Conditions: Alzheimer Disease
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: yes

Brief summary:
This project seeks to develop a novel disease-modifying compound for Alzheimer's disease (AD).

Detailed description:
The primary objective of this study is to evaluate the safety, tolerability, and pharmacokinetics of BMS-984923 in healthy participants. A secondary objective of this study is to conduct a receptor occupancy sub-study aimed at determining drug receptor occupancy at each dose using \[18F\]FPEB Positron Emission Tomography.

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None

Interventions: intervention 1: BMS-984923
Intervention descriptions: intervention 1: Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: Discharge following the completion of all scheduled procedures.

Protocol document:
Prot_SAP_000.pdf: 
Title: Evaluating the Safety, Tolerability, Pharmacokinetics and Receptor 
Occupancy of BMS-984923 
ClinicalTrials.gov ID: NCT04805983 
Date: 12/15/2021 
Document: Protocol and SAP 


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HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
(2016-1)
Protocol Title: An Open-Label, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Receptor Occupancy of BMS-984923
Principal Investigator: Adam Mecca, MD, PhD 
Version Date: November 29, 2021 
(If applicable) Clinicaltrials.gov Registration #:  NCT04805983
INSTRUCTIONS
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needed by the IRB to determine whether a study meets approval criteria. Read the following instructions 
before proceeding:
1.
Use this protocol template for a PI initiated study that includes direct interactions with research 
subjects. Additional templates for other types of research protocols are available in the system Library.
2.
If a section or question does not apply to your research study, type “Not Applicable” underneath.
3.
Once completed, upload your protocol in the “Basic Information” screen in IRES IRB system. 
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SECTION I: RESEARCH PLAN
1.
Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
Primary Objective: To evaluate the safety, tolerability, and pharmacokinetics of BMS-984923 in healthy 
participants.
Secondary Objective: A receptor occupancy substudy will determine drug receptor occupancy at each dose 
using [18F]FPEB PET.
2.
Probable Duration of Project: State the expected duration of the project, including all follow-up and data 
analysis activities.
Each participant will complete a screening period of up to 90 days, a treatment period of up to two days and a 
follow up period of seven days. The total duration of participation in this study is approximately 14 weeks. 
The study will enroll up to six cohorts of 6 participants each. Study drug will be administered in sequentially 
increasing dose groups. For all 6 participants at a dose cohort, a safety assessment review will be completed 
prior to advancing the next higher dose level.
It is anticipated that enrollment will occur in less than 15 months and all protocol activities will be completed 
in less than 18 months, with up to 12 months for data analysis.
3.
Background: Describe the background information that led to the plan for this project. Provide references to 
support the expectation of obtaining useful scientific data.
This project seeks to develop a novel disease-modifying compound for Alzheimer’s disease (AD). Brain 
synapse loss in AD has been tightly correlated with cognitive symptoms and is triggered initially by amyloid beta 
(Aß) peptide accumulation. We have described a pathway in which soluble Aß oligomers (Aßo) bind to cellular 
prion protein (PRPc), thereby engaging metabotrophic glutamate receptor subtype 5 (mGluR5) as a co-receptor, 
and activating PTK2B (Pyk2) and Fyn kinases to couple with Tau pathology and synapse loss. mGluR5 is a G 
protein-coupled receptor (GPCR), and multiple groups have shown that interrupting mGluR5 function rescues 
preclinical AD phenotypes, making it an attractive drug target. However, mGluR5 has a physiological role as a 
glutamate receptor, and full inhibition impairs function. Consequently, typical antagonists have a narrow 
therapeutic window. 
We have identified a highly potent, orally bioavailable mGluR5 ligand that does not alter basal or 
glutamate activity, but does block Aßo/PrPC activation of mGluR5. This compound is considered a silent allosteric 
modulator, or SAM, for mGluR5, meaning “silent” with regard to glutamate, while antagonistic with regard to 
Aßo/PrPC. Preliminary studies demonstrate robust efficacy of this SAM compound for multiple preclinical mouse 
AD phenotypes. Drug treatment recovers synapse density, restores long term potentiation (LTP) and returns 
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memory performance to wild-type (WT) levels. The overall goal is to develop disease-modifying oral therapy 
effective to slow, halt or partially reverse AD progression both in the Mild Cognitive Impairment (MCI) state and in 
mild dementia.
Significance:
Today, no disease-modifying therapy for AD is available. The hypothesis that the Aß peptide plays an early 
causative role is supported by pathology, human genetics and biomarker studies (Hardy 2002; Selkoe 2016). More 
specifically, Aßo triggers a toxic cascade that impairs synaptic function and leads to progressive synapse loss and 
cognitive dysfunction (Berman 2008; Cleary 2005; Hong 2016; Lacor 2007; Lambert 1998; Lauren 2009; Lesne 
2006; Li 2009; Palop 2010; Shankar 2008; Walsh 2002). Recent clinical trials have focused on restricting 
production of Aβ by - or β-secretase inhibition, or on accelerating clearance of Aβ by active or passive 
immunization. As these strategies have thus far failed to produce substantial benefit, new treatment approaches 
are urgently needed. Thus, target-based therapies directed at suppressing AD-related synapse damage offer an 
alternate, unexplored strategy distinct from amyloid-lowering approaches, which may also be complementary to 
Aß-lowering strategies. 
Aßo is thought to trigger the onset of AD, followed by a cascade of events over a multi-year course, 
involving synaptic loss, inflammation, tauopathy, and cell loss. The extent to which this process is subject to 
cessation or reversal upon elimination of synapse damage at different stages of progression is not fully 
defined. Effectiveness of synapse protection is predicted to be greatest in early disease. Therefore, the 
therapy envisioned here should be most valuable when administered to patients with amnestic MCI plus 
amyloid biomarkers, or those with mild AD dementia, rather than moderate-severe AD dementia. 
Biological Rationale and Profile of the Therapeutic Agent:
The Amyloid hypothesis of AD is supported by the early 
and progressive accumulation of the Aβ peptide as well as the 
genetic effects of APP and PS1/2 mutations, suggesting that Aβ 
peptide species are the initial trigger (Hardy 2002; Selkoe 2016). 
Aβo have been implicated in initiating synaptic dysfunction, 
dendritic spine loss, inflammatory mediator recruitment and 
memory dysfunction, all of which are key characteristics of AD 
(Berman 2008; Cleary 2005; Hong 2016; Lacor 2007; M. P. Lambert 
1998; Lauren 2009; Lesne 2006; Li 2009; Palop 2010; Shankar 
2008; Walsh 2002). PrPC is a high affinity receptor for Aβo, which 
we discovered by an unbiased genome wide screen. Pathological 
signals from Aßo/PrPC are transmitted via its co-receptor 
metabotropic glutamate receptor 5 (mGluR5) to intracellular 
signaling (Figure 1) (Beraldo 2016; Gimbel 2010; Haas 2016a; Haas 
2016b; Hu 2014; Kaufman 2015; Larson 2012; Lauren 2009; Um 
2013; Um 2012). Aβo enhances the interaction of PrPC with 
mGluR5, which is critically involved in AD disease pathogenesis 
(Haas 2014; Haas 2016a). Fyn regulation links mGluR5 to Tau 
pathology (Bhaskar 2010; Bhaskar 2005; Chin 2005; Chin 2004; 
Ittner 2010; Kaufman 2015; Larson 2012; Lee 1998; Lee 2004; 
Roberson 2011; Um 2013; Um 2012), and Pyk2 (PTK2B) regulation 
by mGluR5 and Fyn provides validation of this pathway by human 
Figure 1 mGluR5 at the center of an 
Aβo-PrPC-Fyn-Pyk2 cascade of AD 
synapse damage. Schematic illustrates 
the role of mGluR5 in linking cell surface 
Aßo–PrPC complexes to intracellular 
Fyn/Pyk2, Tau and synaptic loss. 
Proteins are clustered in the PSD and 
alter NMDA-Rs, calcium and protein 
translation. Pyk2 (PTK2B) variation is a 
verified genetic risk for Late Onset AD 
and is associated with mGluR5 in an AD 
transduction network. Aberrant PrPC–
mGluR5–Fyn-Tau signaling leads to 
synaptic malfunction and loss.
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genetic risk assessment (Beecham 2014; Dourlen 2017; Haas 2016a; Haas 2016b; Kaufman 2015; Lambert 2013).
Separately from PrPC coupling, multiple studies of AD models have implicated mGluR5 and altered 
glutamate signaling (Hamilton 2014; Hamilton 2016; Hu 2014; Overk 2014; Renner 2010; Wang 2004; Zhang 
2015). Glu activation of mGluR5 leads to a range of signaling pathways, including phospholipase C, IP3, and 
intracellular calcium release, as well as Homer, Arc, eEF2 and FRMP regulation of protein translation at synapses, 
plus CamKII, Fyn and Pyk2 kinases (Bhakar 2012; Haas 2016a; Haas 2016b; Heidinger 2002; Kaufman 2015; Lesne 
2006; Li 2009; Luscher 2010; Nicodemo 2010; Um 2013; Um 2012). The regulation of mGluR5 and synaptic 
plasticity by therapeutic molecules has been studied extensively, as mGluR5 is implicated in the pathogenesis of 
several neurodegenerative and psychiatric CNS disorders (Bruno 2001; Gasparini 2007; Gregory 2011; Gregory 
2012; Molck 2014; Ribeiro 2010; Sheffler 2011).
Genetic loss and pharmacological inhibition studies by multiple groups have demonstrated that reduced 
mGluR5 activity alleviates synaptic and memory deficits in diverse AD-related models (Beraldo 2016; Haas 2016a; 
Hamilton 2014; Hamilton 2016; Hu 2014; Kumar 2015; Overk 2014; Raka 2015; Renner 2010; Um 2013; Wang 
2004; Zhang 2017; Zhang 2015). Pharmacological inhibition studies have utilized the negative allosteric 
modulators (NAMs), MPEP, MTEP and CTEP, all of which reduce physiological glutamate signaling as well as 
pathological AD signaling. While this initially appears promising, it must be noted that full blockade of mGluR5 
glutamate signaling genetically or pharmacologically impairs mouse learning and memory, and disrupts behavior 
in WT control animals (Abou Farha 2014; Campbell 2004; Lu 1997; Porter 2005; Rodriguez 2010; Um 2013; Xu 
2009). Clinically, the mGluR5 NAM mavoglurant impairs cognitive performance at the 200 mg dosage, even 
though peak receptor occupancy reaches only 55% at 100 mg and 85% with 400 mg (Rutrick 2017). For this 
reason, separating blockade of glutamate signaling at mGluR5 from the beneficial effects of inhibiting 
Aβo/PrPC/mGluR5 signaling is critical to enhance the therapeutic index of this target. 
Here, we focus on mGluR5 ligands that distinguish between glutamate and Aβo/PrPC signaling. Allosteric 
modulators of mGluR5 are subdivided into positive allosteric modulators (PAMs), negative allosteric modulators 
(NAMs), and silent allosteric modulators (SAMs). PAMs and NAMs shift the potency or efficacy of Glu-induced G-
protein-mediated intracellular Ca2+ mobilization; some also alter basal activity via direct agonism or antagonism. 
In contrast, SAMs do not alter basal or Glu-induced Ca2+ signaling (Gregory 2011; Gregory 2010; Gregory 2012). 
Our Preliminary Studies (Haas 2017) showed that BMS-984923, compound 16 of (Huang 2016) potently inhibits 
the PrPC-mGluR5 interaction and prevents pathological Aβo signaling without affecting physiological Glu signaling. 
Critically, inhibition of Glu signaling at mGluR5 is not essential for the benefits of blocking Aβo/PrPC signaling at 
mGluR5 for in vivo AD models, thereby greatly 
expanding the therapeutic window for mGluR5 as 
a disease-modifying therapeutic target in AD. 
BMS-984923, High Potency SAM for mGluR5 
Our Preliminary Studies use a potent 
mGluR5 SAM to distinguish blockade of 
Glu/mGluR5 function from inhibition of AD-
specific Aβo/PrPC signaling through mGluR5 (Haas 
2017). BMS-984923 was identified in an extensive 
drug development program initiated to identify 
mGluR5 PAMs for schizophrenia (Huang 2016). 
The compound is competitive antagonist of 
[3H]MPEPy binding to human mGluR5 with a Ki of 
0.6 nM, but has no detectable agonist or 
Figure 2 Pharmacokinetic properties of BMS-984923 in mice. 
A. Structure of BMS-984923, its chemical and pharmacological 
properties are summarized. Three separate batches have been 
generated, each >97% purity. B. The plasma levels of BMS-
984923 in C57Bl6J male mice after a single oral dose are 
plotted as a function of time. Data are mean ± SEM, n=9. 
Calculated PK properties are provided. C. The brain and plasma 
levels of BMS-984923 in C57Bl6J male mice was measured 3 
hours after a single 7.5 mg/kg dose. Data are mean ± SEM, n=3.
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antagonist or PAM or NAM activity at mGluR5 signaling (Figure 2A) (Huang 2016). 
We confirmed that the BMS-984923 does not affect glutamate/DHPG-induced Ca2+ signaling in mGluR5-
overexpressing HEK-293T cells and extended these observations to DIV21 cortical neurons (Figure 3A) (Haas 
2017). In contrast, a NAM, MTEP, strongly suppresses glutamate/DHPG-induced Ca2+ responses. Co-application of 
BMS-984923 and MTEP prevents MTEP-induced inhibition of glutamate/DHPG-induced Ca2+ responses (Figure 3A) 
(Haas 2017). This confirms that the BMS-984923 behaves as silent allosteric modulator of mGluR5, consistent 
with competition at the MTEP site.
BMS-984923 has good oral bioavailability and an 
apparently linear dose response (Figure 2B). At 7.5 or 15 mg/kg, 
plasma concentration exceeds 2 µM at 10 h. Brain 
concentrations are nearly as high 3 hours after a 7.5 mg/kg oral 
dose (Figure 2C). Compounds chemically related to the BMS-
984923, but with PAM activity, induce seizures (Compound 5 of 
(Yang 2016)). To determine whether the BMS-984923 compound 
at the 7.5 mg/kg dose occupies brain mGluR5, we assessed the 
degree to which BMS-984923 prevented PAM-induced seizures 
(Haas 2017). During the 90 min after PAM administration, 50% of 
vehicle-pretreated mice exhibited seizures, whereas none of the 
SAM-pretreated mice did so (Haas 2017). Thus, the SAM 
effectively occupies brain mGluR5 sites to prevent PAM action. 
Based on the BMS-984923 pharmacokinetics, brain penetration 
and potency for mGluR5, we chose the BMS-984923 dose of 
3.75 mg/kg by oral gavage twice a day as the dose to ensure 
essentially complete continuous receptor occupancy.
It is known that higher doses of mGluR5 NAMs such as 
MTEP negatively affect EEG amplitude in mice (Um 2013). At 15 
mg/kg/d B.I.D., MTEP is tolerated in mice, and has been applied 
successfully to recover AD-like phenotypes in transgenic mice 
(Um 2013). However, we observed that a 5-fold increased dose of MTEP (75 mg/kg) strongly impairs EEG 
amplitude and alters the power spectrum in mice (Haas 2017), demonstrating MTEP's limited therapeutic 
window. In contrast, neither a 1x dose (3.75 mg/kg) nor a 10x dose (37.5 mg/kg) of BMS-984923 impairs EEG 
amplitude or power spectrum in mice (Haas 2017). Thus, doses of SAM BMS-984923 well above the effective 
dose appear to be well tolerated with regard to CNS function in mice.
Protection from Aβo action by BMS-984923 
While it is clear that BMS-984923 does not alter mGluR5 activation with or without glutamate, a key issue 
is whether it interrupts AD-related Aβo signaling via PrPC through mGluR5. Aβo has been shown to enhance the 
association of PrPC and mGluR5 detected by immunoprecipitation from transfected HEK293T cells (Haas 2014). 
With Aβo, mGluR5 interaction with PrPC is increased two-fold (Figure 4A-C) (Haas 2017). BMS-984923 eliminates 
Aβo-driven association with an IC50 of 1-10 nM (Figure 4A-C), consistent with the concentrations required for 
BMS-984923 displacement of [3H]MPEPy from mGluR5 (Figure 2A). Thus, in this non-neuronal assay BMS-984923 
has properties that allow selective blockade of Aβo action even though there is no effect on basal or glutamate 
signaling. 
To determine whether inhibition of Aβo-enhanced binding of PrPC to mGluR5 has functional 
consequences in neurons, we analyzed the effect of BMS-984923 with or without Aβo on mouse hippocampal 
slice synaptic plasticity in the CA3 to CA1 Shaffer collateral pathway (Fig. 3 of (Haas 2017)). Aβo are known to 
Figure 3 BMS-984923 does not interfere with 
glutamate signaling but competes with the 
NAM, MTEP. DIV21 mouse cortical neurons 
were exposed to SAM and/or MTEP for 20 min 
prior to recording intracellular Ca2+ 
concentration in response to 50 μM DHPG 
(mGluR5-specific analogue of Glu) at 18 s. 
Each line represents the induced mean ± SEM 
averaged from 18-20 wells.
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impair synaptic function by inhibiting long-
term potentiation (LTP) acutely (Shankar 
2008; Walsh 2002). The presence of 100 nM 
BMS-984923 does not alter basal fEPSP 
amplitude or theta-burst-induced LTP in the 
absence of Aβo (Haas 2017). Critically, 
preincubation of brain slices with BMS-
984923 prevents Aβo-induced inhibition of 
LTP. Thus, BMS-984923 prevents Aβo-induced 
impairment of synaptic plasticity in brain 
slices.
SAM treatment of AD model mice rescues 
established memory deficits
To investigate whether BMS-984923 
could ameliorate behavioral deficits of aged 
APP/PS1 transgenic mice (Jankowsky 2004; 
Jankowsky, Xu, Fromholt, Gonzales, & 
Borchelt, 2003), we assessed their behavior in 
multiple behavioral paradigms to 4 weeks of 
treatment with SAM or vehicle. Mice were 
randomized to treatment group, and all 
behavioral assessments were by an observer 
unaware of group. Since this mouse strain 
develops behavioral deficits starting at 6 
months of age when Aβo levels rise (Gimbel 
2010; Kostylev 2015; J. H. Park 2006), their 
deficits were well established when SAM 
treatment started at an average age of 14 
months. Wild type mice express a clear 
preference for a novel over a familiar object, 
which is not affected by SAM treatment 
(Figure 5) (Haas 2017). Vehicle-treated 
transgenic mice lack a preference for either 
object, revealing a memory deficit in this 
paradigm. Importantly, SAM-treated 
transgenic mice show a significant preference 
for the novel object. Thus, BMS-984923 
recovers memory by transgenic mice back to 
wild type behavior (Figure 5A). 
Figure 4 SAM (BMS-984923) reduces the interaction of PrPC 
with mGluR5 in membrane fractions. A. HEK-293 cells were co-
transfected for PrPC and Myc-mGluR5. Membrane fractions 
were pre-incubated for 2 hours at 4°C with indicated 
concentrations of SAM, followed by 1 µM Aβo for 30 min 
(monomer equivalent concentration, estimated oligomer of 10 
nM). NP-40 membrane extractions (input) and 
immunoprecipitates were immunoblotted with either anti-Myc 
or anti-PrPC. B-C. Data are mean ± SEM from n=3 independent 
experiments. B. Quantification of the PrPC signal in anti-Myc 
immunoprecipitates after treatment is normalized to the signal 
of untreated samples. Aβo trigger a significant enhancement of 
the co-immunoprecipitation of PrPC with Myc-mGluR5 in 
membrane fractions, which can be significantly reversed by 1 
µM SAM (***, p<0.001; ****, p<0.0001 by one-way ANOVA 
with Tukey’s post-hoc multiple comparisons test). C. 
Quantification of the Myc signal in anti-PrPC 
immunoprecipitates after treatment is normalized to the signal 
of untreated samples. Co-immunoprecipitation of Myc-mGluR5 
with PrPC is significantly enhanced by Aβo only when SAM 
concentration is absent, or less than 10 nM (**, p<0.01 by one-
way ANOVA with Tukey’s post-hoc test).
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We used the Morris water maze spatial navigation task as a second behavioral assessment. A total of 24 training 
trials were completed in three consecutive days, and mice were analyzed in a probe trial test on day four. During 
the last 8 trials, the vehicle-treated APP/PS1 group differs significantly from all other groups by one-way repeated 
measures ANOVA (RM-ANOVA) with Tukey’s post-hoc multiple comparisons test, whereas all other comparisons 
