as follows:  working 
memory (increase, frontal & parietal), episodic verbal encoding/retrieval (increase, hippocampal & 
DLPFC) and resting state (increase DMN & hippocampal/DLPFC connectivity). PCASL perfusion may 
show parallel increases to fMRI (above).  DTI white matter tractography and gray matter density/cortical 
thickness will be examined for possible drug effects such as improvement in GM and WM markers.  
Additional exploratory analyses will assess whether baseline imaging variables predict treatment response 
and relationships with cognition and ERP measures (below) will also be evaluated. 
 
Event Related Potentials Analyses   
 
The data analytic plan for the three ERP measures (P300, MMN, and ASSR ERSP) will follow the 
repeated measures approach outlined above for other secondary variables and described in our previous 
protocols (7, 8, 92).  Each variable is listed with the predicted effect on the LY500307 treated compared 
to the placebo treated control group:  P300 amplitude (increased), P300 latency (decreased), MMN 
amplitude (increased), ASSR ERSP power (increased).  In exploratory analyses, it will be tested whether 


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baseline ERP values predict response on the primary and secondary clinical outcome measures in the 
treated groups. 
 
 
17. 
Privacy and Confidentiality Issues 
 
Confidentiality will be protected by ensuring all research staff have been properly trained in 
confidentiality and human subject research procedures, coding all subject information when 
possible, and by securing subject files in a locked filing cabinet or on secured databases with 
access available only to the principal investigator and research staff. Furthermore, data entered 
into a computer database will only use subject codes on secured computers that will be password 
protected with access available only to the principal investigator and research staff. Any 
screening information obtained from potential research subjects who subsequently do not 
participate in the research study will be destroyed. 
 
 
18. 
Record Retention 
 
Paper copies of medical records and source documentation will be kept for seven years after the study is 
closed with the IRB. One year after study closure, the documents will be shipped to the Indiana 
University Department of Psychiatry long-term storage facility until destruction. 
 


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ATTACHMENT A 
Study Procedures Table 
Visit
1
2
2.5
3
4
5
6 /ET
Day
0
7
14
28
42
56
Visit Window (days)
0-30
5-9
5-9
11-17 11-17 11-17
Informed Consent
X
SCID & Demographics
X
Med/Psych/Medication History
X
Physical Exam
X
Xg
Xg
Xg
Xg
Xg
X
Vitals
X
X
X
X
X
X
X
ECG
X
X
X
BARS & SAS
X
X
X
X
NSA-16 & CDSS
X
X
X
X
X
CGI-I
X
X
X
X
CSSRSf
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
PANSS, PSP, EQ-5D, & Quality of Life
X
X
X
Current Substance Use Habitsh 
X
X
X
X
X
Hopkins Verbal Learning Test-Revised, Wechsler 
Memory Scale-Third Ed: Spatial Span, and Letter-
Number Sequencinga
X
X
MCCB
X
X
X
MRI
X
X
ERP
X
X
X
Labs (CBC w/ diff, CMP, Luteinizing Hormone, 
Prolactin)c,e
X
Xb
X
X
Testosterone (Total and Free)c,e
X
X
X
X
X
X
Urine Toxicology
X
X
Hepatitis Panel
X
TSH, Lipid Panel, and HgbA1cc,e
X
X
PK Blood Drawd,e
X
X
X
X
Adverse Event (AE's)i
X
X
X
X
X
X
Concomitant Medication & ABS
X
X
X
X
X
X
X
Medication Dispensation
X
X
X
X
Medication Accountability
X
X
X
X
 
bIf Visit 2 occurs within 14 days from Visit 1, the following labs will NOT be repeated at Visit 2: Luteinizing Hormone, CBC w/ diff, CMP, Prolactin
hLifetime substance use will be captured at Visit 1.
iPre-existing medical conditions will be tracked as AE's at the discretion of the principal investigator.
aHopkins Verbal Learning Test-Revised, Wechsler Memory Scale-Third Ed: Spatial Span, and Letter-Number Sequencing are included in the MCCB. At Visit 3 and 
5 they will be administered separately from the full MCCB. 
gBrief physical examination will be performed at Visits 2-5 including a general examination assessing for health changes, an assessment for breast tenderness, 
gynecomastia, sexual dysfunction, and thrombogenic events
cLabs and baseline assessments to be obtained pre-dose 
dPK samples will be collected from all randomized subjects. PK samples will be collected at Visits 2.5, 3, 4, and 6.  The exact time of the blood draws and dosing 
will be recorded.
eAll blood samples for clinical laboratories will be drawn in the morning after an 8-hour overnight fast
fBaseline version of CSSRS will be conducted at the screening visit/Visit 1. The “Since Last Visit” version will be used on subsequent visits. 
 


LY500307: Schizophrenia 
Version: 05.01.17 (Amendment L) 
Page 30 of 36 
ATTACHMENT B 
Concomitant Medication Table 
Medication
Allowed
Notes
Amphetamines (e.g., methylphenidate, 
dextroamphetamine)
Yes-Conditional
Stable dose, no changes or additions 
for one week prior to screening and 
during the trial
Androgens
No
Antiemetics with dopamine blocking 
properties (eg., metoclopramide, 
domperidone, others)
No
Antiepileptic mood stabilizers
Yes
Stable dose, no changes or additions 
for one week prior to screening
Antihistamines, nonsedating (eg., 
loratidine, fexofenadine, cetirizine)
Yes
Antihistamines, sedating (e.g. 
diphenhydramine, hydroxyzine, 
meclizine, benztropine)
Yes
Stable dose OR No use within 8 hours 
prior to cognitive assessments
Antipsychotic medications
Yes
Barbiturates
No
Benzodiazepines
Yes
Stable dose OR No use within 8 hours 
prior to cognitive assessments
Bupropion
Yes
Stable dose, no changes or additions 
for one week prior to screening
Corticosteroids (except topical, 
intranasal, or inhaled)
No
Decongestants (eg., pseudophedrine)
Yes
Stable dose OR No use within 8 hours 
prior to cognitive assessments
Dicyclomine
No
Estrogens
No
Herbal medications or Over the Counter 
medications w/ primary CNS activity
No
Ketamine
No
Lithium
Yes
Stable dose, no changes or additions 
for one week prior to screening
MAOIs
Yes
Stable dose, no changes or additions 
for one week prior to screening, patient 
must maintain low tyramine diet
Methadone
No
Mirtazepine
Yes
Stable dose, no changes or additions 
for one week prior to screening
Muscle Relaxants
Yes
Stable dose OR No use within 8 hours 
prior to cognitive assessments
Nicotine Replacement
Yes
Opiates
No
Progestins
No
Benzodiazepine derivative sleeping 
medications (eg., zolpidem)
Yes
Stable dose OR No use within 8 hours 
prior to cognitive assessments
SNRIs
Yes
Stable dose, no changes or additions 
for one week prior to screening
SSRIs
(note: Citalopram must be at dose of 40 
mg or less)
Yes
Stable dose, no changes or additions 
for one week prior to screening
Tricyclic antidepressants
Yes
Stable dose, no changes or additions 
for one week prior to screening
Trazodone
Yes
Stable dose OR No use within 8 hours 
prior to cognitive assessments
 


LY500307: Schizophrenia 
Version: 05.01.17 (Amendment L) 
Page 31 of 36 
ATTACHMENT C 
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