Conditions: Alzheimer's Disease
Keywords: Cognition mild Alzheimer's disease Sleep
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 371
Healthy volunteers: no

Brief summary:
This study is a Phase 2, randomized, placebo-controlled, dose-ranging study of piromelatine (5, 20, and 50 mg daily for 6 months) versus placebo to determine an effective dose based on efficacy (cognitive performance), safety, and tolerability in patients with mild dementia due to Alzheimer's Disease (AD).

Detailed description:
Patients with a documented history of mild dementia due to AD for at least 6 months, having a Mini-Mental State Examination (MMSE) score of 20 to 27 (inclusive) at Screening.

A score of 27 is allowed only if accompanied by a score of ≥ 12 in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog) ADAS-cog11 portion of the ADAS-cog14 at screening, and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5 or 1 will be recruited and further screened for eligibility. Caregiver commitment to the study is also necessary.

At Screening (Visit 1), patients will undergo neuropsychiatric assessments, psychometric testing, and general medical assessments (including medical history, pre-existing conditions, physical examination, vital signs, and ECG). If patients have not had brain imaging with findings consistent with the diagnosis of dementia due to AD in the last 12 months, a computed tomography (CT) or magnetic resonance imaging (MRI) scan will be obtained to rule out clinically significant comorbid pathologies.

Eligible patients will start a 2-week run-in period of placebo (single-blind), followed by 26 weeks of double-blind treatment comprising administration of piromelatine or placebo, for a total treatment duration of 28 weeks. During the double-blind period, patients will be enrolled in a 1.2:1:1:1 randomization ratio to the 4 trial arms (placebo \[1.2\], and the equal piromelatine treatment arms 5, 20, and 50 mg \[1:1:1\]).

Intermediate visits will be carried out at 4 weeks (Visit 3) and 13 weeks (Visit 4) after randomization. A follow-up phone call to elicit any safety concerns will be completed 2 weeks after the last dose of study medication. Patients who discontinue before Visit 5 (Week 26) will be brought back for a termination visit.

Assuming an effect size between the treatment dose and placebo of 0.35 over 26 weeks, a significant level (α) of 0.05, and power of 88%, a sample size of 143 patients for the placebo arm and 119 patients for each of the 3 piromelatine arms is calculated. Assuming a 50% screen failure rate and allowing for 15% patient withdrawal, 1150 patients should be screened to randomly assign 575 patients, of whom it is expected that 500 will complete the study.

Piromelatine (5, 20, and 50 mg tablets) and placebo will be administered orally, once daily after a meal, before habitual bedtime, preferably between 2100h and 2300h. Patients will be required to spend at least 2 hours a day exposed to daylight.

Arms:
arm 1: 2 weeks of Placebo (run-in), followed by 26 weeks of 5 mg tablets once daily. arm 2: 2 weeks of Placebo (run-in), followed by 26 weeks of 20 mg tablets once daily. arm 3: 2 weeks of Placebo (run-in), followed by 26 weeks of 50 mg tablets once daily. arm 4: 2 weeks of Placebo (run-in), followed by 26 weeks of Placebo tablets once daily.

Interventions: intervention 1: Piromelatine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 1/92 
 
 
 
Neurim Pharmaceuticals (1991) Ltd 
27 Habarzel Street 
Tel-Aviv 69710 
ISRAEL 
 
 
 
STUDY NUMBER: NEUP11-AD2 
 
RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, 
PLACEBO-CONTROLLED, DOSE-RANGING STUDY OF 
PIROMELATINE IN PATIENTS WITH MILD DEMENTIA DUE TO 
ALZHEIMER’S DISEASE 
 
PHASE: 2 
 
 
CONFIDENTIAL 
 
 
 
 
CRO:  
 
 
 
INC Research, LLC 
 
 
 
 
 
3201 Beechleaf Court, Suite 600 
 
 
 
 
 
Raleigh, North Carolina 27604 
 
 
 
 
 
USA 
 
DATE OF PROTOCOL: 
 
Version 1, 23 July 2015 
STATUS OF PROTOCOL:  
Final 
 
 
 
 
 