are not significantly different (Figure 5B). A 2-way RM-ANOVA over the last 8 trials further shows a significant 
effect of genotype, treatment, and of their interaction (Figure 5B). The apparent improvement in learning by the 
transgenic mice after BMS-984923 treatment cannot be attributed to changes in swimming or overall activity, 
because the distance traveled to the platform during the last block of trials showed the same rescue of transgenic 
mouse performance by BMS-984923 (Figure 5C) and no differences in swim speeds (Figure 5D). During the 
memory probe trial 24 hours after completion of training, the vehicle-treated APP/PS1 group show a significant 
deficit compared to wild type (Figure 5E). Importantly, SAM-treated APP/PS1 mice have a significant improvement 
compared to vehicle-treated APP/PS1 mice. A 2-way ANOVA further reveals a significant effect of genotype, of 
treatment, and of their interaction (Figure 5E). Thus, BMS-984923 treatment rescues behavioral deficits of 
transgenic mice in the Morris Water Maze 
spatial navigation task.
Passive avoidance testing was used as a 
third behavioral assessment for mouse 
memory. Transgenic mice demonstrate clear 
deficits in passive avoidance testing, as can be 
observed by a reduced latency to enter the dark 
compartment in the retention test (Figure 5F). 
Importantly, BMS-984923 treatment 
significantly recovers memory deficits of 
Figure 5 SAM (BMS-984923) reverses learning and memory deficits 
in APP/PS1 transgenic mice after 4 weeks of treatment. A. Time 
spent interacting with a novel object compared to the time spent 
interacting with a familiar object in plotted. Mean ± SEM, n=18-25 
mice per group. Vehicle-treated APP/PS1 mice have no preference 
(p>0.05), while other groups show a preference for novel object 
(***, p<0.001). B. Spatial learning in Morris water maze is plotted as 
the latency to a hidden platform after 4 weeks of treatment. Mean ± 
SEM of n=21-28 mice per group. Performance was analyzed by 2-
way analysis of variance with repeated measures (RM-ANOVA) over 
the last 8 trials and showed a significant effect of genotype 
(p=0.0001), of treatment (p=0.043), and of their interaction 
(p=0.045). The vehicle-treated APP/PS1 group differed from other 
groups over the last 8 trials (*, p<0.05, ***, p<0.001). C-D. Distance 
travelled to reach hidden platform and average swim speed during 
the last block of swim trials from B is plotted. Mean ± SEM of n=21-
28 mice per group. Distance travelled for vehicle-treated APP/PS1 
group differed from all other groups (**, p<0.01, ***, p<0.005), 
whereas all other comparisons were not significantly different 
(p>0.05). E. Plotted is percent time in the quadrant where platform 
had been located. Mean ± SEM of n=21-28 mice per group. 
Performance showed a significant effect of genotype (p=0.0001), of 
treatment (p=0.043), and of their interaction (p=0.046). Vehicle-
treated APP/PS1 group differed significantly from other groups (*, 
p<0.05, ****, p<0.0001), whereas other comparisons were not 
different (p>0.05). Dashed line represents chance. F. Mice were 
trained to avoid a dark compartment in passive avoidance paradigm. 
Latency of vehicle-treated APP/PS1 mice to enter dark compartment 
5 min after training was significantly decreased compared to WT (*, 
p<0.05). Deficit of APP/PS1 mice was rescued by SAM-treatment 
(**, p<0.01). Mean ± SEM, n=21-27 mice per group. For all, 
male:female ratio between 0.89-1.17.
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transgenic mice to wild type levels in passive avoidance testing (Figure 5F). Notably, BMS-984923 treatment does 
not affect wild type behavior in any behavioral assessment (Figure 5A-F).
Plaque and gliosis are not altered by BMS-984923
To investigate the underlying cause of behavioral recovery, we analyzed the brains of treated mice 
immunohistologically. No change in amyloid accumulation or gliosis was observed (Haas 2017). This is consistent 
with BMS-984923 blocking downstream action of mGluR5-mediated events at neuronal synapses, and not altering 
upstream Aβ accumulation or glial reaction to its accumulation.
BMS-984923 treatment reverses synapse 
loss in AD mice
We analyzed the density of synaptic 
markers by immunostaining, since synaptic 
depletion is a characteristic of AD tightly 
linked to memory deficits (Scheff 1990), and 
expected to be downstream of 
Aβo/PrPC/mGluR5 signaling. By 
predetermined automated quantitation 
method applied without knowledge of 
group, we observed a significant loss of the 
presynaptic marker SV2a as well as the 
postsynaptic marker PSD95 in transgenic 
brain compared to wild type (Figure 6) (Haas 
2017). Importantly, BMS-984923 treatment 
significantly recovers synaptic marker levels 
to wild type levels (Figure 6B, C). Thus, 
restoration of synapse density is a plausible 
explanation for memory recovery by SAM 
therapy, via interruption of Aβo signaling 
without changes in glutamate/mGluR5 
coupling.
We found that Pyk2 as well as 
eukaryotic elongation factor 2 (eEF2) are 
aberrantly activated in transgenic AD model 
brain as measured by phosphorylation of specific sites (Haas 2016; Kaufman 2015; Um 2013). Specifically, the 
pPyk2/Pyk2 ratio in cortical lysates of APP/PS1 vehicle group is 1.57+0.14 relative to WT vehicle control ratio 
defined as 1.00+0.05 (p=0.0005 by ANOVA with Tukey post-hoc; mean+SEM, n=22-26). BMS-984923 therapy does 
not affect signaling in the wild type brain (Haas 2017), but significantly relieves signaling abnormalities in the 
APP/PS1 transgenic brain with a pPyk2/Pyk2 ratio of 1.13+0.07 (n.s. vs WT ; p=0.014 vs APP/PS1 veh). Thus, 
normalization of Aβo/PrPC/mGluR5 signal transduction abnormalities in BMS-984923 treated transgenic mice is 
likely to underlie synaptic and behavioral recovery.
BMS-984923 rescues Tau pathology in triple transgenic mice
Pathological tau is a further characteristic of AD, but it is not modeled in the APP/PS1 transgenic model. 
Therefore, we studied triple transgenic (3xTg) mice expressing human mutant Tau, as well as mutant APP and PS1 
(Oddo 2003), in which pathology driven by the Tau transgene is enhanced by the APP/PS1 transgene pathology. 
Figure 6 SAM (BMS-984923) recovers loss of synaptic markers in 
APP/PS1 mice after 5 weeks of treatment. A. Representative 
immunofluorescent images of the dentate gyrus of indicated groups 
stained with SV2a. Scale, 12 μm. B. Fractional area of immunoreactive 
puncta for SV2a in the dentate gyrus. One-way ANOVA with Tukey 
post hoc comparisons shows that vehicle-treated APP/PS1 group 
differs significantly from the SAM-treated WT group as well as the 
SAM-treated APP/PS1 group (*, p<0.05). Mean ± SEM, n=15-23 mice 
per group. C. Fractional area of immunoreactive puncta for PSD-95 in 
the dentate gyrus. Mean ± SEM, n=16-23 mice per group. One-way 
ANOVA with Tukey post hoc comparisons shows that the vehicle-
treated APP/PS1 group differs from the vehicle-treated WT group (*, 
p<0.05), but the SAM-treated APP/PS1 group is rescued to WT levels 
(ns, p>0.05).
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We treated 3xTg mice with 7.5 mg/kg/d of BMS-984923 over 4 weeks to investigate the effect of SAM on tau 
pathology. Phospho(S199/S202)-Tau is significantly enhanced in 3xTg brain compared to wild type brain in RIPA-
soluble fractions (5.1+0.8 fold, mean+SEM, n=4), which is recovered close to wild type levels in 3xTg mice treated 
with BMS-984923 (2.5+0.2 fold, p<0.01 vs 3xTG veh by ANOVA with Dunnett post-hoc) (Haas 2017). We also 
observed an increase of total Tau in formic acid extracted RIPA-insoluble brain fractions in 3xTg mice (1.7+0.1 
fold), which is reduced to wild type levels by BMS-984923 therapy (1.2+0.1 fold, p<0.05 vs 3xTG veh by ANOVA 
with Dunnett post-hoc). We further analyzed pathological Tau by immunostaining of 3xTg brain treated with 
vehicle or BMS-984923 compared to wild type brain. Without intervention, there is a trend to increased 
phospho(S199/S202)-Tau immunostaining in the hippocampal CA1 area as well as in the frontal cortex of 3xTg 
mice. The pathological accumulation is eliminated by BMS-984923 (Haas 2017). Thus, BMS-984923 induced 
conformational changes of the PrPC-mGluR5 complex are beneficial for reducing Tau pathology.
BMS-984923 rescues synapse loss by PET in APP/PS1 and double KI mice
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To further maximize translational relevance, we conducted 
preclinical studies in which mice were aged to the 
point that synapse loss was detectable using SV2A 
PET, a new tool for monitoring synapse density 
with documented clinical utility in AD and other 
conditions. First generation scans utilized 
[11C]UCB-J (Chen 2018; Finnema 2016; Toyonaga 
2019), but here we used the longer half-life, higher 
resolution [18F]SDM-8 ligand (Li 2019) to further 
enhance clinical translation. At 12 months of age, 
synapse density is reduced in the hippocampus 
and cerebral cortex of APPswe/PS1∆E9 (Jankowsky 
2004) mice relative to WT (Figure 7A). Critically, rescans of the same 
mice after a one month treatment course with the mGluR5 SAM, 
showed a highly significant increase in hippocampal/brainstem 
[18F]SDM-8 SUVR-1 to a level matching WT mice (Figure 7B, C).
Transgenic mouse overexpression models of AD (such as 
APPswe/PS1∆E9 (Jankowsky 2004)) mimic certain aspects of AD, 
including Aß plaque, soluble Aßo, synapse loss, and age-dependent 
memory impairment. However, confidence in these phenotypes is restricted due to mutant human protein 
overexpression, competition with WT mouse genes and transgenic promotors. One way to overcome these issues 
is to utilize APP knock-in strains (Saito 2014; Saito 2019). We are using the NL-G-F knock-in allele, which inserts 
Aß-containing exons from human APP containing the Swedish, Arctic and Iberian mutations into the mouse locus. 
By replacing the relevant murine coding sequence, expression level and pattern are maintained. Such mice 
develop Aß plaque, decreases in synaptic markers and memory deficits (Saito 2014). In addition, Dr. Saido has 
Figure 7 Rescue of Synaptic Density in Multiple Mouse Models by 
Interruption of Synaptic Signaling. (A) At 12 months of age, WT 
and APPswe/PS1∆E9 mice were imaged with [18F]SDM-8 to 
visualize SV2A levels. Uptake from 30-60 min for n = 12 (6M, 6F) 
mice of each genotype were registered to an MRI brain template 
and average Standardized Uptake Value (SUV) intensity is 
displayed. Voxel-based subtraction of the signal from the two 
strains is at right. Decreases greater than 2 standard deviations 
from the mean signal are displayed by the LUT at right. There 
were no areas of increase in APP/PS1 mice. More than 95% of 
uptake was blocked in WT by unlabeled levetiracetam (not 
shown). (B) Mice as in A were imaged at 12 months of age and 
then treated by oral gavage with 3.75 mg/kg BMS984923 (SAM) 
or vehicle twice a day as described. After one month treatment, 
the mice were reimaged. The hippocampal SUVR relative to 
brain stem minus 1 for the SV2A ligand [18F]SDM-8 is plotted. 
Each mouse is shown as a dot, mean + sem. The data are 
compared by one-way ANOVA with Sidak’s multiple comparisons 
test. (C) The data from the 5th and 6th bars in B are replotted to 
illustrate the change per animal. (D) At 12 months of age, WT 
and APPNL-G-F/hMAPT double knock-in (dKI) mice were imaged 
with [18F]SDM-8 to visualize SV2A levels as in A. Decreases 
greater than 2 standard deviations from the mean signal are 
displayed at top. Uptake from 30-60 min for n = 12 (6M, 6F) mice 
of each genotype. The dKI mice were treated by oral gavage with 
3.75 mg/kg BMS984923 (SAM) twice a day as in B and reimaged. 
The map of increases greater than 2 standard deviations from 
the mean signal is displayed at bottom. (E) WT and dKI mice as in 
D were imaged 12 months of age and then treated with by oral 
gavage with 3.75 mg/kg BMS984923 (SAM) or vehicle twice a 
day. After one month treatment, the mice were reimaged. The 
hippocampal SUVR relative to brain stem minus 1 for the SV2A 
ligand [18F]SDM-8 is plotted. Data are mean + sem n=12 group. 
The data are compared by one-way ANOVA with Sidak’s multiple 
comparisons test as indicated.
Figure 8 Disease-Modifying BMS984923 
Benefit after Washout. (A, B) Transgenic 
APPswe/PS1∆E9 mice at 12 months of age 
were treated by oral gavage with 3.75 mg/kg 
BMS984923 or vehicle twice a day. After one 
month treatment, brain was collected for 
immunohistology. Fractional area of 
immunoreactive puncta for SV2A (A) or PSD-
95 (B) in the dentate gyrus is shown. Each 
mouse is shown as a dot, mean + sem. One-
way ANOVA with Tukey’s post hoc 
comparisons as indicated. **, P<0.01, ***, 
P<0.001, ****, P<0.0001. (C, D) A separate 
group of transgenic APPswe/PS1∆E9 was 
treated by oral gavage with 3.75 mg/kg 
BMS984923 or vehicle twice a day from 12-13 
months of age and then treatment was 
stopped for one month prior to tissue 
collection and analysis for SV2A (C) and PSD-
95 (D) by the same method as in A, B. Since 
the half-life of BMS984923 in mice is 
approximately 8 hours, the concentration of 
drug is nil after 3 days (9 half-lives) and 
washout persists for 3.5 weeks beyond this 
time. Statistics as in A, B.
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generated a strain in which the human wild type MAPT locus with its full sequence and splice sites replace the 
murine locus. In the APPNL-G-F/hMAPT double knock-in strain (hTau-NLGF dKI, or simply dKI here) there is a 
moderate increase of MAPT phosphorylation at AD-relevant sites detected by AT8 and PHF-1 antibodies, as well 
as greater spread of misfolded human Tau aggregation (Saito 2019). We repeated the mGluR5 SAM treatment in 
this strain with PET imaging of SV2A sites. At 12 months of age, there is a decrement in synapse density in the dKI 
strain (Figure 7D). Importantly, the one month BMS984923 treatment restores the PET signal upon rescans of the 
same mice (Figure 7D, E). Thus, in multiple strains, blocking the PrPC/mGluR5 pathway prevents synapse loss, 
allowing recovery. 
We also tested whether the mGluR5 SAM (Figure 8) and anti-PrPC treatment (Cox 2019) had a disease-
modifying effect in the weeks after the treatment was stopped. Here, we used the APP/PS1 strain and monitored 
the area of SV2A and PSD-95 puncta in the hippocampus after one month treatment followed by one month 
washout of the compounds. In both cases, the decrement of synaptic area of transgenic mice was recovered by 
treatment, and the benefit persisted one month (Figure 8 and (Cox 2019)). We suspect that synapse loss would 
gradually recur at latter times; the initial synapse loss after Aß accumulation requires 4-6 months to develop. 
However, the data show that there is clearly a disease-modifying benefit of blocking the PrPC/mGluR5 synaptic 
signaling pathway.
Receptor occupancy by FPEB-PET
The Yale PET Center has substantial experience in 
performing brain receptor occupancy studies. These are 
typically performed first in nonhuman primates (NHP), and 
subsequently in human participants. Examples of occupancy 
studies in nonhuman primates include occupancy at 
norepinephrine transporters (Gallezot 2011), serotonin 
receptors (Cosgrove 2011), dopamine receptors (Gallezot 2012), 
acetylcholine receptors (Hillmer 2016), glycine transporters 
(Castner 2014; Xia 2015), histamine receptors (Sawant-Basak 
2017), kappa opioid receptors (Kim 2013), and synaptic vesicular 
protein (SV2A) (Nabulsi 2016; Nicolas 2016). In general, we have 
found there to be good correlation between occupancy in NHP 
and occupancy in humans, following adjustments for 
bioavailability and plasma free fraction of drug. 
At Yale, we have developed [18F]FPEB as a mGluR5 
specific PET ligand (Esterlis 2017; Park 2015; Sullivan 2013). This 
included development of infusion methodology (Park 2015; 
Sullivan 2013), which allowed convenient application in clinical 
populations. Here, we assess receptor occupancy in brain by 
characterizing competitive displacement of the FPEB from the 
shared binding site after pre-administration of different BMS-
984923 concentrations in multiple species. Our plan will allow 
receptor occupancy to guide dose equivalency across species in 
translation. 
In mice, we measured the % decrease in brain FPEB 
uptake after dosing mice with the minimal SAM required to 
achieve rescue of transgenic AD mouse synapse density and 
memory. mGluR5 occupancy in mice was calculated using SUV 
Figure 9 BMS-984923 blocks [18F]FPEB brain 
uptake. A-B. Two mice received BMS-984923 
(7.5 mg/kg by oral gavage, B) and two mice 
received vehicle (A) one hour prior to 
injection of [18F]FPEB tracer. A static PET 
image was acquired on the Inveon 
microPET/CT for 15 min beginning 45 min 
post-injection of tracer. The image presents a 
sagittal view containing the brain (arrow) with 
rostral left, caudal right, dorsal up and ventral 
down. C. The CT was used to delineate a 
cortical region of interest. An average value 
for the region was generated and converted 
to Standard Uptake Values (SUV), with 
correction for weight and injected dose. Data 
are mean ± SEM. The 87% inhibition by BMS-
984923 is likely an underestimate of receptor 
occupancy since no correction for non-
displaceable binding was performed. Typical 
non-displaceable uptake level in the presence 
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values. Our studies in adult WT mice demonstrated that BMS-984923 (7.5 mg/kg p.o. pretreatment) blocks 87% 
of total [18F]FPEB brain uptake (Figure 9). PET imaging will be used to assess mGluR5 occupancy of BMS-984923 in 
human participants 
The present clinical evaluation of BMS-984923 is being conducted in healthy participants. Safety and 
tolerability studies in this population will allow longer term safety studies and ultimately efficacy studies in 
participants with AD. Please refer to the Investigator’s Brochure (IB) for a more detailed description of toxicology 
investigations.
Clinical Experience with BMS-984923
The present study represents the first evaluation of BMS-984923 in humans.
4.
Research Plan: Summarize the study design and research procedures using non-technical language that can 
be readily understood by someone outside the discipline. Be sure to distinguish between standard of care vs. 
research procedures when applicable, and include any flowcharts of visits specifying their individual times and 
lengths. Describe the setting in which the research will take place.
Overall Study Design
This will be conducted at the Yale University Alzheimer’s Disease Research Unit (ADRU), the Yale PET Center, 
and Yale Hospital Research Unit (HRU).
Eligible participants will be between the ages of 50 to 80 years old, male or female, with normal cognition and 
without neuropsychiatric diagnoses.
This study is an open-label, single ascending dose study in health participants. Up to six cohorts of 6 
participants each are planned where the participants within each cohort are expected to receive the same 
dose of study drug. A total of approximately 36 participants will be enrolled and each will receive a single 
dose of BMS-984923.
If the Maximum Tolerated Dose (MTD) is reached prior to the sixth cohort, the remaining participants may be 
enrolled to obtain further data at the tolerated dose levels. During this process, the  Principal Investigator (PI) 
(Dr. Adam Mecca), the medical monitor, and the DSMB must agree to proceed with the study and escalate to 
the next dose cohort, independent of the influence of the IND holder (Dr. Stephen Strittmatter) and in 
compliance with the management of the Conflict of Interest for Dr. Strittmatter. The process is further 
described in Section 12 (Data and Safety Monitoring Plan). Briefly, a safety assessment will be completed and 
reviewed for all treated participants per cohort prior to opening enrollment into the next increased dose 
level. 
The study periods protocol are as follows:

Screening: (within 90 days prior to Day 1) Patients have 90 days from the time of signing informed 
consent to complete their screening assessments and, if needed, their washout period for prohibited 
concomitant medications. The screening laboratory tests must be completed within 30 days prior to Day 
1.

Treatment period: Day 1: Admission, administration of study drug, and 2 night in-patient stay; Day 3: 
Discharge following the completion of all scheduled procedures.
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
Follow-up: Participants will have follow-up visits for up to 7 days post-dose as follows: Participants will 
return to clinic for visits on Study Days 4 and 7. Participants will receive a phone call on Study Day 5 to 
inquire about their general health.
Screening
The PI or designee is responsible for administering and obtaining freely given consent in writing from all 
participants using the study-specific Informed Consent Form (ICF) prior to undergoing any screening 
procedures; this may also include consent to participate in the optional receptor occupancy substudy. 
Screening procedures will take place within 90 days prior to Day 1.  The participant’s eligibility (per Inclusion 
and Exclusion Criteria listed in Section 8), demographics, medical history, and concomitant medications will 
be recorded. Screening/baseline assessments will be performed, and participants will undergo blood draws 
for laboratory tests. Urine samples will also be collected. If eligibility criteria are met, and the participant is 
enrolled in the receptor occupancy substudy, a brain MRI will be performed for quantitative evaluation of PET 
scans. The MRI will be reviewed and participants with anatomical abnormalities or findings indicating 
neurological disease will be excluded. A full list of procedures and assessments is included in Table 3: 
Schedule of Study Events.
If a participant is rescreened, the original screening MRI and expert review of the images may be used for the 
rescreening provided the MRI was completed within 6 months prior to study drug administration. Similarly, 
neurologic examinations and questionnaires do not need to be repeated provided these assessments were 
completed within 6 months prior to study drug administration.
In-Patient Treatment Period
Eligible participants will be admitted to the HRU on either the evening prior to or the day of dosing (Study Day 
1) depending on participant needs. Following final pre-treatment assessments, participants will receive their 
single dose of study drug administered orally. Dosing will be according to Table 1.
Participants will remain as in-patients until discharge on Study Day 3 and will undergo safety assessments and 
close observation.
Blood samples will be obtained to assess safety and pharmacokinetics (PK). The timing for PK sample 
collection may be adjusted for subsequent cohorts based on data from the preceding cohorts. 
Table 1: Treatment by Cohort
Cohort
Treatment
Number of Participants
1
10 mg BMS-984923
6
2
40  mg BMS-984923
6
3
70  mg BMS-984923
6
4
100 mg BMS-984923
6
5
150 mg BMS-984923
6
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6
200 mg BMS-984923
6
Follow-Up
Site will contact the participants via telephone on Study Days 5 to inquire as to their general health status.
Participants will return to the Clinic on Study Days 4 and 7 for PK sample collection, safety laboratory blood 
tests, vital signs, concomitant medications, AEs, and a general health status assessment according the 
Schedule of Study Events (Table 3).
Number of Participants
This study will enroll approximately 36 participants in cohorts of 6 participants each.
If the dropout rate is such that the power of the study could be compromised, or that the study objectives 
cannot reliably be achieved, the PI, in consultation with the medical monitor and agreement of Dr. 
Strittmatter (FDA IND holder) may elect to replace those participants who discontinue prematurely.
Treatment Assignment
Six sequentially-treated cohorts planned. BMS-984923 will be administered orally in a single dose.
The starting dose of 10 mg is estimated to be below the pharmacologically active dose. Dose escalation will 
proceed to 40 mg, 70 mg, 100 mg, 150 mg, and 200 mg contingent on safety and tolerability.
Dose Escalation Decisions 
Determination of whether to open the next escalated dose cohort for enrollment will be made jointly by the 
PI, medical monitor, DSMB, and IND holder after review of all available clinical, safety, and PK data (See 
Section 12 for details of the Data and Safety Monitoring Plan).
Determination of whether to open the next escalated dose cohort for enrollment will be made jointly by the 
PI, medical monitor, DSMB, and IND holder (Dr. Strittmatter) after review of all available clinical, safety, and 
PK data. Dose escalation (for each sequential cohort) will not occur until all participants in the prior cohort 
have completed the study. The DSMB will perform an independent review. In addition, the PI and medical 
monitor will make a determination independent from the IND holder. Dr. Strittmatter will be consulted in 
scenarios where alterations to the planned dose escalation strategy are being considered. As the IND holder, 
Dr. Strittmatter must also agree with a decision to proceed with dose escalation before the next cohort is 
dosed.
Selection and Withdrawal of Participants
Participants must meet the inclusion and exclusion criteria as described in Section 8: Inclusion/Exclusion 
Criteria.
Participant Withdrawal and Discontinuation
Participants may withdraw from the study at any time at their own request, or they may be discontinued at 
any time at the discretion of the PI for safety, behavioral, or administrative reasons. The reason for a 
participant discontinuing from the study will be recorded in the source documents and case report form 
(CRF). 
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A withdrawal or discontinuation occurs when an enrolled participant ceases participation in the study, 
regardless of the circumstances, prior to completion of the protocol. The PI must determine the primary 
reason for discontinuation. If a participant does not return for a scheduled visit, every effort will be made to 
contact the participant. A participant will be considered lost-to-follow-up after 3 failed attempts to contact 
participant are made, including two documented attempts by phone and one certified letter.  In any 
circumstance, every effort should be made to document participant outcome, if possible.  Withdrawal due to 
an adverse event will be distinguished from other withdrawal reasons and will include relevant details 
according to the definition of adverse event noted. 
A discontinuation must be reported immediately if it is due to a serious adverse event. The treatment consists 
of a single dose of study drug. Therefore, every attempt will be made to perform all post dose assessments, 
since all are designed to monitor participant safety. If a participant is withdrawn or discontinued prior to 
receiving study drug, then no further assessments are required. The PI will record the reason for study 
discontinuation, provide or arrange for appropriate follow-up (if required), and document the course of the 
participant’s condition.
If the participant withdraws from the study and withdraws consent for disclosure of future information, no 
further evaluations should be performed, and no additional data should be collected. The PI may retain and 
continue to use any data collected before such withdrawal of consent.
Treatment of Participants
This study involves a single-dose oral treatment for each participant with monitoring of safety as described in 
the protocol.
 
Description of Study Medication
“Study drug” in this protocol refers to the investigational product BMS-984923.
Formulation development was contracted by Yale University to the Aptuit (Verona) division of Evotec for the 
development of a formulation for non-clinical toxicology studies as well as the production of a final clinical 
dosage form. Study medication will be packaged and capsules containing 5 mg, 50 mg or 100 mg of nano-
milled Active Pharmaceutical Ingredient (API) sprayed on granules will be prepared. Medication will be stored 
at Aptuit and transferred as needed to the Yale Investigational Drug Service. Study medication will be 
distributed to the participants from the Yale Investigational Drug Service. Doses for each cohort will be 
achieved using combinations of the capsules listed above. 
Table 2: Study Drug
Study Drug
Product Name:
BMS-984923
Route of Administration
Oral
Physical Description
Capsules containing nano-milled Active 
Pharmaceutical Ingredient (API) sprayed on granules. 
Manufacturer
Aptuit (Verona) division of Evotec*
Aptuit (Center for Drug Discovery & Development)
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Via Fleming, 4 37135 Verona (Italy)
*Study drug was produced by Aptuit through a contract with Yale University using NIH funds and will be 
supplied directly for this protocol. Allyx Therapeutics is licensing this technology from both Yale University 
and Bristol Meyers Squibb for future commercialization.
Concomitant Medications
All concomitant medications, whether prescription, over-the-counter, herbal treatments or other therapy, taken 
or used by the participant within 2 months of screening through end of study assessments will be recorded in the 
participant’s medical record and in the Concomitant Medications CRF with start and stop dates.
Regular use of medications which, in the assessment of the PI or medical monitor, may confound efficacy and/or 
safety assessments is prohibited. Prohibited medications may include but are not limited to those listed in the 
inclusion/exclusion criteria, as well as those with CYP inhibitor/inducer activity listed in Appendix A.
Prospective participants who are taking prohibited medications at the time of screening (listed in Section 8: 
Inclusion/Exclusion Criteria or Appendix A) may stop them in consultation with their physician, after signing the 
ICF and receiving instructions on the discontinuation of these medications. In this case, the prohibited medication 
must be discontinued prior to study drug administration as outlined in the Inclusion/Exclusion Criteria. The 
prospective participant must be willing to discontinue treatment and the PI must deem this to be feasible and 
safe. If a prospective participant is taking prohibited medication(s) at the time of screening, they may be 
considered eligible at the time of study drug administration (Visit 2, Study Day 1) provided no reintroduction of 
the prohibited medication is being considered, the appropriate time window since last administration has 
elapsed, and the participant continues to meet other eligibility criteria. Upon signing the ICF and enrollment into 
the study, participants must remain off prohibited medications until all assessments are completed in the study 
(Visit 5, Study Day 7), unless the PI determines that a medication is required for participant safety and/or to treat 
an (S)AE. The PI will first discuss starting prohibited medications with the medical monitor unless that cannot be 
done due to an immediate safety need.
Treatment Compliance
Treatment compliance with study drug during the treatment period is expected to be high, as participants will be 
dosed directly at the research unit under well-controlled conditions. The date and time of study drug 
administration, dose group, and quantity of study drug administered will be recorded on the source documents 
and CRF. Non-compliance with other aspects of the study protocol (e.g., use of prohibited medications, missed 
study visits) will be documented on the participant’s source document and on the CRF.
Randomization and Blinding
This study is open-label and does not include a reference therapy, therefore there is no randomization.
Study Procedures
Participants will participate in the study for a total duration of up to 14 weeks. Visits will be scheduled at:

Screening Visit 1 (Study Days -90 to -1)

In-patient Treatment Visit 2 (Study Days 1, 2, and 3)