Version 7, 10 April 2017 
NCT02615002


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 2/92 
 
 
 
2. 
APPROVAL SIGNATURES 
 
RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, PLACEBO-CONTROLLED, 
DOSE-RANGING STUDY OF PIROMELATINE IN PATIENTS WITH MILD DEMENTIA DUE 
TO ALZHEIMER’S DISEASE 
 
Protocol No. NEUP11-AD2 
 
 
 
 
NEURIM PHARMACEUTICALS (1991) LTD 
 
  
 
 
 
April 12, 2017 
________________________ 
 
 
Date:  _____________ 
Amnon Katz, PhD 
VP, Clinical Development 
Neurim Pharmaceuticals (1991) Ltd 
27 Habarzel Street 
Tel-Aviv 69710 
ISRAEL 
 
 
 
SPONSOR’S SAFETY OFFICER 
 
 
________________________ 
 
 
Date:  _____________ 
Tali Nir, DVM 
VP, Clinical and Regulatory Affairs 
Neurim Pharmaceuticals (1991) Ltd 
27 Habarzel Street 
Tel-Aviv 69710 
ISRAEL 
 
 
12th April 2017


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 3/92 
 
 
 
INVESTIGATOR 
I have carefully read the foregoing protocol, including all appendices, and agree that it contains 
all the necessary information for conducting the study safely. 
 
I will conduct the study in strict accordance with this protocol and according to the current Good 
Clinical Practice (GCP) guidelines, and will attempt to complete the study within the designated 
time. 
 
I will provide copies of the protocol and all other information relating to the preclinical and prior 
clinical experience submitted by the sponsor (Neurim Pharmaceuticals [1991] Ltd) to all study 
personnel. I will discuss this information with them to assure they are adequately informed 
regarding the drug and the conduct of the study. 
 
I agree to keep records on all patient information (case report forms, shipment and drug return 
forms, and all other information collected during the study) in accordance with the current GCP 
and local regulations. 
                                                                                     Amnon Katz, PhD 
_____________________________  
 
__________________________ 
Principal Investigator  
 
 
 
Sponsor Representative 
                                                                                    
 
_____________________________  
 
__________________________ 
Signature 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
April 12, 2017 
_____________________________  
 
__________________________ 
Date 
 
 
 
 
 
 
Date 
 
____________________________________________________________________ 
Name of Site 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 4/92 
 
 
 
3. 
SUMMARY/SYNOPSIS OF PROTOCOL 
STUDY NUMBER 
NEUP11-AD2 
STUDY DRUGS 
     Test drug 
 
     Control drug 
 
Piromelatine 5, 20, and 50 mg tablets 
 
Matched placebo tablets 
TITLE 
Randomized, 
Double-blind, 
Parallel-group, 
Placebo-controlled, 
Dose-ranging Study of Piromelatine in Patients with Mild Dementia 
Due to Alzheimer’s Disease 
STUDY PHASE 
2 
COUNTRIES 
United States 
ESTIMATED NUMBER OF 
CENTERS 
Approximately 75 sites 
STUDY RATIONALE 
Alzheimer's disease (AD), a progressive neurodegenerative disorder, 
is the leading cause of dementia in the elderly population. People 
progressing to AD develop distressing changes in memory, thought, 
function, and behavior, which worsen over time. These changes 
increasingly impact the person's daily life and reduce their 
independence until ultimately these patients are entirely dependent 
on others (Querfurth and LaFerla, 2010). Worldwide, it is estimated 
that about 36 million people have dementia. Alzheimer’s disease 
accounts for 50% to 80% of these patients (Duthey, 2013). At 
early-stage AD, the episodic memory is the most noticeable 
impairment (Gold and Budson, 2008). With the shift towards an 
increasingly elderly population, it is predicted that the number of 
people affected by early-stage AD that will progress to dementia will 
almost double every 20 years, and by the year 2050, 115 million 
people will have the condition (Duthey, 2013). Effective treatments 
for the devastating disease are urgently needed as the world’s 
population continues to age. 
The diagnosis of AD is generally based on consensus diagnostic 
criteria developed by the National Institute on Aging-Alzheimer's 
Association (NIA-AA) (McKhann et al., 2011). These criteria are 
clinical in nature and require that patients must exhibit impairments 
in both cognitive and functional domains. In the earliest clinical 
stages of AD, subtle cognitive deficits may be evident only through 
use of sensitive measures of neuropsychological performance. 
Thereafter, but before developing overt dementia, patients proceed 
through a clinical phase where cognition becomes increasingly 
affected and relatively mild but detectable impairments in some 
functional abilities emerge as well. 
The hallmark pathological feature of AD is the presence of brain 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 5/92 
 