Post Treatment Follow-up
o
Visits 3 (Study Day 4)
o
Visit 4 (Phone call on Study Day 5)
o
Visit 5 (Study Day 7)
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Refer to the Schedule of Events (Table 3) for all the procedures and assessments. The following sections provide 
important details of the procedures.
Screening Period, Visit 1 (Study Days -90 through -1)
Participants will undergo informed consent and sign an ICF before any screening-related procedures are 
performed. The Screening Visit (Visit 1) should occur between Study Days -90 to -1 and screening procedures 
completed during this time.
The inclusion and exclusion criteria will be carefully assessed. The participant’s demographics, medical history, 
and concomitant medications will be recorded. See the Schedule of Study Events (Table 3) for details on the 
assessments on each Study Day.
Potentially eligible participants will undergo a Screening Diagnostic Evaluation to ensure study eligibility. 
Assessments will consist of Clinical Dementia Rating (CDR) scale (Morris, 1993), Modified Hachinski Scale (MHS) 
(Rosen 1980), MMSE (Folstein 1975), Geriatric Depression Scale (GDS) (Sheikh 1986), Montreal Cognitive 
Assessment (MOCA), vital signs, Glasgow Coma Scale (GCS), ECG, physical examination, and blood collection for 
screening laboratory studies. 
Screening laboratory studies will include a comprehensive metabolic panel [glucose, blood urea nitrogen (BUN), 
creatinine, sodium, potassium, chloride, bicarbonate, calcium, total protein, albumin, total bilirubin, alkaline 
phosphatase, aspartate transaminase (AST), alanine transaminase (ALT)], phosphate, a lipid panel [total 
cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides], a complete blood count 
and differential, lactate acid dehydrogenase (LDH), creatine kinase (CK), amylase, thyroid function tests (TSH, 
reflex FT4), Vitamin B12, and a urinalysis with reflex microscopic examination. For all women, menopausal status 
will be confirmed by serum follicle stimulating hormone (FSH) measurement or documentation of bilateral tubal 
ligation or hysterectomy.
Vital signs (blood pressure, pulse rate, respiratory rate, and oral body temperature) will be obtained after the 
participant has been in a sitting (or recumbent) position for 5 minutes. Blood pressure will be taken from the 
same arm each time when possible.
The 12-lead ECG will be taken in triplicate after the patient has been in a supine position for at least 5 minutes 
and before blood is drawn (whenever possible). All ECGs will be read by the PI or designee. The following 
parameters and intervals will be assessed: HR, RR, PR, QRS, and QTc. The occurrence of depolarization or 
repolarization disorders, arrhythmic disorders or other abnormalities will be noted. Any clinically significant 
finding must be reported as an adverse event.
If an individual is participating in the receptor occupancy substudy, a MRI must be completed, and results 
reviewed prior to the participant’s admission to the HRU on Visit 2 (Pre-Dose). Results from the MRI will be read 
by a local expert.
If a participant fails to meet entry criteria prior to the end of the screening period it will be considered a screen 
failure. Participants who have screen failed are not required to return for additional visits (although a participant 
can be seen at any time for safety reasons). Participants who are screen failed due to lab values can be 
rescreened as determined by the PI in consultation with the study medical monitor. Participants who rescreen will 
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be assigned a new screening number.
Serious AEs will be recorded and monitored starting at the time of participant signing the ICF. Non-serious AEs will 
only be collected after the administration of the study drug.
In-patient Treatment, Visit 2 (Study Days 1 to 3 [Pre-Dose and Post-Dose])
Eligible participants will be admitted to the HRU on the evening prior to or morning of the scheduled drug dose 
depending on scheduling needs. If, during this visit and prior to dosing, a participant is determined to no longer 
be eligible to continue in the study, the appropriate Screening CRFs will be completed and the participant deemed 
a Screen Failure and will not be required to return for additional visits (although a participant can be seen at any 
time for safety reasons.)
All inclusion and exclusion criteria, medical history, and concomitant medications will be reviewed to confirm 
eligibility prior to performing additional study procedures/assessments. New (S)AEs and concomitant medications 
reported by the participant since the Screening Visit (Visit 1) will be recorded on the CRF. 
If participating in the receptor occupancy substudy, results obtained during the Screening Visit (Visit 1) including 
the results of the MRI scan must be reviewed by the PI prior to participant treatment with study drug to ensure 
participant remains eligible for the substudy.
Vital signs (blood pressure, pulse rate, respiratory rate, and oral body temperature) will be obtained after the 
patient has been in a sitting position for 5 minutes. 12- lead pre- and post-dose ECG will be taken in triplicate 
after the patient has been in a supine (resting) position for at least 5 minutes. An abbreviated physical exam will 
be performed.
If the participant remains eligible for study participation, visit information will be entered, and the required CRFs 
completed. The research pharmacist will be contacted regarding the participant’s enrollment and for specifics 
about the preparation and availability of study drug necessary for oral administration of BMS-984923. 
Study Drug BMS-984923 will be administered orally as a single dose. Details including dose and quantity 
administered, staff administering the study drug, and date and time of administration will be recorded on the CRF 
and in the participant’s record. Post-dose, participants will be monitored for any adverse events.
After study drug administration, vital signs will be monitored every 1 hr for the first 8 hours and then every 3 
hours until discharge on Day 3. An EKG will be performed at approximately 6 hours, 24 hours, and 48 hours after 
drug administration. The participant will have ready access to a call button and instructed in its use. There is a 
registered nurse present at the HRU and a physician who is on call at all times. The HRU is within Yale New Haven 
Hospital where a rapid response and “code” team are also available to respond if needed.
In order to monitor for changes in consciousness, the Glasgow Coma Scale (GCS) (Teasdale 1974) will be 
administered pre-dose and then every 2 hour for the first 8 hours and then every 3 hours until discharge on Day 
3. Participants with a GCS below 15 will be evaluated for appropriate level of inpatient care. No participant will be 
discharged with a GCS below 15.
In order to monitor cognitive or psychiatric side effects, the Montreal Cognitive Assessment (MOCA) (Nasreddine 
2005), Geriatric Depression Scale (GDS) (Sheikh 1986) and Neuropsychiatric Inventory Questionnaire (Cummings 
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1994) will be administered prior to oral dose administration, again at approximately 6 hours post-dose 
(approximate peak concentration) and approximately 24 hours post-dose. 
If a participant is found to be depressed, a clinician will perform further assessment and refer the participant to 
care as necessary. As part of ongoing adverse event monitoring, participants will be asked about changes in mood 
during in-person and phone visits. Additionally, they will be advised to call to inform the study team of changes in 
mood, specifically depression, between visits. 
Blood will be collected for safety laboratory studies prior to drug dose administration and on Days 2 and 3. Safety 
laboratory studies will include a comprehensive metabolic panel [glucose, blood urea nitrogen (BUN), creatinine, 
sodium, potassium, chloride, bicarbonate, calcium, total protein, albumin, total bilirubin, alkaline phosphatase, 
aspartate transaminase (AST), alanine transaminase (ALT)], phosphate, a lipid panel [total cholesterol, low density 
lipoprotein (LDL), high density lipoprotein (HDL), triglycerides], a complete blood count and differential, lactate 
acid dehydrogenase (LDH), creatine kinase (CK), amylase, and a urinalysis with reflex microscopic examination. 
Plasma will be collected for PK analysis as shown in Table 4.
A 24-hour urine collection will be performed starting at the time of study drug administration. A second 24-hour 
urine collection will be performed from 24-48 hours after study drug administration These samples will be used to 
measure urine drug and metabolite levels.
The participant will remain in the HRU on Study Days 1 and 2, and discharged on Study Day 3 after all required 
assessments have been completed. During the inpatient stay, abnormal assessments and laboratory values will be 
evaluated by the PI in collaboration with the medical monitor in real time. See the schedule of events (Table 3) for 
details on the assessments on each Study Day.
Post Treatment Follow-up Visits 
See the schedule of events (Table 3) for details on the assessments on each Study Day.
Visit 3 (Day 4) – Vital signs (BP, pulse, respiratory rate, and oral body temperature) will be obtained. Plasma 
samples for PK assessments will be collected. Information on changes or newly administered concomitant 
medications as well as any new or ongoing (S)AEs will be collected at each visit. 
Visit 4 (Day 5 phone call) - Participants do not have to visit the clinic for Post-treatment follow-up on Day 5 unless 
necessary to follow-up on adverse events. Participants will receive a telephone call from study site personnel 
inquiring as to their general health. Information on changes or newly administered concomitant medications as 
well as any new or ongoing (S)AEs will be assessed.
Visit 5 (Day 7) – Vital signs (BP, pulse, respiratory rate, and oral body temperature) will be obtained. The MOCA, 
GDS, NPI-Q, and safety laboratory assessments will be repeated on day 7. Plasma samples for PK assessments will 
be collected. Information on changes or newly administered concomitant medications as well as any new or 
ongoing (S)AEs will be collected at each visit.
Pregnancy Follow-up – Although we will exclude females of child-bearing potential, if a woman becomes pregnant 
during the study, we will follow it to outcome. 
Table 3: Schedule of Study Events1
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Study Phase
Screening
Inpatient Treatment
Post-Treatment Follow-
Up
1
Study Day
-90
through -
1
Pre-
Dose
Post
2
3
4
5
7
± 1 
days
Visit Number
1
2
3
42
5
Informed consent
X
Assign Participant ID
X
Inclusion & Exclusion Criteria
X
X
CDR
X
Modified Hachinski
X
MMSE
X
GDS
X
X
6 h
24 h
X
MOCA
X
X
6 h
24 h
X
NPI-Q
X
6 h
24 h
X
Instructions for potential 
washout period for 
concomitant medications
X
Medical History
X
X
Full Physical Examination
X
Demographics
X
Vital signs (BP, pulse, RR, oral 
temp)3
X
X
X
X
X
X
X
GCS4
X
X
X4
X4
X4
X
X
ECG5
X
X
X5
X5
X5
Confirmation of non-child bearing 
potential for women
X
MRI6
X
Admission/Discharge to/from 
HRU
Admit
Discharge 
(48 h post-
dose)
Physical Examination 
(abbreviated)
X
X
Dosing of Investigational Product7
X
Study Drug Accountability
X
Urine metabolites
24-hour 
urine 
collection
24-hour 
urine 
collection
Plasma for PK8
X8
X8
X8
X8
X8
X8
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Clinical laboratory sample 
collection
X
X
X
X
X
Urinalysis
X
X
X
X
FSH (all females without 
documented bilateral tubal 
ligation or hysterectomy)
X
[18F]FPEB PET Scans9
X
X
X
Concomitant Medications
X
X
X
Adverse Events10
X
X
Serious Adverse Events
X
X
X
1Abbreviations: AE = adverse events, ECG = electrocardiogram, ID = identification, PK = pharmacokinetic, SAE = serious 
adverse event, GCS = Glasgow Coma Scale
2Visit 4 is a phone visit.
3Vital signs (blood pressure, pulse rate, respiratory rate, and oral body temperature) will be measured after the patient has 
been in a sitting or recumbent position for 5 minutes. Frequency noted below:
Screening visit - Once
Day 1 – Once pre-dose, once post-dose, then every 1 hour for the first 8 hours following dosing, then every 3 hours 
Day 2 and 3- every 3 hours until discharge 
Day 4, 7 - Pre-blood draw
4GCS will be administered pre-dose, post-dose, every 2 hours for the first 8 hours and then every 3 hours until discharge on 
Day 3. 
5ECGs will be taken in triplicate and will be obtained after the patient has been in a supine (resting) position for at least 5 
minutes. At Visit 2, triplicate ECGs will be performed pre-dose, approximately 6 hours post-dose, and approximately 24 and 
48 hours post-dose.
6MRIs will be read by an expert prior to participant enrollment into the study and only performed for participants enrolled in 
the receptor occupancy sub-study.
7The study drug will be administered in a fasted state. Dosing will occur at least 8 hours after the last meal and no food will 
be provided for 1 hour post-dose.
8PK sampling will be done at the time points shown in Table 4. Participants in the receptor occupancy sub-study will also 
have up to 5 plasma PK samples collected during each PET scan for a total of up to 15 additional PK samples.
9Only for participants enrolled in the receptor occupancy sub-study. A pre-dose (baseline) scan will be performed within 60 
days of study drug administration. Post-dose scans will be performed at approximately 4 and 24 hours after dose 
administration. The baseline [18F]FPEB PET scan may be done after the inpatient and clinic follow-up visits if needed. 
10AEs are only collected upon the start of study drug. Events occurring prior to this are to be reported as part of the 
participant medical history. However, SAEs are to be collected from the time of informed consent
Assessment of Efficacy and Pharmacokinetics
Efficacy
This study is focused on safety, tolerability, and pharmacokinetics in healthy participants. Therefore, no efficacy 
assessments will be performed as primary outcomes.
Exploratory endpoints will include drug receptor occupancy assessment with [18F]FPEB PET by comparing within-
participant changes in mGluR5 availability pre-treatment and at the time of presumed maximal brain drug 
concentration. This analysis will be performed in a subset of 2 participants per dose cohort for the 10-100 mg 
dose levels.  PET scans may occur in a subset of 2 participants per cohort for dose level 150 mg and 200 mg. 
Pharmacokinetics
Plasma samples will be collected for analysis, as shown in Table 4. The timing for plasma sample collection may be 
adjusted for subsequent cohorts based on PK data from the preceding cohorts. 
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Table 4: Schedule for Pharmacokinetic Sampling*
Day 1 (Dosing day)
Day 2
Day 3
Day 4
Day 7
Plasma 
Samples
Pre-Dose, and post-dose at 30 min (± 
10 min), 1 h (± 10 min), 2 h (± 10 min), 
4 h (± 10 min), 8h (± 1 h), 12 h (± 1 h)
24 h (± 1 h)
48 h (± 2 h) 72 h ( ± 6h)
Day 7 ± 1 day
Urine 
Samples
24 hour collection starting 
immediately post-dose
Second 24 hour 
collection from 
24 to 48 hours 
post-dose
*Participants in the receptor occupancy sub-study will have up to five additional PK samples collected 
during each PET scan. The timing of these samples will be with respect to [18F]FPEB injection as follows: 
within 10 minutes prior to tracer injection, 1 h after tracer injection, and 2 hours after tracer injection.
Pharmacokinetic assessment will be carried out at Aptuit (Verona) Center for Drug Discovery and Development 
upon shipment to:
Luciana Romanelli/ Elena Bonesini/Michela Vecchini
Aptuit (Center for Drug Discovery & Development)
       
Via Fleming, 4 37135 Verona (Italy)
       
Email box: VERGMSampleManagement@evotec.com
       
Tel: + 39 045 8218342 or +39 045 8218854 or +39 045 821960
Remaining plasma and urine may be transferred to a separate (non GLP) experimental protocol wherein individual 
samples will be pooled and used to investigate the metabolism and excretion of study drug and related 
components.
Receptor Occupancy Substudy
The goal is to collect adequate PET scan data for at least 2 participants per cohort. Up to four participants in each 
cohort may participate in the Receptor Occupancy Sub-study. These participants will undergo an MRI during 
screening and three [18F]FPEB PET Scans. PET scans will occur at screening (within 60 days of study drug 
administration), approximately 4 hours post-dose and approximately 24 hours post-dose. The timing of post-dose 
PET scans may be adjusted after review of human PK data collected in this study. Each participant may be asked 
to repeat up to one [18F]FPEB PET scan if a scan fails quality control for a total of up to four [18F]FPEB PET scans 
during the course of study participation. The baseline [18F]FPEB PET scan may be done after the inpatient and 
clinic follow-up visits if needed.
The rationale for enrolling up to four participants from each Cohort in the sub-study is to help ensure that quality 
[18F]FPEB PET scan data is collected at all three timepoints on at least two participants per cohort. This over-
enrollment is necessary due to possibility of failed [18F]FPEB PET tracer synthesis and the time sensitive nature of 
the post-dose [18F]FPEB PET scans. The goal is to collect adequate PET scan data for 2 participants per cohort. We 
will not scan additional participants per cohort once adequate scan data has been captured. 
MRI Procedures
Magnetic Resonance Imaging (MRI) will be performed for enrollment in the receptor occupancy substudy. To be 
screened by MRI, participants must meet all clinical eligibility criteria. MRI will be used for quantitative evaluation 
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of PET scans, to screen for anatomical abnormalities, and to screen for neurological disease. MRI exclusion criteria 
will consist of focal or global atrophy, evidence of chronic or acute cerebrovascular disease, any space occupying 
lesion or other indication of underlying pathology. All MRIs will be read by a local expert to ensure consistent 
interpretation. MRIs will take place at the Anlyan Center, 300 Cedar Street, New Haven, CT.
MRI will be performed on a 3 Tesla system using pulse sequences selected to accommodate clinical reading, 
anatomical identification of VOIs, gray/white matter segmentation, and registration to a common space. 
Sequences will include:

3 Plane/Tri-Planar Scout

Axial T2 Star/GRE

Axial T2 FLAIR

Axial fcMRI (Participant should have eyes OPEN)

Sagittal 3D Accelerated MPRAGE/IRSPGR

Axial DWI

Axial DTI

Axial PASL (eyes open)

High Resolution Hippocampal T2
PET Scan Procedures
PET scanning sessions will take place at the Yale University PET Center, 801 Howard Ave, New Haven, CT. 
Participants with history of prior radiation exposure within the past year such that participation in this study 
would place them over FDA limits for annual radiation exposure will be excluded from this study.
Arterial Line Placement: A radial artery catheter will be inserted by an experienced provider before the PET scan 
to draw arterial blood samples for metabolite analysis and for determination of the fraction of plasma 
radioactivity unbound to protein. The goal of the arterial line is to be able to measure absolute physiological 
functions by mathematically relating the signal (from the PET scanner) to the tracer availability (from the blood). 
This approach is the gold standard for obtaining quantitative PET data and is required for receptor occupancy 
studies using orally administered drug. In scenarios where the arterial line cannot be placed or maintained, an 
additional intravenous catheter may be placed for blood sampling.
Radiotracer Injection: At each PET scanning session, participants will receive ≤ 5 mCi of [18F]FPEB administered by 
bolus injection via a venous catheter. The participant’s head will be immobilized and a transmission or CT scan will 
be obtained and used for attenuation correction. Vital signs will be taken immediately prior to injection of 
[18F]FPEB and will be monitored during the scan. Any adverse events will be evaluated and recorded continuously 
through the PET imaging visit.
Scanning Session: The scanning period is 0 - 120 min post injection. Dynamic images of radioactivity concentration 
are reconstructed with corrections for attenuation, normalization, random events, scatter, and dead time. 
Post-Scan: Upon completion of the PET Scanning days, the IV and arterial catheter will be removed and local 
pressure applied at the arterial catheter site for a minimum of 15 minutes to prevent bleeding under the skin. A 
pressure dressing will then be applied. 
Inclusion of women of childbearing potential: Women who are pregnant or lactating, and women of 
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childbearing potential will be excluded from the study. The PI will provide the PET center with documentation 
of non-childbearing potential status of female participants.
Radiation Exposure: Participants in this sub-study will receive a target radiation exposure from three injections of 
≤ 5 mCi of [18F]FPEB. This is equal to an effective dose of 0.930 rem. If a scan fails quality control, participants may 
be asked to repeat one [18F]FPEB PET scan. If a scan is repeated, participants will receive radiation exposure from 
four injections of ≤ 5 mCi of [18F]FPEB. This is equal to an effect dose of 1.24 rem.
Participants will also receive radiation exposure from either 3 low dose head CT scans or 3 transmission scans. If 
scans are completed on the High Resolution Research Tomograph (HRRT), participants will receive up to 0.0045 
rem from transmission scans. If scans are completed on the mCT, participants will receive up to 135mrem (0.135 
rem) from low dose head CT scans. 
Participants who repeat a [18F]FPEB PET scan will receive radiation exposure from an additional low dose head CT 
scan or transmission scan for a total of 4 low dose head CT scans or 4 transmission scans. If scans are completed 
on the HRRT, these participants will receive up to 0.006 rem from transmission scans. If scans are completed on 
the mCT, these participants will receive up to 180mrem (0.180 rem) from low dose head CT scans.
The targeted amount of radiation exposure participants will receive from this study is an effective dose of 1.065 
rem. The maximum possible radiation exposure participants will receive from participating in this study, if a scan 
is repeated, is an effective dose of 1.42 rem.
5.
Genetic Testing 
N/A ☒
A. Describe
i.
the types of future research to be conducted using the materials, specifying if immortalization of 
cell lines, whole exome or genome sequencing, genome wide association studies, or animal 
studies are planned 
ii.
the plan for the collection of material or the conditions under which material will be received 
iii. the types of information about the donor/individual contributors that will be entered into a 
database 
iv. the methods to uphold confidentiality 
B. What are the conditions or procedures for sharing of materials and/or distributing for future research 
projects? 
C. Is widespread sharing of materials planned? 
D. When and under what conditions will materials be stripped of all identifiers? 
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers that connect 
them to their materials? 
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i.
How will requests to withdraw materials be handled (e.g., material no longer identified: that is, 
anonymized) or material destroyed)? 
F.
Describe the provisions for protection of participant privacy 
G. Describe the methods for the security of storage and sharing of materials 
6.
Subject Population: Provide a detailed description of the types of human subjects who will be recruited into 
this study.
The study will recruit healthy male and female adults. Up to six cohorts of six participants will be recruited for 
a total of 36 participants.
7. Subject classification: Check off all classifications of subjects that will be specifically recruited for enrollment in 
the research project. Will subjects who may require additional safeguards or other considerations be enrolled 
in the study? If so, identify the population of subjects requiring special safeguards and provide a justification 
for their involvement.
☐Children
☒ Healthy 
☐Fetal material, placenta, or dead fetus
☐Non-English Speaking
☐ Prisoners
☐Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees
☐Pregnant women and/or fetuses
☐Yale Students 
☐ Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as potential subjects?
Yes ☐ No ☒ 
8. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or exclusion?
Participant Inclusion Criteria
Participants must meet all of the following inclusion criteria on the day of drug administration (Day 1) to be 
eligible for enrollment into the study:

Men or women between the ages of 50 and 80 years, inclusive

No history of cognitive impairment

Capable of providing written informed consent and willing to comply with all study requirements and 
procedures

Participant is not pregnant, lactating, or of childbearing potential
1.
Non-childbearing potential for women is defined as postmenopausal (last natural menses greater 
than 24 months; menopausal status will be documented with serum follicle stimulating hormone 
(FSH) or documentation of bilateral tubal ligation or hysterectomy
2.
Male participants who are sexually active with a woman of child-bearing potential must agree to 
use condoms during the trial and for 3 months after the last dose unless the woman is using an 
acceptable means of birth control. Acceptable forms of birth control include abstinence, birth 
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control pills, or any double combination of: intrauterine device (IUD), male or female condom, 
diaphragm, sponge, and cervical cap.
3.
Male participants must also agree not to donate sperm for 90 days after the last dose. 

GCS of 15 (Teasdale & Jennett, 1974)

CDR of 0 (Morris 1993)

Has a reliable study partner who has frequent contact with the participant (e.g., average of 10 hours per 
week or more), who can be available for study partner assessments, who can accompany the participant 
for 48 hours, without absence, after discharge from Visit 2.

Score on the MMSE > 26 (Folstein 1975)
Participant Exclusion Criteria
Participants who meet any of the following criteria will be excluded from the study:

Body mass index (BMI) > 38 kg/m2 or body weight < 50 kg.

Significant cerebrovascular disease: Modified Hachinski score > 4.

Any significant neurologic disease, such as AD, Parkinson’s disease, multi-infarct dementia, Huntington’s 
disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, 
subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent 
neurologic defaults or known structural brain abnormalities.

Major depression, bipolar disorder as described in DSM-IV within the past 1 year. 

Psychotic features, agitation or behavioral problems within 3 months, which could lead to difficulty 
complying with the protocol.

History of schizophrenia (DSM IV criteria).

History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).

Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled 
diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease in the 
opinion of the PI, may either put the patient at risk because of participation in the study, or influence the 
results, or the patient’s ability to participate in the study.

Clinically significant abnormalities in B12 or TFTs that might interfere with the study.

Use of psychoactive medications (typical neuroleptics, narcotic analgesics, antiparkinsonian medications, 
systemic corticosteroids, or medications with significant central anticholinergic activity) within 2 weeks or 
5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial. 

Use of medications with significant CYP1A2, 2D6, or 3A4 inhibitor or inducer activity (See Appendix A) for 
a list of these medications) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug 
administration and for the duration of the trial.

Use of anticoagulants within 30 days or 5 half-lives (whichever is greater) prior to study drug 
administration and for the duration of the trial.

Use of investigational amyloid lowering therapies within 2 months prior to study drug administration and 
for the duration of the trial. 

Use of another investigational agent within 30 days or 5 half-lives (whichever is greater) prior to screening 
and for the duration of the trial.

Neutropenia defined as absolute neutrophils count of < 1,500/microliter.

Thrombocytopenia defined as platelet count < 100,000/microliter.

Clinically significant abnormalities in screening laboratories, including Aspartate aminotransferase (AST) 
>1.5 times ULN; Alanine aminotransferase (ALT) >1.5 times ULN; Total bilirubin >1.5 times ULN; Serum 
creatinine >2.0 times ULN.
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Receptor Occupancy Substudy Eligiblity Criteria
Inclusion Criteria

Eligibility for and enrollment in Main Study

Participant consent to the optional substudy
Exclusion Criteria

Screening/baseline MRI scan with evidence of infection, infarction, or other focal lesions.

Presence of multiple lacunes or lacunes in a critical memory structure in the brain as evidenced in an MRI.

Any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) 
implants, metal fragments or foreign objects in the eyes, skin, or body or a cardiac pacemaker.

Current or recent participation in research procedures involving radioactive agents such that the total 
radiation dose exposure to the participant in any given year would exceed the limits of annual and total 
dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1.
9. How will eligibility be determined, and by whom? 
See above question for specific eligibility criteria. Eligibility will be determined by the PI based on review of 
Inclusion/Exclusion criteria.
10. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, or 
inconveniences associated with subjects participating in the research. 
Risks Associated with BMS-984923
BMS-984923 has not previously been administered to humans. Toxicology studies have been completed in rat 
and non-human primate, with no adverse effects at the doses comparable to the planned doses. At doses 
higher than those planned for this study in humans [see Investigator Brochure (IB) section 4.3.2.1), serious 
adverse effects related to drug accumulation were observed in rats receiving repeated doses greater than 15 
mg/kg/day. These adverse effects were gradual in onset over days and were manifest by lethargy, generalized 
stress responses, and death without organ specific or acute toxicity.  This constellation of serious adverse 
effects was reversed after cessation of daily 100 mg/kg/day administration.  There was no evidence for acute 
onset cardio-respiratory or CNS toxic effects. In order to mitigate the risk of similar adverse effects in humans, 
our planned maximal dose is well below the human equivalent of the rat and monkey no observed adverse 
effect level (NOAEL). Please refer to the Investigator Brochure (IB) for more detailed information on 
toxicology investigations.
Risks Associated with Electrocardiograms (ECGs) 
There is no pain or discomfort during an ECG; however, removing the pads may cause some irritation to the 
skin. 
Risks Associated with Blood Drawing and IV Line Insertion
Drawing blood and inserting an intravenous line (IV) into an arm vein are safe and standard medical 
procedures.  Sometimes a bruise will occur at the puncture site and rarely a blood clot or infection will occur 
in the vein.  Certain individuals may feel light-headed during venipuncture.  A total of approximately 70 mL (~ 
5 tablespoons) of blood will be collected from each participant during this study.  A total of approximately 140 
mL (~10 tablespoons) of blood will be collected from each participant in Cohort 4 and subsequent dose 
cohorts.  
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Psychological Stress 
The tests used to assess the participant’s mental performance may sometimes cause anxiety or fatigue. 
Risks Associated with Unanticipated Events 
The participant’s health and safety will always be the primary concern of the PI and staff performing the 
study. In the event of an unanticipated event, all necessary medical action will be taken. Medication might be 
administered as needed, per the YNHH HRU/ Yale PET Center standard operating procedure for medical 
emergencies, in order to treat any unanticipated events/complications. 
Receptor Occupancy Substudy Risks
Risks Associated with MRI
Magnetic resonance (MR) is a technique that uses magnetism and radio waves, not x-rays, to take pictures 
and measure chemicals of various parts of the body. The United States Food and Drug Administration (FDA) 
has set guidelines for magnet strength and exposure to radio waves, and we carefully observe those 
guidelines. 
Participants will be watched closely throughout the study. Some people may feel uncomfortable or anxious. If 
this happens, participants may ask to stop the study at any time and we will take the participant out of the 
MR scanner. On rare occasions, some people might feel dizzy, get an upset stomach, have a metallic taste or 
feel tingling sensations or muscle twitches. These sensations usually go away quickly but we will have 
participants tell the research staff if they have these symptoms. 
There are some risks with an MR study for certain people. Participants with a pacemaker or metal object 
inside their body will be excluded because the strong magnets in the MR scanner might harm the participant. 
Another risk is the possibility of metal objects being pulled into the magnet and hitting the participant. To 
reduce this risk we require that all people involved with the study remove all metal from their clothing and all 
metal objects from their pockets. We also ask all people involved with the study to walk through a detector 
designed to detect metal objects. It is important to know that no metal can be brought into the magnet room 
at any time. Also, once participants are in the magnet, the door to the room will be closed so that no one 
from outside accidentally goes near the magnet.
This MR study is for research purposes only and is not in any way a clinical examination. The scans performed 
in this study are not designed to find abnormalities. The PI, the lab, the MR technologist, and the Magnetic 
Resonance Research Center are not qualified to interpret the MR scans and are not responsible for providing 
a diagnostic evaluation of the images. If a worrisome finding is seen on a scan, a radiologist will be asked to 
review the relevant images. Based on his or her recommendation (if any), the PI or consulting physician will 
contact the participant, inform the participant of the finding, and recommend that the participant seek 
medical advice as a precautionary measure. The decision for additional examination or treatment would lie 
solely with the participant and the participant’s physician. The PI, the consulting physician, the Magnetic 
Resonance Research Center, and Yale University are not responsible for any examination or treatment that 
the participant receives based on these findings. The images collected in this study are not a clinical MR exam 
and for that reason, they will not be made available for diagnostic purposes.
The MRI scans will be read by an outside neuro-radiologist (Dr. Pradeep Varma) assess for exclusion criteria. 
In the event that Dr. Varma is unavailable for these readings, we will arrange for another qualified radiologist 
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to evaluate the scans.
Risks Associated with Use of an Arterial Catheter
On the PET scanning day, a radial arterial catheter will be inserted. Certain individuals may feel light-headed 
during arterial catheter placement. Arterial catheter placement may be associated with mild-to-moderate 
pain, hematoma, inflammation, bleeding, or bruising at the puncture site. If any of these, or other symptoms 
occur and do not diminish within 24 to 72 hours after the arterial line removal, or in the event that they 
worsen, subjects will be advised to call the on-call doctor listed on the PET discharge instructions. In rare 
instances, blocking of the artery, tearing of the artery, arterial leakage, poor healing, nerve damage, or 
infection at the catheter insertion site may occur.
Risks Associated with Radiation
The RSC will review the use of radiation in this research study, and no participants will be scanned until 
approval is obtained. This research study involves exposure to radiation from [18F]FPEB and associated 
transmission scans or low dose head CTs. 
This study will involve 3 [18F]FPEB PET scan sessions. The targeted amount of radiation an individual 
participant may receive from this study is from a maximum of three injections of ≤ 5 mCi of [18F]FPEB plus 
three accompanying transmission scans or low dose head CTs. 
Although each organ will receive a different dose, the amount of radiation exposure participants will generally 
receive during participation in this study is equal to an effective dose of 0.930 rem from [18F]FPEB and 0.0045 
rem from transmission scans if scans are performed on the HRRT or 0.135 rem from low dose head CTs if 
scans are performed on the mCT. The total radiation exposure from all three scanning sessions would be 
0.935 rem if scans are performed on the HRRT and 1.065 rem if scans are performed on the mCT. 
In the case of quality control failure, participants may be asked to repeat one [18F]FPEB PET scan. In this case, 
the maximum amount of radiation exposure that a participant may receive from this study is 1.24 rem from 
four injections of ≤5 mci [18F]FPEB and .006 rem from transmission scans if scans are performed on the HRRT 
or .180 rem from low dose head CTs if scans are performed on the mCT. The total radiation exposure from all 
four scans is 1.246 rem if scans are performed on the HRRT and 1.42 rem if scans are performed on the mCT.
The amount of radiation participants will receive in this study is below the dose guidelines established by the 
FDA and monitored by the Yale-New Haven Hospital Radiation Safety Committee for research participants. 
This guideline sets an effective dose limit of 5 rem per year. (FDA 21 CFR 361.1; 5 rads per year for whole 
body, active blood forming organs, lens of the eye and gonads; 15 rads per year for other organs).
Risks Associated with IV Line Insertion
To minimize risks associated with blood draws and infusions, experienced medical personnel will do all the 
blood drawing procedures.  At the PET Center the risks of bruising, clotting, and infection will be minimized by 
having venipuncture performed by trained and experienced personnel using aseptic technique. To avoid 
injury due to fainting, the catheter will be inserted when the participants are in a recumbent position. The 
blood draws during PET scanning sessions will be obtained from the already inserted catheter, to minimize 
discomfort.
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11. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.
Risks Associated with Study Drug, BMS-984923
To minimize the potential risks of BMS-984923, participants with unstable medical conditions will be 
excluded. At doses higher than those planned for this study in humans, serious adverse effects related to drug 
accumulation were observed in rats. These adverse effects were gradual in onset over days, were reversed by 
cessation of daily administration, and were manifest by lethargy and generalized stress responses without 
organ specific or acute toxicity. There was no evidence for acute onset cardio-respiratory or CNS toxic effects. 
In order to mitigate the risk of similar adverse effects in humans, our planned maximal dose is well below the 
human equivalent of the rat and monkey NOAEL.  Risks will be further minimized by the safety assessments 
detailed in the protocol, including neurological checks using the GCS, physical/neurological examinations, vital 
signs, ECGs, and clinical laboratories (See Table 3: Schedule of Study Events).  Finally, safety of participants 
will be further enhanced according to the provisions of the Data Safety Monitoring Plan (DSMP).
Participants in the receptor occupancy sub-study will undergo increased monitoring while in the PET scanner. 
The monitoring will continue as described in the protocol and a PET technician and research coordinator will 
also be monitoring the participant for signs of physiologic or psychiatric distress during the scan. In additional, 
participants will have continuous blood pressure and heart rate monitoring by arterial line. 
Risks Associated with Blood Drawing and IV Line Insertion 
To minimize risks of associated with blood draws and IV line insertion, experienced medical personnel will do 
all the blood-drawing procedures.
Risks Associated with MRI 
To minimize risks associated with MRI, the MRI’s will be conducted by experienced personnel at The Anlyan 
Center at Yale. All participants will complete the MRI safety questionnaire prior to having the MRI.
Risks Associated with Psychological Stress 
To minimize psychological stress, appropriate breaks will be provided to participants as needed
Minimization of Risks Associated with Receptor Occupancy Substudy
Risks Associated with MRI
To minimize risks associated with MRI, the MRI’s will be conducted by experienced personnel at The Anlyan 
Center at Yale.  All participants will complete the MRI safety questionnaire prior to having the MRI.
Risks Associated with Arterial Catheter
Risks of radial artery cannulation are minimized by having the procedure performed by an experienced health 
care provider.  The health care provider will be either a physician or an advanced practice registered nurse 
(APRN) with experience in critical care and placement of arterial catheters,  as is the practice at Yale-New 
Haven Hospital. For an APRN to place the arterial line at the Yale PET Center, they must meet the following 
criteria:
1.) Be currently credentialed at Yale-New Haven Hospital or similar institute and
2.) Perform 3 arterial line procedures supervised by a currently privileged PET Center physician.
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The 3 supervised arterial line placements will be documented and signed off by both the APRN and 
supervising physician. The completed document must be on file at the Yale PET Center prior to an APRN 
performing any arterial line catheterizations independently.
Pain is minimized by using local anesthesia. Infection is avoided by adequate cleansing of the skin prior to 
intravascular line insertion. After arterial catheter removal, bleeding is prevented by direct pressure applied 
to the site for a minimum of 15 minutes followed by a pressure dressing (coban) that should be kept clean 
and dry until evening. Subjects will have their hand and finger blood supply examined after arterial 
cannulation, throughout the study, and again following catheter removal. Also, subjects will be asked to 
abstain from aspirin and other NSAIDs for 7-10 days prior to arterial line insertion and 7-10 days following 
arterial line removal. Subjects will be provided a 24 hour emergency physician contact number to call if they 
encounter pain, discoloration, numbness, tingling, coolness, hematoma, inflammation, or any other unusual 
symptoms in the wrist or hand, or fever, chills or drainage from the vascular puncture sites, following the 
procedure.  In addition, if an emergency arises at the time of cannulation or scanning, 911 will be called, and 
the subject will be sent to the Emergency Department for evaluation and treatment.  A nurse will provide 
discharge instructions outlining general instructions in addition to post-arterial catheter precautions, 
problems to watch for, and procedures to follow should such problems occur. 
Risks Associated with Radiation 
The dose of radiation will be submitted for approval to the Yale institutional review board. All scans will be 
done in the presence of medical supervision and trained staff in an institution specifically designed to support 
imaging studies. In the event of serious medical complications, the PET scan facilities have immediate access 
to or consultation with specialized medical units at the Yale-New Haven Hospital. Preparation of radiotracers 
and performance of PET scans will be by radiochemists, physicians, and technologists of the Department of 
Diagnostic Radiology, Yale University School of Medicine. These professionals are qualified by training and 
experience in the safe use and handling of radiopharmaceuticals. Participants will be asked about their 
previous radiation exposure and those who have had research exposure within the past year will be excluded 
if their cumulative annual exposure (including the present study) exceeds FDA limits. The information on the 
previous radiation exposure of study participants will be notified to the study doctor. 
No PET studies will be performed on pregnant women or potentially pregnant women, as female participants 
of childbearing potential will be excluded from participation. If participants are breastfeeding, they will not be 
able to participate in this research study. 
Risks Associated with Blood Drawing and IV Line Insertion 
The risks of bruising, clotting, and infection will be minimized by having venipuncture performed by trained 
and experienced personnel using aseptic technique. To avoid injury due to fainting, the catheter will be 
inserted when the participants are in a recumbent position.
12. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan (DSMP) based on 
the investigator’s risk assessment stated below. (Note: the HIC will make the final determination of the risk to 
subjects.)
a. 
What is the investigator’s assessment of the overall risk level for subjects participating in this 
study? Moderate.  The assessment of the risks to participants associated with study participation 
is based on the fact that the study drug has extensive safety data in animals.  However, this is the 
first in human study. Safety monitoring will be performed by the DSMB in conjunction with the PI 
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and medical monitor.  There is little uncertainty about the possible occurrence or nature of risks, 
and there is adequate surveillance and protections to discover adverse events promptly and 
minimize their effects. 
b.
If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study? N/A
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are 
available here http://your.yale.edu/policies-procedures/forms/420-fr-01-data-and-safety-
monitoring-plans-templates for
i.
Minimal risk
ii.
Greater than minimal
Data and Safety Monitoring Board (DSMB)
An independent Data Safety Monitoring Board (DSMB) will be established, which will consist of individuals 
with expertise in: 1) Alzheimer’s disease and clinical medicine, 2) clinical trials methodology and 3) 
biostatistics.  Potential members will be appointed by the PI, after a review of experience and credentials.
The DSMB will provide an initial review of the final protocol and consent.  They will provide ongoing 
review of safety data, participant accrual, and outcome data.  The DSMB will review and approve changes 
to the protocol and consent forms, and provide routine oversight of both safety issues and data flow.  
They will receive serious adverse event (SAE) reports in real time and will review non-serious adverse 
events at the end of each dose cohort.  Other safety data will be reported in summary tables to the DSMB 
within 3 days of each DSMB meeting.  At their request, safety data will be reported in unblinded fashion.
The DSMB will meet following the last participant visit for each of the four dose cohorts.  The PI will be 
responsible for scheduling the meetings (in-person or by teleconference) and to ensure that all materials 
needed for review are provided with sufficient time prior to the meeting.  Each meeting will be divided 
into two parts.  First, an open session in which the principal investigators may be present, at the request 
of the DSMB, to review the conduct of the trial and to answer questions from members of the DSMB.  
The focus in the open session may be on accrual, protocol compliance, and general toxicity issues.  
Following this session, a closed session involving only DSMB members will be held to allow the DSMB 
opportunity to discuss the general conduct of the trial and all outcome results, including toxicities and 
adverse events, develop recommendations, and take votes as necessary.  A written report will be 
provided by the DSMB to the PI, IND holder (Dr. Strittmatter), and sponsors (NIA, Alzheimer’s 
Association).  At minimum this will include a recommendation to continue the protocol as planned and an 
approval of the dose escalation for the next dose cohort.  Protocol changes or discontinuation may also 
be recommended.
Safety Assessment and Dose Escalation Decisions
For the first 3 participants enrolled in the study, drug dosing will be conducted at a minimum of 48 hours 
between the first and second, and between the second and third participants. For subsequent cohorts, 
there will be at least 24 hours between dosing the first and second participants, and between the second 
and third participants, to allow for a 24-hour safety assessment review by the PI and medical monitor for 
each prior participant.
Determination of whether to open the next escalated dose cohort for enrollment will be made jointly by 
the PI, medical monitor, DSMB, and IND holder (Dr. Strittmatter) after review of all available clinical, 
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safety, and PK data. Dose escalation (for each sequential cohort) will not occur until all participants in the 
prior cohort have completed the study. The DSMB will perform an independent review. In addition, the PI 
and medical monitor will make a determination independent from the IND holder. Dr. Strittmatter will be 
consulted in scenarios where alterations to the planned dose escalation strategy are being considered. As 
the IND holder, Dr. Strittmatter must also agree with a decision to proceed with dose escalation before 
the next cohort is dosed. 
Dose escalation decisions will be determined with the following approach. At the completion of each 
cohort, 0-72 h PK data will be used to assess the plasma exposure derived from the area under the curve 
(AUC) from 0-24 h. Our dose escalation decisions will be based on the human data relative to the rat 28 
day GLP toxicology study to determine maximal NOAEL. In that study, the plasma exposure at NOAEL 
based on AUC (0-24h)  was 192,000 ng*h/mL (see IB). Furthermore, the plasma exposure in 
corresponding Cynomolgus study was similar at 169,000 ng*h/mL. 
The maximal doses for each cohort will be 10, 40, 70, 100, 150 and 200 mg. The human equivalent dose 
derived from the NOAEL dose in the 28D toxicology study in the most sensitive species (rat) is 140 mg.  
Thus, the starting dose is less than 10% of the 140 mg amount. Dose escalation in cohorts 2-6 will follow 
the plan above, but will be decreased based on the observed plasma exposure of the AUC (0-24 h) as 
detailed in the schedule below. The dose escalation for the next cohort will be based on the most recent 
cohort observed PK analysis as follows:
If plasma  AUC0-24h < 24,000 ng*h/ml (12.5% NOAEL), then dose increase according to schedule
If plasma AUC0-24h  24,000-48,000 ng*h/(12.5-25% NOAEL), then dose increase maximum of 2 fold
If  plasma AUC0-24h 48,001-96,000 ng*h/ml (25-50% NOAEL), then dose increase maximum of 1.5 fold
If plasma  AUC0-24h 96,001-120,000 ng*h/ml (50-67.5% NOAEL), then dose increase maximum of 1.3 fold
If plasma AUC0-24h > 120,000 ng*h/ml (>67.5% NOAEL), then stop escalation
Any serious adverse events or other safety concern might also constitute a rationale to stop or reduce 
escalation.
Criteria for intervention discontinuation
The PI and medical monitor may elect to stop dosing or stop the study based on any treatment emergent 
concerns. Although not expected based on animal toxicology and PK studies, participants will be 
monitored for clinically significant neuropsychiatric symptoms with the GDS and NPI-Q, neurological 
symptoms by exam, cognitive toxicity with testing, and laboratory abnormalities. While the planned doses 
are below the human equivalent of the repeated doses which caused serious adverse effects with 
lethargy in rat, participants will be monitored by frequent repeated GCS observations. Dosing may be 
stopped due to the occurrence of any individual adverse events which, in the judgment of the PI and 
medical monitor, need further characterization with respect to progression and reversibility before 
further dosing is conducted. Such adverse events may include non-serious unusual events. If dosing is 
stopped, review of the data by the medical monitor and DSMB must occur with a positive 
recommendation before dosing can be resumed.
Attribution of Adverse Events
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
Definite: Adverse event(s) will clearly be related to investigational agent or other intervention and 
cannot be reasonably explained by an alternative explanation – i.e., concomitant drug(s), 
concomitant disease(s).  The relationship in time is very suggestive.