 
 
plaques, consisting primarily of β-amyloid peptide (Aβ) aggregates 
(Selkoe, 2002). Accordingly, the abnormal production and 
aggregation of Aβ, associated particularly with late-stage disease, 
has been the principal target of many drug development efforts. 
However, 3 trials of Aβ lowering agents involving patients with 
overt dementia failed to show improvements in cognition. A leading 
theory posits that the attempts at intervention may have been made 
too late in the progression of disease, at a stage when neuronal 
damage had become too widespread, and therefore more trials now 
focus on patients in whom overt dementia seems imminent. An ideal 
drug for such patients will improve neuropsychological performance 
and functional abilities, slow down Aβ buildup, and promote 
neuroprotection and neurogenesis. 
The 
investigational 
compound, 
N-(2-(5-methoxy-1H-indol-3-
yl)ethyl)-4-oxo-4H-pyran-2-carboxamide (piromelatine) is a novel 
melatonin MT1, 2, and 3 and serotonin 5-HT-1A and -1D receptors 
agonist with a different proposed mechanism of action than currently 
available AD medications. Through this unique molecular mode of 
action, piromelatine demonstrated in preclinical studies in rodents 
neuroprotective (Buendia et al., 2014, Tang et al., 2012), memory 
enhancing (He et al., 2013, Tian et al., 2010), sleep promoting (Liu 
et al., 2014), and neurogeneration enhancing capabilities (Tian et al., 
2015 unpublished) with relevance to AD risk factors, comorbidities, 
and 
symptoms. 
The 
5HT-1a 
agonists 
have 
demonstrated 
neuroprotective effects (Kline et al., 2004) by increasing both cell 
proliferation and neurogenesis in the hippocampal subgranular zone 
of the dentate gyrus and the subventricular zone (Banasr et al., 2004, 
Islam et al., 2014) and increase slow wave sleep (SWS) specifically 
by inhibition of hypothalamic orexin neurons and the dorsal raphe 
nuclei that act as wake promoting centers (Muraki et al., 2004, 
Tabuchi et al., 2013). Simultaneous activation of melatonergic and 
5HT-1a receptors may synergistically promote neurogenesis (Fava et 
al., 2012). 
The sleep enhancing capacities of piromelatine may also be relevant 
to the therapeutic potential. Recent clinical and biochemical 
evidence has identified an interesting link between sleep, Aβ, 
cognitive dysfunction, and AD. In mice, Aβ clearance through the 
glymphatic system (the biomolecule clearance system operating the 
convective flow between the cerebrospinal fluid [CSF] and 
interstitial fluid to remove toxic metabolites) is strongly stimulated 
by sleep (Mendelsohn and Larrick, 2013, Xie et al., 2013). 
Bidirectional relationships between sleep and Aβ production have 
been demonstrated in mice overexpressing Aβ (Roh et al., 2012). In 
humans, normal soluble Aβ concentrations in the CSF fluctuate with 
the sleep-wake cycle with 6 hours delay (Huang et al., 2012). 
Disruption of non-rapid eye movement (NREM) SWS resulted in 
impaired overnight consolidation of long-term memory in healthy 
older adults (Mander et al., 2015). Since Aβ production is highest at 
times of neural activity such as during wakefulness and lowest at 
times of decreased neural activity such as during SWS, sleep 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 6/92 
 