Probable: Adverse event(s) will likely be related to investigational agent.  The relationship in time is 
suggestive that the adverse event is likely related to the investigational agent.  An alternative 
explanation is less likely – i.e., concomitant drug(s), concomitant disease(s).

Possible: Adverse event(s) may be related to investigational agent. An alternative explanation – i.e., 
concomitant drug(s), concomitant disease(s), - is inconclusive.  The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded.

Unlikely: Adverse event(s) will doubtfully be related to investigational agent(s). An adverse event for 
which an alternative explanation is more likely – i.e., concomitant drug(s), concomitant disease(s), 
and/or the relationship in time suggests that a causal relationship is unlikely. 

Unrelated: Adverse event(s) will clearly not be related to the investigational agent
Plan for Grading Adverse Events
Adverse event (AE): An adverse event (AE) is any adverse change from the participant’s baseline 
condition, regardless of relationship to study drug, including clinical or laboratory tests, or abnormalities 
which occur after informed consent is signed and up to 7 days after the study drug has been 
discontinued. Clinically significant adverse changes in clinical status, ECGs, and physical examinations are 
considered AEs. Any participant complaint associated with such an abnormal finding will also be reported 
as an AE. AEs are only collected upon the start of study drug. Events occurring prior to this are to be 
reported as part of the participant medical history. However, SAEs are to be collected from the time of 
informed consent.
Adverse events include but are not limited to: (1) worsening or change in nature, severity, or frequency of 
conditions or symptoms present at the start of the study; (2) participant deterioration due to primary 
illness; (3) intercurrent illness; and (4) drug interaction. An abnormal laboratory value will only be 
reported as an AE it if requires therapeutic medical intervention, if the investigator considers it to be an 
AE, or if it leads to the participant being withdrawn from the study. 
The investigator should attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis should be documented as the AE and not the 
individual signs/symptoms. Symptoms and conditions present at the beginning of the study will be 
characterized, so that AEs can be defined as any new symptom, or any increase in frequency or severity 
of an existing symptom. 
Following questioning and evaluation, all AEs, whether determined to be related or unrelated to the 
study drug by the Site Protocol Principal Investigator, must be documented in the participant’s medical 
records, in accordance with the investigator’s normal clinical practice. Each AE is evaluated for duration, 
severity, seriousness, and causal relationship to the study drug.
The intensity of each AE will be rated according to the following 3-point scale:

Mild: 
Awareness of signs or symptoms, but no disruption of usual activity

Moderate: Event sufficient to affect usual activity (disturbing)

Severe: Inability to work or perform usual activities (unacceptable)
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Serious Adverse Event (SAE): Any untoward medical occurrence that at any dose: results in death, is life-
threatening, require inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (NIH Guide-6/11/99).
Note 1: Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the outcomes listed in the definition above.
Note 2: Hospitalizations that fulfill one of the following conditions will not have to be reported as SAE:

Hospitalizations for social reasons and thus unrelated to a deterioration of the participant’s condition 
or adverse event (e.g., deterioration of the living conditions related to environmental factors rather 
than to a deterioration of the disease, lack of transportation to the investigational site, respite care 
for the caregiver)

Hospitalizations for elective surgical interventions for which the date had already been determined 
prior to the study participation.
Unlisted (Unexpected) adverse event: An adverse event, the nature or severity of which is not consistent 
with the applicable product information (e.g., package insert/summary of product characteristics for an 
approved product (ICH and GCP)).
Life-Threatening: Any event in which the participant was at risk of death at the time of the event; it does 
not refer to an event, which hypothetically might have caused death if it were more severe.
Associated with the use of the drug: An adverse event is considered associated with the use of the drug if 
the attribution is possible, probable, or definite.
Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as an AE are 
as follows:
test result is associated with accompanying symptoms, and/or
test result requires additional diagnostic testing or medical/surgical intervention, and/or
test result leads to a discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy, and/or
test result is considered to be an AE by the investigator in consultation with the medical monitor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE.
Adverse Events of Special Interest (AESI)
No Adverse Events of Special Interest (AESI) for this study have been identified in non-clinical toxicology 
studies with BMS-984923. Based on drug mechanism of action, the following are considered AESI for this 
study: central nervous system complications.
Plans for Reporting Adverse Events and Serious Adverse Events
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The PI and research staff will monitor the study procedures for this trial for overall safety and scientific 
relevance on an ongoing basis. Dr. Mecca (in conjunction with the medical monitor and DSMB as 
necessary) will evaluate every adverse event for safety and causality, and will determine whether the 
adverse event affects the Risk/Benefit ratio of the study and whether modifications to the protocol or 
consent form are required. 
The PI will report the following types of adverse events to the Yale University HIC, DSMB, and IND holder 
within 48 hours of it becoming known to the investigator: a) all serious adverse events; b) non-serious 
adverse events occurring with a greater magnitude or frequency than expected; and c) other 
unanticipated problems involving risks to participants or others. 
All adverse events post administration of a PET tracer will be reported to the PET center, the PET 
authorized user, and the YNHH RSC.
SAEs as defined in the HIC DSMP will be reported to the HIC, DSMB, and IND holder within 48 hours (using 
HIC Form 6A). In this report, the PI will give a brief description of the SAE including severity, duration, 
action taken, outcome, and plan. He will also give an opinion regarding the relationship of the SAE to the 
study drug and determine whether or not the protocol or consent form needs to be modified as a result 
of the SAE. If available, a report from the DSMB will accompany the HIC report submission. Reporting will 
not be delayed pending resolution or outcome of an event. If an outcome for an adverse event is not 
available at the time of the initial report, participant follow-up will proceed until such time as an outcome 
is known. A progress report of the study that includes all of the SAEs will be reported to the HIC in an 
annual request for renewal. 
The DSMB will review all non-serious AEs at the completion of each dose cohort (approximately every 3 
months). This will be done via teleconference.
The IND holder (Dr. Strittmatter) will report adverse events to the FDA following Guideline Section 312.32 
IND Safety Reporting standards. In particular, the sponsor will notify FDA in an IND safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. Upon 
request from FDA, the IND holder will submit to FDA any additional data or information that the agency 
deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the 
request. The IND holder will also notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of 
the information.
13. Statistical Considerations: Describe the statistical analyses that support the study design. 
Sample Size
The sample size was derived empirically from experience with previous single ascending dose clinical studies 
and PET occupancy studies in other disorders and is deemed appropriate to achieve the study objectives.
General Methods
Data will be tabulated by dose cohort, as well as by pooled (all participants combined), and no inferential 
statistics are planned.
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Handling of Missing Data
All data collected will be included in by-domain data listings, sorted by participant number and time point, or 
as appropriate. Every attempt will be made to collect data at each time point. For participants who 
discontinue treatment (for any reason), participants will continue to be followed and efficacy endpoints and 
safety data collected where possible.
Subgroups
The sample size precludes analysis by-subgroup. However, exploratory assessment of any trends among 
subgroups (eg, by dose) may be performed, after initial review if the data warrant.
Analysis Populations
Safety Population: Safety outcomes will be assessed for all participants who are given at least one dose of 
study drug.
Alpha Level Considerations
No inferential statistical testing is planned. However, if used for exploratory analysis, inferences will be 
assessed against a 5% alpha, and therefore p-values ≤ 0.05 will be considered statistically significant. All tests 
will be two-sided. No adjustment will be made to p-values for multiple testing.
Participant Disposition and Exposure
The numbers of participants completing or withdrawing, along with reasons for withdrawal, will be 
summarized by dose.
Tabulation of the number of doses of study drug, duration of treatment as well as total dose given will be 
provided.
Demographics and Baseline Characteristics Analyses
Demographic variables (age, sex, race, and ethnicity) as well as height (cm), weight (kg), Body Mass Index 
(BMI), temperature, heart rate, blood pressure and respiratory rate or pulse oximetry (from the vital signs) at 
baseline will be summarized using descriptive statistics. All demographic data will be provided in a data listing.
Efficacy Endpoints
No efficacy endpoints will be assessed since this is a sample of healthy participants.
Safety Endpoints
The safety analysis will be descriptive in nature. All safety data will be listed, and data will be tabulated by 
dose. Safety data include:

AEs
o
Events occurring prior to the first dose of study drug will be defined as pre- treatment events.
o
TEAEs will be defined as any AE occurring during or after oral administration of the study 
drug. Therefore, this will include all events occurring through Day 7/ET.
Incidence of AEs will be summarized for each cohort by MedDRA system organ class (SOC) and preferred term 
(PT), sorted in descending frequency by SOC, and then by PT within SOC. These summaries will be given by 
dose in separate tables for each of the following TEAE event sets:
•
All events
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•
Treatment related events (defined by a relationship to study drug of possible, probable, or definite).
•
Serious adverse events
•
Events leading to premature discontinuation from study
•
Events by maximum severity
•
AEs of Special Interest, ie, events relating to cognitive decline or neuropsychiatric symptoms. 
Other safety outcomes will include:
•
Clinical laboratory tests presented as changes over time. Potentially clinically significant (PCS) ranges will 
be defined and used to determine the incidence of participants experiencing new- onset PCS laboratory 
values, where new-onset is defined as a PCS value for a participant following initiation of study treatment 
for which the participant did NOT have a PCS value for that analyte PRIOR to initiation of study treatment.
•
Vital signs including: respiratory rate, heart rate, temperature, and blood pressure, as per the schedule of 
events. BMI will be assessed, with height collected only at screening.
•
Physical examination
•
12-lead ECG. ECG parameters will be analyzed in a fashion similar to that of clinical laboratory 
parameters.
Concomitant treatments will be assessed according to the timing of their start/stop dates as they relate 
to the study drug treatment, as follows:
•
Prior medications with start AND stop date before date of first dose of study drug.
•
Concomitant medications with participant exposure that includes at least one dose of study drug.
•
New-onset medications. Concomitant medications with a start date AFTER the first dose of study drug. 
New-onset medications are a subset of the full set of concomitant medications.
Changes from pre-treatment will be calculated in a similar fashion as for the efficacy endpoints, but no 
inferential statistics will be provided for safety endpoints. Shifts from baseline in ECG will be tabulated for 
heart rate and QTc. Other endpoints will be assessed according to the scale of the variable.
Pharmacokinetic Endpoints
Concentration data in plasma will be assessed descriptively over time. Correlation with safety and receptor 
occupancy outcomes may be performed, as the data warrant.
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
If this section (or one of its parts, A or B) is not applicable, check off N/A and delete the rest of the section.
A. RADIOTRACERS
☐N/A
1.
Name of the radiotracer: [18F]FPEB 
2.
Is the radiotracer FDA approved? ☐YES 
☒NO
If NO, an FDA issued IND is required for the investigational use unless RDRC assumes oversight. 
3.
Check one: ☒IND# 150912
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or ☐RDRC oversight (RDRC approval will be required prior to use)
4.
Background Information: Provide a description of previous human use, known risks, and data addressing 
dosage(s), interval(s), route(s) of administration, and any other factors that might influence risks. If this is the 
first time this radiotracer is being administered to humans, include relevant data on animal models. 
[18F]FPEB
The radiotracer [18F]FPEB has previously been used in human participants; 5 individuals at the 
Neurodegenerative Disorders (IND) in New Haven CT, and over 100 individuals at Yale University. No 
participants have reported any adverse event with this radiotracer. However, participants will be monitored 
carefully during and after the PET scan for any potential side effects.
The radiation dose estimates are based on the biodistribution data for [18F18]FPEB in 6 healthy adults (3 
men and 3 women) and calculated using OLINDA/EXM software (Wong 2013). Based on these numbers, the 
critical organ is the gallbladder wall (0.191 mGy/MBq, i.e., 0.708 rad/mCi). Another radiation dose study 
(Kessler 2014) also reported gallbladder wall (0.193 mGy/MBq, 0.714 rad/mCi) as the critical organ based 
on the biodistribution data in 9 healthy adults (5 men and 4 women). However, Kessler et al. reported the 
urinary bladder wall as the critical organ (0.258 mGy/MBq, 0.955 rad/mCi) when no voiding takes place 
prior to a 3.5 h period. Thus, the maximum allowable injection doses for [F-18]FPEB to remain below the 21 
CFR 361.1 dose limits for research participants are 5.2 mCi per single injection (calculations based upon the 
urinary bladder wall for a 3.5 h voiding), and 7 mCi per single injection (calculations based upon the 
gallbladder wall as the critical organs); 3 rads per single study for whole body, active blood forming organs, 
lens of the eyes and gonads; 5 rads for other organs per single study limit.
5.
Source: Identify the source of the radiotracer to be used. 
[18F]FPEB will be synthesized at the Yale University PET Center radiochemistry Laboratory under the 
supervision of Drs. Henry Huang & Nabeel Nabulsi.
6.
Storage, Preparation and Use: Describe the method of storage, preparation, stability information, method 
of sterilization and method of testing sterility and pyrogenicity.
Due to the short half-life, PET drugs are prepared and formulated immediately before administration, and 
therefore there are no issues with storage or stability. PET drug products are stored at room temperature 
and are stable for at least 60 min after preparation.
The preparation of sterile PET drug products is validated prior to human use. Sterility is achieved by passing 
the PET drug product through a 0.22 micron membrane filter during the last step of the formulation 
process. Prior to release for administration, a bubble point test is performed on the membrane filter used 
for terminal sterilization in order to validate and verify its integrity during the filtration process. Due to the 
short half-life, a sample of the PET drug product is tested for sterility after administration for further 
confirmation.
The level of endotoxin in each batch of the final PET drug product is determined quantitatively prior to 
release for administration using the FDA approved Charles River Laboratory’s Portable Testing System 
(Endosafe®-PTS).
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[18F]FPEB will be prepared at the Yale PET Center in accordance with our Chemistry Manufacturing & 
Control (CMC) procedures and quality specifications described in our FDA approved Drug Master File 
(DMF), under IND#059121. 
B. DRUGS/BIOLOGICS ☐N/A
1.
If an exemption from IND filing requirements is sought for a clinical investigation of a drug product that is 
lawfully marketed in the United States, review the following categories and complete the category that 
applies (and delete the inapplicable categories):
N/A
2.
Background Information: Provide a description of previous human use, known risks, and data addressing 
dosage(s), interval(s), route(s) of administration, and any other factors that might influence risks. If this is the 
first time this drug is being administered to humans, include relevant data on animal models. 
The present clinical evaluation of BMS-984923 is being conducted in healthy participants. Safety and 
tolerability studies in this population will allow longer term safety studies and ultimately efficacy studies in 
participants with AD. 
Nonclinical Summary
Preclinical animal data are summarized in the background above for BMS-984923. Please refer to the IB for a 
more detailed description of toxicology investigations.
Clinical Experience with BMS-984923
The present study represents the first evaluation of BMS-984923 in humans.
3. Source: Identify the source of the drug or biologic to be used.
a)
Is the drug provided free of charge to subjects? ☒YES 
☐NO 
If yes, by whom? Allyx Therapeutics, Inc.
4.Storage, Preparation and Use: Describe the method of storage, preparation, stability information, and for 
parenteral products, method of sterilization and method of testing sterility and pyrogenicity.
Study Drug Packaging and Labeling
The clinical trial supply label will be in accordance with ICH GCP and local requirements for investigational 
product labelling. Investigational products are for investigational use only and the study drug supplied for this 
study is intended for use only within the context of this study. The study drug supplied for this study should be 
stored in a secure, temperature controlled, locked place with restricted access, maintained under adequate 
security until dispensed for participant use or returned to Investigational Drug Service.
Please see page 16 “Description of Study Medication” for and Table 2 footnote for a description of how the 
drug is being provided for this study. 
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Study Drug Storage
BMS-984923 is stored at 15-25° C.
Study Drug Management
The PI, pharmacist, or their designee will verify that study drug supplies are received intact and in the correct 
amounts by signing and dating the investigational product receipt log. The person receiving the supplies must 
verify that the shipment contains all the items noted in the shipment inventory. Any damaged or unusable drug 
in a given shipment will be documented in the study files. 
The site will maintain a Drug Inventory Log (includes, but not limited to, the following: lot number, number of 
units received, and number of capsules dispensed. The site will also maintain patient-specific drug dispensing 
logs.
Study Drug Accountability
Participants will be treated at the clinical site, in-patient clinical unit, or other approved location and therefore 
the Pharmacist or other investigational staff via documentation of receipt of the study drug and 
dosing/treatment given will perform/maintain drug accountability.
Study Drug Handling and Disposal
Records of receipt, dispensing records and inventory forms, as applicable, will be examined and reconciled 
during and at the end of the study. Both the study drug that is used during the study, as well as any remaining 
unused study drug, must be accounted for on a drug accountability record.
At the end of the study, all used and unused investigational drug capsules, accompanied by a packing slip, must 
be returned to the designated clinical supplies vendor for disposal or destroyed per site SOPs. In addition, a 
copy of all completed drug accountability records will be retained. The product is to be stored in a safe place 
(locked facility) at the appropriate temperature.
Check applicable Investigational Drug Service utilized:
 ☒ YNHH IDS              ☐ CMHC Pharmacy           ☐ West Haven VA
 ☒ PET Center              ☐ None  
 ☐ Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in detail how the PI 
will oversee these aspects of drug accountability, storage, and preparation. 
5.
Use of Placebo: 
☒Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a)
Describe the safety and efficacy of other available therapies. If there are no other available therapies, state 
this. 
b)
State the maximum total length of time a participant may receive placebo while on the study. 
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c)
Address the greatest potential harm that may come to a participant as a result of receiving placebo. 
d)
Describe the procedures that are in place to safeguard participants receiving placebo. 
6.
Continuation of Drug Therapy After Study Closure ☐Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has ended?
☐ Yes If yes, describe the conditions under which continued access to study drug(s) may apply as well as 
conditions for termination of such access. Write here
☒ NO If no, explain why this is acceptable. This is a Phase 1a study designed to determine the safety, tolerability, 
and efficacy of BMS-984923 in healthy participants. Therefore, the investigational treatments will not likely be 
available to patients beyond their participation in this clinical trial and would not be clinically indicated.
 C. DEVICES
 ☒N/A
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects: 
a.
Targeted for enrollment at Yale for this protocol: We plan to consent and enroll four cohorts of six 
participants each for a total of 24 participants. Up to three participants per cohort, or a total of 12 
participants, will enroll in the Receptor Occupancy sub-study.
b.
If this is a multi-site study, give the total number of subjects targeted across all sites: N/A
2.
Indicate recruitment methods below. Attach copies of any recruitment materials that will be used.
☐Flyers
☐ Internet/web postings
☐ Radio
☐ Posters
☐ Mass email solicitation
☐ Telephone
☐ Letter
☐ Departmental/Center website
☐ Television
☒ Medical record review* 
☐ Departmental/Center research boards
☐ Newspaper
☐ Departmental/Center newsletters
☐ Web-based clinical trial registries
☐ Clinicaltrails.gov 
☒ YCCI Recruitment database
☐ Social Media (Twitter/Facebook): 
☒ Other: Physicians that are familiar with the ADRU may provide our contact information to his/her patients so 
that the patient can initiate contact with us.
* Requests for medical records should be made through JDAT as described at 
http://medicine.yale.edu/ycci/oncore/availableservices/datarequests/datarequests.aspx
3.  Recruitment Procedures: 
a. Describe how potential subjects will be identified. 
Participants may be identified from among those already known to the Alzheimer's Disease Research Unit 
(ADRU). Participants in the “Subject Recruitment Database” (HIC #25374) have either participated in a 
previous study or contacted the ADRU about participation and have asked to be contacted for future studies. 
In addition, physicians and other health professionals who are familiar with the ADRU may provide our 
contact information to their patients so that they may initiate contact with us.
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b. Describe how potential subjects are contacted. 
Before contacting potential participants already known to the ADRU, we may perform reviews of charts that 
contain Protected Health Information to assess participant eligibility. We have permission from our 
participants to contact them for new studies, which is provided in the participant information forms (see 
“Subject Recruitment Database” HIC #25374).
For new participants who contact the ADRU (from the various sources advertising sources detailed above), 
after obtaining the required permission, we will conduct phone interviews that may include questions 
pertaining to Protected Health Information such as demographics, medical history, current medications, and 
family history (see “Subject Recruitment Database” HIC #25374).
c. Who is recruiting potential subjects? 
The PI or members of his staff who work under his supervision.
4. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical relationship with any 
potential subject? 
☐Yes, all subjects
☐Yes, some of the subjects
☒No
If yes, describe the nature of this relationship. 
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization for either the 
entire study, or for recruitment purposes only. Note: if you are collecting PHI as part of a phone or email 
screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment/screening purposes only
☐ For inclusion of non-English speaking subject if short form is being used and there is no translated HIPAA 
research authorization form available on the University’s HIPAA website at hipaa.yale.edu.
i.
Describe why it would be impracticable to obtain the subject’s authorization for use/disclosure of this 
data: 
N/A – requesting waiver of signed authorization only. We will obtain verbal authorization for 
use/disclosure of data.
ii.
If requesting a waiver of signed authorization, describe why it would be impracticable to obtain the 
subject’s signed authorization for use/disclosure of this data: 
Information may be collected during a phone screen for recruitment purposes. At the end of a phone 
screen, individuals are read a paragraph for authorization for storing screening information (see HIC 
protocol 0307025374). If authorization is denied, all screening information is destroyed.
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The investigator assures that the protected health information for which a Waiver of Authorization has been 
requested will not be reused or disclosed to any person or entity other than those listed in this application, except 
as required by law, for authorized oversight of this research study, or as specifically approved for use in another 
study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale HIPAA-Covered 
entity must be accounted for in the “accounting for disclosures log”, by subject name, purpose, date, recipients, 
and a description of information provided. Logs are to be forwarded to the Deputy HIPAA Privacy Officer.
6.
Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be obtained, 
including parental permission or surrogate permission and the steps taken to ensure subjects’ independent 
decision-making. 
The specific steps in the informed consent process will be as follows: 
1. The informed consent form will be discussed with the participant.
2. The participant will be given adequate opportunity to read the consent form. 
4. The Consent Personnel will answer any questions, correcting and discussing any misconceptions. 
5. The participant will sign the consent form if they wish to participate. 
The participant will not take part in any part of the clinical study, including the initial screening, until they 
have signed and dated the informed consent form to individuate that he or she understands and agrees to its 
contents.
7.
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the personnel obtaining 
consent will assess the potential participant’s ability and capacity to consent to the research being proposed. 
As this study is designed to determine the safety and tolerability of study drug and lacks potential benefit to 
participants, only participants capable of providing informed consent will be enrolled (no surrogate consent 
will be allowed). The PI or surrogate obtaining informed consent will make a judgment about whether the 
participant is capable of providing informed consent. This judgment will be based on an overall impression of 
the participant’s ability to comprehend relevant information and make reasoned decisions.
If the participant is judged capable of providing informed consent, they will sign the “Participant Informed 
Consent” page. Participants who are not able to provide informed consent at the start of the trial will be 
excluded from participation in the study.
8.
Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for research involving 
non-English speaking participants. If enrollment of these participants is anticipated, translated copies of all 
consent materials must be submitted for approval prior to use. 
Only English-speaking participants will be enrolled.
As a limited alternative to the above requirement, will you use the short form* for consenting process if you 
unexpectedly encounter a non-English speaking individual interested in study participation and the translation of 
the long form is not possible prior to intended enrollment? YES ☐ NO ☒
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Note* If more than 2 study participants are enrolled using a short form translated into the same language, then 
the full consent form should be translated into that language for use the next time a subject speaking that 
language is to be enrolled.
Several translated short form templates are available on the HRPP website (yale.edu/hrpp) and translated HIPAA 
Research Authorization Forms are available on the HIPAA website (hipaa.yale.edu). If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the IRB office for 
approval via modification prior to enrolling the subject. Please review the guidance and presentation on use of the 
short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please request a HIPAA waiver in 
the section above. 
9.
Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or a full waiver 
of consent, depending on the study. If you will request either a waiver of consent, or a waiver of signed consent 
for this study, complete the appropriate section below. 
☐Not Requesting any consent waivers 
☒Requesting a waiver of signed consent:
☒ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐ Entire Study (Note that an information sheet may be required.)
 For a waiver of signed consent, address the following:
Would the signed consent form be the only record linking the subject and the research? YES ☒ NO ☐ 
Does a breach of confidentiality constitute the principal risk to subjects? YES ☒ NO ☐
 
OR
Does the research pose greater than minimal risk? YES ☐ NO☐ 
Does the research include any activities that would require signed consent in a non-research context? YES ☐ 
NO ☐
 ☐ Requesting a waiver of consent:
☐ Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐ Entire Study 
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For a full waiver of consent, please address all of the following:

Does the research pose greater than minimal risk to subjects? 
☐ Yes If you answered yes, stop. A waiver cannot be granted. 
☐ No

Will the waiver adversely affect subjects’ rights and welfare? YES ☐ NO☐

Why would the research be impracticable to conduct without the waiver? Write here

Where appropriate, how will pertinent information be returned to, or shared with subjects at a later date? 
Write here
SECTION IV: PROTECTION OF RESEARCH SUBJECTS
 Confidentiality & Security of Data:
1.
What protected health information (medical information along with the HIPAA identifiers) about subjects will 
be collected and used for the research? 
2.
Required private identifiable information about individuals, such as their medical history, current 
medications, clinical laboratory and EKG results, physical exam information, psychiatric problems, MRI and 
PET scan results, and family history will be collected by the research staff and be used for research purposes 
and charting after consent is obtained.
3.
How will the research data be collected, recorded and stored? 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an electronic 
data record or both, depending on the data collection method used in this study.
An CRF is required and should be completed for each included participant. The CRFs must be signed by the PI 
to attest that the data contained on the CRFs is true. Any corrections to entries made on the CRFs must be 
dated, initialed, and explained (if necessary) and should not obscure the original entry.
In most cases, the source documents are the hospital's or the physician's participant chart. In these cases, 
data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents. In these cases, a document 
should be available at the PI’s site and clearly identify those data that will be recorded on the CRF, and for 
which the CRF will stand as the source document.
To enable evaluations and/or audits from regulatory authorities, the PI will keep records, including the 
identity of all participants (sufficient information to link records, eg, CRFs and hospital records), all original 
signed ICFs, copies of all CRFs, SAE forms, source documents, and detailed records of treatment disposition, 
and adequate documentation of relevant correspondence (eg, letters, meeting minutes, telephone calls 
reports). The records should be retained by the PI according to ICH, local regulations, or as specified in the 
Clinical Study Agreement, whichever is longer.
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4.
How will the digital data be stored? ☐CD ☐DVD ☐Flash Drive ☐Portable Hard Drive ☒Secured Server 
☐Laptop Computer ☐Desktop Computer ☐Other
5.
What methods and procedures will be used to safeguard the confidentiality and security of the identifiable 
study data and the storage media indicated above during and after the subject’s participation in the study? 
Strict confidentiality will be maintained in all records of the study by identifying participants by code numbers. 
Information that is obtained in connection with this study and that can be identified with a participant will be 
kept confidential (participant’s charts are kept in an area protected with a security system, in a locked room 
and file cabinet). Files will be kept in locked cabinets in a security system protected office. All desktop 
computers contain encryption software and are password protected.
All portable devices must contain encryption software, per University Policy 5100. If there is a technical reason a 
device cannot be encrypted please submit an exception request to the Information Security, Policy and 
Compliance Office by clicking on url http://its.yale.edu/egrc or email it.compliance@yale.edu
6.
What will be done with the data when the research is completed? Are there plans to destroy the identifiable 
data? If yes, describe how, by whom and when identifiers will be destroyed. If no, describe how the data 
and/or identifiers will be secured. 
Identifiable information is stored in paper files in locked cabinets in a security system protected office. The 
link between participants’ identities and their coded information will be kept for a maximum of 15 years, after 
which time the link will be destroyed and the data will become anonymous.
7.
If appropriate, has a Certificate of Confidentiality been obtained? Not applicable.
  SECTION V: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the research, either to 
the subject(s) or to society at large. (Payment of subjects is not considered a benefit in this context of the risk 
benefit assessment.) 
The expected benefit to society at large is a better understanding of the safety of BMS-984923. This study offers 
no direct individual benefit to participants. Participants in this study may derive subjective benefit from 
volunteering to take part in a study for the advancement of scientific knowledge.
   SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research? 
The alternative to participating in this study is to choose not to participate. Study participants are healthy 
individuals so there are not alternative treatments available outside of research.
2.
Payments for Participation (Economic Considerations): Describe any payments that will be made to subjects, 
the amount and schedule of payments, and the conditions for receiving this compensation. 
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Participants will be compensated for their time commitment and inconveniences necessary for completing 
the study. Participants will have no financial responsibilities for any portion of the study. 
Compensation will be
• $75 for the initial screening visit ($25 for repeat screening, if needed) 
• $100 for the MRI session 
• $300 for each completed PET scan 
• $50 for each Arterial Line 
• $200 for administration of the study drug 
• $250 for each overnight stay.
The expected compensation amounts are as follows: 
For individuals not participating in the receptor occupancy sub-study: $775 for completion of the following: 
Screening, one dose of study drug, and 2 inpatient nights. This amount may increase if the participant 
requires a repeat screening visit or additional overnight stay during the in-clinic period.
For individuals participating in the receptor occupancy sub-study: $1925 for completion of the following: 
Screening, one MRI, three PET scans, three arterial lines, one dose of study drug, and 2 inpatient nights. This 
amount may increase if the participant requires a repeat screening visit, repeat MRI, repeat PET scan (and 
arterial line placement), or additional overnight stay during the in-clinic period.
An additional compensation of $300 will be provided if all procedures are completed. Individuals not 
participating in the receptor occupancy sub-study would receive $1075. Individuals participating in the 
receptor occupancy sub-study would receive $2225.
Because of the amount of compensation, only experienced research staff will be allowed to consent 
participants. This consent process will include an in-depth conversation regarding the risks of the study such 
that participants are given a complete understanding of the risks involved in the study.
Parking and transportation costs will not be reimbursed. These costs are considered to be covered in the 
study payment that participants will receive.
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs associated with 
participation in the research, and the interventions or procedures of the study that will be provided at no cost 
to subjects. 
The entire medical evaluation, including physical examination, ECG and laboratory work, and all research 
procedures (PET and MRI) will be provided at no cost to the study participant. 
4.
In Case of Injury: This section is required for any research involving more than minimal risk, and for minimal 
risk research that presents the potential for physical harm (e.g., research involving blood draws).
a.
Will medical treatment be available if research-related injury occurs? If a participant is injured as 
a result of participation in this study, medical treatment will be available to them. However, the 
participant’s insurance carrier will be expected to pay for the cost of treatment.
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b.
Where and from whom may treatment be obtained? Participants should receive medical 
treatment from wherever and however is appropriate (e.g., ED, primary physician, etc.)
c.
Are there any limits to the treatment being provided? The participant’s insurance carrier may 
have limits.
d.
Who will pay for this treatment? The participant’s insurance carrier will be expected to pay for 
the cost of treatment.
e.
How will the medical treatment be accessed? As they normally would as appropriate (e.g., ED, 
primary physician, etc.)
5.
Conflict of Interest Disclosure: Stephen Strittmatter, MD, PhD, Professor of Neurology, Yale School of 
Medicine, is the Investigational New Drug (IND) application holder for the study drug, as well as founder of 
Allyx Therapeutics, a company that seeks to license the study drug from Yale and develop it for clinical use in 
Alzheimer’s disease. Dr. Strittmatter will not have any contact with study participants during the conduct of 
this trial.
IMPORTANT REMINDERS
Will this study have a billable service? Yes ☒ 
 No☐
A billable service is defined as any service rendered to a study subject that, if he/she was not on a study, would 
normally generate a bill from either Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s 
insurer. The service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include x-rays, MRIs, CT 
scans, specimens sent to central labs, or specimens sent to pathology). Notes: 1. There is no distinction made 
whether the service is paid for by the subject or their insurance (Standard of Care) or by the study’s funding 
mechanism (Research Sponsored). 2. This generally includes new services or orders placed in EPIC for research 
subjects. 
If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research management system, for 
Epic to appropriately route research related charges. Please contact oncore.support@yale.edu
Are there any procedures involved in this protocol that will be performed at YNHH or one of its affiliated entities? 
Yes ☒ No ☐ 
If Yes, please answer questions a through c and note instructions below. 
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a. Does your YNHH privilege delineation currently include the specific procedure that you will perform? Yes ☒ No 
☐
b. Will you be using any new equipment or equipment that you have not used in the past for this procedure? Yes 
☐ No ☒
c. Will a novel approach using existing equipment be applied? Yes ☐ No ☒
 
If you answered “no” to question 4a, or "yes" to question 4b or c, please contact the YNHH Department of 
Physician Services (688-2615) for prior approval before commencing with your research protocol.
IMPORTANT REMINDER ABOUT RESEARCH AT YNHH 
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at the HRU, the 
Principal Investigator and any co-investigators who are physicians or mid-level practitioners (includes PAs, APRNs, 
psychologists and speech pathologists) who may have direct patient contact with patients on YNHH premises 
must have medical staff appointment and appropriate clinical privileges at YNHH. If you are uncertain whether 
the study personnel meet the criteria, please telephone the Physician Services Department at 203-688-2615. By 
submitting this protocol as a PI, you attest that you and any co-investigator who may have patient contact has a 
medical staff appointment and appropriate clinical privileges at YNHH.
Appendix A Excluded Medications based on CYP Inhibition/Induction
1A2 Inhibitors
Ciprofloxacin Enoxacin
Fluvoxamine
Interferon Alpha-2b
Vemurafenib
Amiodarone
1A2 Inducers
Carbamazepine
Fosphenytoin
Nicotine
Phenytoin
Rifampin
2D6 Inhibitors
Bupriopion
Fluoxetine
Paroxetine
Quinidine
Terbinafine
Cinacalcet
Duloxetine
Mirabegron
Rolapitant
2D6 Inducers
None
3A4 Inhibitors
Boceprevir
Clarithromycin
Cobicistat
Conivaptan
Grapefruit Juice
Idelalisib
Indinavir
Itraconazole
Ketoconazole
Lopinavir/ritonavir
Nefazodone
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Aprepitant
3A4 Inducers
Apalutamide
Carbamazepine
Enzalutamide
Fosphenytoin
Lumacaftor
Mitotane
Phenytoin
Rifampin
St. John’s Wort
Bosentan
Cenobamate
Efavirenz
Etravirine
Lorlatinib
Modafinil
Nafcillin
Phenobarbital
Primidone
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Atazanavir
Ciprofloxacin
Crizotinib
Cyclosporin
Diltiazem
Dronedarone
Erythromycin
Fluconazole
Fluvoxamine
Fosnetupitant
Imatinib
Letermovir
Netupitant
Nilotinib
Verapamil
Rifabutin
Dexamethasone
Nevirapine
Oxcarbazepine
Prednisone
Rifapentine
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modulation in phase I clinical trial: potential impact of circadian rhythm on the neuropsychiatric 
adverse 
reactions-do 
hallucinations 
matter? 
ISRN 
Psychiatry, 
2014, 
652750. 
doi:10.1155/2014/652750
Beecham, G. W., Hamilton, K., Naj, A. C., Martin, E. R., Huentelman, M., Myers, A. J., . . . Montine, T. 
J. (2014). Genome-wide association meta-analysis of neuropathologic features of Alzheimer's 
disease and related dementias. PLoS Genet, 10(9), e1004606. doi:10.1371/journal.pgen.1004606
Beraldo, F. H., Ostapchenko, V. G., Caetano, F. A., Guimaraes, A. L., Ferretti, G. D., Daude, N., . . . 
Prado, M. A. (2016). Regulation of Amyloid beta Oligomer Binding to Neurons and Neurotoxicity 
by 
the 
Prion 
Protein-mGluR5 
Complex. 
J 
Biol 
Chem, 
291(42), 
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Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., . . . Saido, T. C. (2014). Single App 
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Saito, T., Mihira, N., Matsuba, Y., Sasaguri, H., Hashimoto, S., Narasimhan, S., . . . Saido, T. C. (2019). 
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ICF_001.pdf: 
Title: Evaluating the Safety, Tolerability, Pharmacokinetics and Receptor 
Occupancy of BMS-984923 
ClinicalTrials.gov ID: NCT04805983 
Date: 3/24/2022 
Document: ICF 


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COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A RESEARCH 
STUDY
YALE UNIVERSITY SCHOOL OF MEDICINE
Study Title: An Open-Label, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Receptor Occupancy of BMS-984923 
Principal Investigator: Adam Mecca, MD, PhD, 1 Church Street, Suite 800, New Haven, CT 
06510
Phone Number: 203-764-8100 
Invitation to Participate
We are asking you to join a research study. You have been invited to take part in this study 
because you do not have memory problems and you are between 50 and 80 years old. 24 
subjects will take part in this study at Yale University.
To help you decide, you should understand the study and what it will involve for you. To make an 
informed decision to take part – you should know the purpose of the study, the procedures, the 
benefits and risks of the study, the discomforts and the precautions taken. This process is called 
‘informed consent’. Please take the time to read the following information carefully and discuss it 
with others. Please ask your study doctor if there is anything that is not clear or if you would like 
more information.
Once you have decided that you want to take part, you will be asked to sign the informed consent 
form. You will be given a copy of the signed form to keep, and the original will stay at the study 
center.
This study is funded by the National Institute on Health (NIH).
What is the purpose of this study?
The purpose of this research study is to find out whether the study drug, BMS-984923, is safe 
and well-tolerated in humans. The study also aims to find out what dose of BMS-984923 is 
needed to reach a target level of drug in the blood stream. This drug has never been given to 
humans before.  
What will happen during the study?
If you agree to take part, after signing this Informed Consent Form, you will undergo a series of 
screening tests to confirm if you are eligible for the study and to establish your health status at 
the beginning of the study before receiving treatment. The screening period could take up to 90 
days. The screening visit may take up to 5 hours and require multiple visits to the Yale 
Alzheimer’s Disease Research Unit (ADRU).
If you are eligible, you will enter the in-clinic phase of the study. During this phase, you will 
check-in to the Yale Hospital Research Unit (HRU). The study staff will run a series of tests to 
make sure that you are still eligible to receive the study drug. If you are, the study staff will 
administer the study drug to you. The study drug is taken by mouth. Then, the study staff will 
monitor you and collect blood samples for 48 hours. At the end of the 48 hours, you will undergo 
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additional safety assessments. Once you have completed all the study procedures, you will be 
discharged to go home. 
The study will have six cohorts of six participants each for a total of 36 participants. Each cohort 
will be given a different dose of the study drug. The dose you receive will depend on when you 
enroll in the study. Subjects who enroll in the study later will receive higher doses of the study 
drug.
Study staff will continue to follow up with you for seven days after you receive the study drug. 
On Day 5 after the in-clinic phase, the study staff will call you to ask about your general health. 
On Days 4 & 7 after the in-clinic phase, you will be required to return to the ADRU for additional 
study assessments. Each of these in-person visits will take up to 2 hours. 
The following tests/assessments will be done at some or all of the study visits: 

Informed Consent: You will need to read, confirm understanding, and sign this informed 
consent. 