 
 
disturbances accompanied by loss of SWS may lead to an increase in 
production of soluble CSF Aβ, increased Aβ aggregation, and 
attenuation of the Aβ diurnal pattern characterizing AD (Lucey and 
Bateman, 2014). Bidirectional relations between Aβ pathology and 
NREM sleep physiology were observed also in patients with mild 
cognitive impairment (MCI) and AD. In MCI patients the reduction 
in SWS was associated with deficits in sleep dependent memory 
consolidation (Pace-Schott and Spencer, 2015). Moreover, MCI 
patients had modified sleep structure characterized by shorter and 
disrupted SWS and lower ∆ and Θ power as compared to controls 
(Westerberg et al., 2012). In AD patients, higher SWS was positively 
associated with retrieval of recent autobiographical memories 
(Rauchs et al., 2013). 
Indeed, 63% of the patients with subtle cognitive deficits (also 
termed MCIs) (McKinnon et al., 2014) and 44% of the patients 
diagnosed with AD (Vitiello and Borson, 2001) demonstrate sleep 
disturbances as determined using the Pittsburgh Sleep Quality Index 
(PSQI). More recently, neuropathological analyses revealed a 
positive correlation between total sleep time, sleep quality, and sleep 
onset latency in demented and nondemented older adults with higher 
Aβ burden in specific brain areas that are linked to early AD (Spira 
et al., 2013). Accordingly, deterioration in cognition from healthy 
controls through MCI to AD patients was associated with parallel 
deterioration in sleep (Economou et al., 2013). The presence of 
insomnia may thus help identify patients with early signs of AD who 
are at a greater risk of deteriorating to dementia. 
The relation becomes evident as poor sleep is directly associated 
with cognitive decline in healthy (Miyata et al., 2013) cognitively 
impaired (McKinnon et al., 2014) and demented adult populations 
(Vitiello et al., 1990), including AD (Carpenter et al., 1996, 
McCurry et al., 1999). Further exploration of interventions that 
promote 
NREM 
SWS 
and 
minimize 
the 
progression 
of 
neurodegeneration and the cognitive dysfunction associated with Aβ 
pathology is needed (Mander et al., 2015). 
Importantly, the mechanism of sleep induction appears to be of key 
importance for the sought cognitive effects. Long-term use of 
benzodiazepine is associated with an increased risk of dementia 
(Billioti de Gage et al., 2012) and AD (Billioti de Gage et al., 2014, 
Yaffe and Boustani, 2014), presumably because of the known 
suppression 
of 
NREM 
SWS 
by 
benzodiazepines 
and 
nonbenzodiazepine hypnotics (Arbon et al., 2015). Treatment of 
patients with AD suffering from sleep disturbances with traditional 
hypnotics is associated with increased risk for a wide range of 
injuries (Chung et al., 2013, Diem et al., 2014) and may actually 
worsen their cognition and memory (Hall-Porter et al., 2014). In 
contrast, melatonin receptor agonism, which maintains the NREM 
SWS (Arbon et al., 2015), appears beneficial for cognition and 
functioning in mild to moderate AD patients (Wade et al., 2014). 
In a Phase 1 study in healthy volunteers, piromelatine (2, 5, 20, 50, 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 7/92 
 
 
 