Medical History:  A complete medical history will be taken, including any medications you 
have used or are currently using and any other therapies you have had.

Physical Exam & Vital Signs: Your blood pressure, temperature, heart rate, height, and 
weight will be measured. Additionally, your study doctor will examine you physically. Some 
of these exams will include a complete physical while others will be based on the 
symptoms you are having. 

Safety Assessments. Tests will be done to assess how well you are thinking, how well you 
are performing your daily activities, and how well you are feeling. They take the form of 
interviews and questionnaires. 
o
Some of the questions will ask about your mood. If there are concerns about your 
mood, you will be referred to appropriate care that may include the emergency 
department.

Monitoring of any adverse effects (side effects) you are experiencing on the treatment.

 Electrocardiogram (ECG):  ECGs measure electrical activity of your heart by putting small 
sticky patches on certain areas of your body. 

Concomitant medication monitoring: The study doctor will record all the medications you 
take while on the study.

You will have the following blood and urine tests: 
o
Blood tests related to how BSM-984923 works, including measuring the levels of 
BSM-984923 in your blood
o
Blood and urine tests for standard safety and health assessments
o
If you are a woman, you will have a blood test to show that you are not of child-
bearing potential unless you have a documented bilateral tubal ligation or 
hysterectomy. You cannot participate if you are pregnant.  
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Schedule of Study Procedures
Study Phase
Screening
In-Clinic
Follow-up
Study Day
-90 to -1
Day 1
Day 2
Day 3
Day 4-7
Admission
6 hours 
post-dose
24 hours 
post-dose
48 hours 
post-dose
Day 4
(Phone 
Call)
Day 5
(Visit)
Day 7
(Visit)
Informed 
Consent
x
Medical History
Questions
x
x
Memory and 
Thinking
Tests
x
x
x
x
x
Blood Tests
x
x
x
x
x
x
x
Urine Tests
x
x
x
x
ECG
x
x
x
x
x
Physical Exam
x
x
x
Vital Signs
x
x
x
x
x
x
x
Demographic 
Questions
x
In-Clinic 
Admission
X (Admit)
Discharge
Study Drug
Administration
x
Review of 
Medications
x
x
x
x
x
x
x
x
General Health
Questions
x
x
x
x
x
x
x
x


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What will I have to do? 

You will have to go to the study visits and follow the instructions the doctors give you.

You must not take part in any other studies while you are taking part in this study.

Some of the assessments regarding how well you are thinking will require you to have a study 
partner. The study partner should be someone who knows you well, for example, a spouse, 
sibling, or close friend. Your study partner is important to this study and by signing the 
statement in this form must agree and be able to: 
o
Accompany you to some of the study visits or be available over the phone. 
o
Provide information about you to the study doctor and staff. Your study partner will be 
asked about how well you are thinking, performing your daily activities, and feeling. 

You should tell the study staff immediately if you get any new symptoms of any kind, worsening 
of already existing symptoms, or any unwanted effects.

You should tell the study staff about any procedures you have had (for example, a dental visit). 

If you are female and able to have children or male and able to get a woman pregnant, you 
must practice effective contraception during the entire study.

If you or your partner become pregnant during the study after receiving a dose of study 
medication, we will follow you to learn the outcome of the pregnancy. 

If you are male, you must practice effective contraception during the study and for three 
months after receiving the study drug. You must agree to use condoms during the trial and for 
3 months after the last dose unless the woman is using an acceptable means of birth control. 
Acceptable forms of birth control include abstinence, birth control pills, or any double 
combination of: intrauterine device (IUD), male or female condom, diaphragm, sponge, and 
cervical cap.

Inform your study doctor about any medication you are taking or changes to your medications 
(including herbal or alternative remedies and health supplements or medicines you buy over 
the counter) and avoid taking prohibited medications during the study. Your study doctor will 
discuss allowed and disallowed medications in more detail with you.
What are the risks associated with participating in this study?
Risks Associated with the Study Drug, BMS-984923
BMS-984923 has not previously been studied in humans. Studies have been completed in rats 
and non-human primates, with no adverse effects at the doses comparable to the dose you will 
receive in this study. There may be side effects that are currently unknown or that are 
unpredictable. 
Side effects can go away shortly after you stop taking the study medicine, but some side effects 
could be long lasting, permanent, serious, life threatening, or even cause death. Everyone in the 
study will be watched carefully for any side effects. You should talk to your study doctor about 
any side effects you have while in the study.
Should information become available that could change your decision to be in this study, you will 
be told immediately. You can always decide whether or not to continue being in this study. As 
new risks are identified, you will also be told of these risks. At times you may be asked to sign a 
new consent form that shows that you have been made aware of the new risks and agree to 
continue taking part in this study.
Exposure to the sun can cause unexpected or exaggerated sunburn, or a rash on sun-exposed 
skin, minutes to hours after exposure to both a drug and ultraviolet light. We will minimize your 
exposure to sunlight during the treatment phase.
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In animal studies, rats experienced serious side effects including lethargy, stress responses, and 
death. However, this was with repeated exposure to the drug at doses higher than will be used in 
this study.
Risks Associated with Blood Draws 
Drawing blood and inserting an intravenous (IV) line into an arm vein are safe and standard 
medical procedures.  Sometimes a bruise will occur at the puncture site and rarely a blood clot 
or infection will occur in the vein.  Some people may feel light-headed, or experience upset 
stomach or fainting when their blood is drawn.  The total volume of blood collected during this 
study will be up to approximately 9.5 tablespoons (2/3 cup). This amount of blood loss is safe 
for study participants.  
Risks Associated with Electrocardiograms (ECGs) 
There is no pain or discomfort during an ECG; however, removing the pads may cause some 
irritation to your skin. 
Risks Associated with Psychological Stress 
You might find some of the test questions boring, frustrating, or embarrassing. You can ask to 
skip a question or stop answering questions at any time.
What are the benefits of participating in this study? 
This study does not directly benefit you. What we learn from your participation may provide 
information to help develop treatments to help others with memory loss and Alzheimer disorder.  
Will I be paid for participating in this study?
You will be paid for participating in this study. You will receive $75 for the screening visit ($25 
for a second screening visit, if needed), $200 for the study drug administration, and $250 for 
each overnight night stay during the in-clinic period. If you complete all study procedures, you 
will receive an additional $300. If you do not complete all study procedures, you will be paid for 
the visits you complete.
The total amount of compensation is $1075 for completion of all parts of the study. This amount 
may increase if you need to repeat study visits or if you need to an additional overnight stay 
during the in-clinic study period. These payments include a stipend to cover your travel and 
parking costs related to the study visits.
Your study partner will not be paid for participation in the study or reimbursed for parking and 
transportation costs. 
You will receive payment(s) via a Bank of America pre-paid debit card. Please note that your 
name, address, and telephone number will be shared with Bank of America for ePayments. 
After your first payment (screening visit), you will receive a card in the mail which you will need 
to activate over the phone. Any subsequent payments will automatically add additional funds to 
your card.
Payment received as a research subject may be taxable income to you. If payment is more than 
$600.00 in a calendar year, the study clinic is required to report this to the Internal Revenue 
Service (IRS). An IRS Form 1099 (Miscellaneous Income) will be issued to you and a copy sent 
to the IRS.
What are the costs associated with participating in this study?
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You will not have to pay for taking part in this study. The only costs include transportation and 
your time coming to the study visits.
What are my choices if I decide not to take part in this study?
You do not have to participate in this study. Because this is a study of healthy individuals, there 
are no alternative treatments to participating in this study. 
Investigator Interest 
A co-investigator in this study, Dr. Strittmatter, has a financial interest in this this study and the 
company Allyx Therapeutics’ intent to license the drug. 
Yale University has an institutional conflict of interest related to this study. The University may 
receive financial benefits related to use of the study drug used in this study. Yale has taken 
actions to protect participants in this research from any risks that may result from these financial 
interests. If you have questions, you may contact the Yale Human Research Protection Program 
at 203-785-3488 or icoi.committee@yale.edu.
Confidentiality and Privacy
Any identifiable information that is obtained in connection with this study will remain confidential 
and will be disclosed only with your permission or as permitted by U.S. or State Law.  Examples 
of information that we are legally required to disclose include abuse of a child or elderly person, 
or certain reportable diseases.  When the results of the research are published or discussed in 
conferences, no information will be included that would reveal your identity unless your specific 
consent for this activity is obtained.
We understand that information about you obtained in connection with your health is personal, 
and we are committed to protecting the privacy of that information.  If you decide to be in this 
study, the researcher will get information that identifies you and your personal health 
information.  This may include information that might directly identify you, such as your name, 
date of birth, address, or telephone number.  This information will be de-identified at the earliest 
reasonable time after we receive it, meaning we will replace your identifying information with a 
code that does not directly identify you.  The principal investigator will keep a link that identifies 
you to your coded information, and this link will be kept secure and available only to the PI or 
selected members of the research team.  Any information that can identify you will remain 
confidential.  The research team will only give this coded information to others to carry out this 
research study.  Files are kept in an area protected by a security system, in a locked room and 
file cabinet.  All desktop computers contain encryption software and are password protected.  
The link to your personal information will be kept indefinitely. Information or specimens collected 
in the course of this research study may be used for future research studies or distributed to 
another investigator for future research studies without additional informed consent, but only 
after all identifying information is removed.
The information about your health that will be collected in this study includes: 

Demographic (personal information) and geographic information which may include 
name, date of birth, gender, race, address, e-mail, and telephone number; 

Research study records, including phone calls made as part of this research, records 
about study visits, and records about any study drug that you received;

Medical and medication history;

Medical and laboratory records of services provided in connection with this study, 
including physical and neurological exams, questionnaires, laboratory results, brain 
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imaging, ECG, and other test results.  
Information about you and your health that might identify you may be used by or given to: 

Representatives from Yale University, the Yale Human Research Protection Program, 
and the Yale Human Investigation Committee (the committee that reviews, approves, 
and monitors research on human subjects), who are responsible for ensuring research 
compliance.  These individuals are required to keep all information confidential;

Those individuals at Yale who are responsible for the financial oversight of research 
including billings and payments;

The Principal Investigator Dr. Mecca, co-investigators, and members of the research 
team;

The U.S. Department of Health and Human Services (DHHS) agencies;

The U.S. Food and Drug Administration (FDA).  This is done so that the FDA can review 
information about the new drug product involved in this research.  The information may 
also be used to meet the reporting requirements of drug regulatory agencies;  

Governmental agencies to whom certain diseases (reportable diseases) must be 
reported;

Health care providers who provide services to you in connection with this study;

Laboratories and other individuals and organizations that analyze your health 
information in connection with this study, according to the study plan;

Data and Safety Monitoring Boards and others authorized to monitor the conduct of the 
study;
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. 
The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects.
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the National Institute of Health (NIH) which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). You should understand that a Certificate of Confidentiality does not 
prevent you from voluntarily releasing information about yourself or your involvement in this 
research. If you want your research information released to an insurer, medical care provider, or 
any other person not connected with the research, you must provide consent to allow the 
researchers to release it.
By signing this form, you authorize the use and/or disclosure of the information described in this 
form for this research study.  The purpose for the uses and disclosures you are authorizing is to 
ensure that the information relating to this research is available to all parties who may need it for 
research purposes.  You do not have to give this authorization.  However, if you do not, you will 
not be able to take part in the study.
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All health care providers subject to HIPAA (Health Insurance Portability and Accountability Act) 
are required to protect the privacy of your information.  The research staff at Yale University 
School of Medicine and Yale-New Haven Hospital are required to comply with HIPAA and to 
ensure the confidentiality of your information.  Some of the individuals or agencies listed above 
may not be subject to HIPAA and therefore may not be required to provide the same type of 
confidentiality protection.  They could use or disclose your information in ways not mentioned in 
this form.  However, to better protect your health information, agreements are in place with 
these individuals and/or companies that require that they keep your information confidential. 
You have the right to review and copy your health information in your research record in 
accordance with institutional medical record policies.  However, by deciding to take part in this 
study and signing this form, you will not be allowed to look at or copy your study related 
information until after the research is completed.
This authorization to use and disclose your health information collected during your participation 
in this study will never expire.  
What happens to the blood samples collected from me? 
Your blood samples will be used for scientific research.  These samples may be used to help 
scientists understand how the study drug might work. The results of tests done on these 
samples are only for scientific research.  They will not be used for your medical care.  They will 
not be used to make a diagnosis about your health. Therefore, results from any of the blood 
tests s will not be reported to you or your doctor or put in your medical record. 
Your samples will be sent to Aptuit (Verona) Center for Drug Discovery and Development, a 
privately owned pharmaceutical services provider, for testing. Your samples may also be shared 
with other investigators studies to learn more about how study drugs work, without additional 
informed consent. If your sample is shared with other studies, it will be pooled with other 
samples. 
To protect your privacy, your samples will be labeled with your study number and participant 
number.  No personal identifiers are used (such as name, initials, social security number). The 
scientists analyzing the samples will not know your identity.
You blood samples will not be used for genetic testing.
You will not be paid for any use of your samples, results, or inventions made from research on 
them.  
In Case of Injury
It is important that you tell your study doctor if you feel that you have been injured because of 
taking part in this study.  If you have any injury, bad effects, or any other unusual health 
experience during this study, make sure that you immediately contact Dr. Adam Mecca or study 
staff at 203-764-8100.  You can call at any time, day, or night, to report such health 
experiences.  If this is not practical because of emergency, travel, or any other reason, you 
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should obtain treatment through an appropriate health care provider and notify your study doctor 
as soon as possible
If you are injured as a result of your participation in this study, treatment will be provided.  You 
or your insurance carrier will be expected to pay the costs of this treatment.  Yale School of 
Medicine and Yale-New Haven Hospital do not provide funds for the treatment of research-
related injury.  No additional financial compensation for injury or lost wages is available.
You do not give up any of your legal rights by signing this consent form.
Voluntary Participation and Withdrawal
Participating in this study is voluntary.  You are free to choose not to take part in this study.  
Declining to participate will involve no penalty or loss of benefits to which you are otherwise 
entitled (such as your health care outside the study, the payment for your health care, and your 
health care benefits).  However, you will not be able to enroll in this research study and will not 
receive study procedures as a study participant if you do not allow use of your information as 
part of this study.
Withdrawing From the Study
If you do agree to participate, you are free to stop and withdraw from this study at any time 
during its course.  There will be no penalty to you.  If you begin thinking about withdrawing from 
the study, you should inform the study personnel so that they may advise you on what follow-up 
care can be most helpful to you. 
To withdraw from the study, you can call a member of the research team at any time and tell 
them that you no longer want to take part.  This will cancel any future appointments.
The researchers may withdraw you from participating in the research if necessary.  The 
researchers may withdraw you from participating if they believe it is in your best interest, if you 
do not follow the study rules, or if the study is stopped, even if you want to continue.
Withdrawing from the study will involve no penalty or loss of benefits to which you are otherwise 
entitled.  It will not harm your relationship with your own doctors, Yale-New Haven Hospital, or 
with Yale University.  
Withdrawing Your Authorization to Use and Disclose Your Health Information
You may withdraw or take away your permission to use and disclose your health information at 
any time.  You do this by telling the study staff or by sending written notice to Dr. Adam Mecca, 
One Church Street, 8th floor, New Haven, CT 06510.  If you withdraw your permission, you will 
not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be gathered 
after that date.  Information that has already been gathered may still be used and given to others 
until the end of the research study, as necessary to insure the integrity of the study and/or study 
oversight.  
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Questions
We have used some technical terms in this form.  Please feel free to ask about anything you don't 
understand and to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision.
If you have questions about the study, please ask us before signing this form.  If you or your 
family has any additional questions later, or during the study, you may contact Dr. Adam Mecca 
or study staff at 203-764-8100.  
If you have any questions regarding your rights as a research subject, you may contact the Yale 
Human Investigation Committee at (203) 785-4688.  If after you have signed this form you have 
any questions about your privacy rights, please contact the Yale Privacy Officer at (203) 432-
5919.  A signed and dated copy of this form will be given to you as a subject in this study if you 
agree to participate.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
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Subject Consent
I have read (or someone has read to me) this form and have decided to participate in the project 
described above.  Its general purposes, the particulars of my involvement and possible hazards 
and inconveniences have been explained to my satisfaction.  My signature also indicates that I 
have received a copy of this consent form.
By signing this form, I give permission to the researchers to use and give out information about 
me for the purposes described in this form.  By refusing to give permission, I understand that I 
will not be able to be in this research. 
_______________________________    _______________________________ ___________________
Name of Participant (Print)                            Signature of Participant
Date 
_______________________________    _______________________________ ___________________
Name of Person Obtaining Consent         Signature of Person Obtaining Consent              Date 
(Print)
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Study Partner Consent
I have read (or someone has read to me) this form and have decided to participate in the project 
described above as the study partner of _______________________(name of participant). My 
responsibilities have been explained to me to my satisfaction.  My signature also indicates that I 
have received a copy of this consent form.
_______________________________    _______________________________ ___________________
Name of Study Partner (Print)                        Signature of Study Partner
Date 
_______________________________    _______________________________ ___________________
Name of Person Obtaining Consent         Signature of Person Obtaining Consent              Date 
(Print)
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