and 200 mg) was found to be safe and well tolerated with no serious 
adverse events (SAEs) and showed a favorable, dose-proportional 
pharmacokinetic (PK) profile following oral intake. In addition, 
piromelatine intake was associated with increase in fatigue and total 
sleep time in the volunteers in a dose-dependent manner (Yalkinoglu 
et al., 2010). In a Phase 1b multiple ascending dose study in 
insomnia patients, piromelatine (2, 5, 20, and 50 mg) had a favorable 
PK profile without any sign of accumulation. This study also 
suggested dose-dependent beneficial effects of piromelatine on sleep 
continuity measures. Importantly, in this study piromelatine 
administered for 5 days to nondemented patients with insomnia had 
no detrimental nor beneficial effect on learning and memory as 
measured using the word-pair association task (Laudon et al., 2012). 
In a Phase 2, randomized, placebo-controlled, sleep laboratory study 
in insomnia patients (aged 18-80), piromelatine (20 mg and 50 mg 
daily for 1 month) enhanced sleep maintenance (wake after sleep 
onset [WASO]) measured by polysomnography (PSG) significantly 
in comparison to placebo (Neurim press release, 2013). Piromelatine 
enhanced NREM ∆ power (NREM SWS) and decreased NREM β 
power, a fast electroencephalogram (EEG) activity that is considered 
to be related to the hyperarousal state experienced by insomniac 
patients (Merica et al., 1998). Both effects may be beneficial for 
early AD and AD patients to enhance Aβ clearance from the brain 
(Grandy, 2013). Overall, piromelatine was generally safe and well 
tolerated. There were no SAEs during the conduct of this study. 
Adverse event (AE) rates during double-blind treatment with study 
medication were low (6.7% in the piromelatine 20 mg group, 0% in 
the piromelatine 50 mg and placebo groups). Laboratory values were 
within normal ranges. No clinically meaningful changes in vital 
signs, electrocardiograms (ECGs), or physical examinations were 
observed. No suicidal behavior or suicidal ideation (Columbia 
Suicide Severity Rating Scale [CSSRS]) was recorded at any time 
during the study. 
Altogether, through its action at melatonin receptors, piromelatine 
may improve sleep, circadian rhythms control, and, subsequently, 
cognition in the patients (Wade et al., 2014). Through the 
serotonergic mechanism, piromelatine may improve memory and 
mood (Rodríguez et al., 2012), enhance SWS, and reduce 
wakefulness (Bjorvatn and Ursin, 1998, Monti and Monti, 2000). 
Through the combined activation of melatonergic and 5HT-1a 
receptors, piromelatine may act synergistically to increase 
neurogenesis (Fava et al., 2012). 
This study is a Phase 2, randomized, placebo-controlled, 
dose-ranging study of piromelatine (5, 20, and 50 mg daily for 
6 months) versus placebo to determine an effective dose to take 
forward to Phase 3 studies based on efficacy (cognitive 
performance), safety, and tolerability in patients with mild dementia 
due to AD.  
PRIMARY OBJECTIVE 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 8/92 
 
 
 
that of placebo in the change from baseline in global 
composite score of the computerized Neuropsychological Test 
Battery (cNTB) after 26 weeks of double-blind treatment 
The global composite score includes the International 
Shopping List Test (ISLT; immediate and delayed recall), One 
Card Learning (OCL), Identification, Detection, and One Back 
Card (OBK). 
KEY SECONDARY 
OBJECTIVES 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo on global impression assessed by the Clinical 
Global Impression of Change (CGIC) after 26 weeks of 
double-blind treatment 
2. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo in the Alzheimer's Disease Cooperative 
Study/Activities of Daily Living scale adapted for MCI 
patients (ADCS-MCI-ADL) at Weeks 13 and 26 and over 
26 weeks of double-blind treatment 
OTHER SECONDARY 
OBJECTIVES 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo in the Alzheimer’s Disease Assessment Scale 
cognitive subscale (ADAS-cog14) at Weeks 13 and 26 and 
over 26 weeks of double-blind treatment 
2. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo in the change from baseline in global 
composite score of the cNTB at Weeks 4 and 13 and over 
26 weeks of double-blind treatment 
3. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo on the episodic memory domain* composite 
score of the cNTB at Weeks 4, 13, and 26 and over 26 weeks 
of double-blind treatment 
* episodic domain tests: ISLT (immediate and delayed 
recall) and OCL 
4. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo on the attention domain* composite score of 
the cNTB at Weeks 4, 13, and 26 and over 26 weeks of 
double-blind treatment 
* attention domain tests: Identification and Detection 
5. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo on the executive function* composite score of 
the Neuropsychological Test Battery (NTB) at Weeks 4, 13, 
and 26 and over 26 weeks of double-blind treatment 
* executive function domain tests: OBK, Controlled Oral 
Word Association Test (COWAT) and Categorical 
Fluency Test (CFT) 
6. To compare the safety and tolerability of piromelatine (5, 20, 
and 50 mg) to that of placebo 
EXPLORATORY 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 9/92 
 
 
 
OBJECTIVES 
that of placebo on cognitive aspects of mental function 
assessed by the Mini-Mental State Examination (MMSE) after 
2 weeks of run-in single-blind placebo followed by 26 weeks 
of double-blind treatment 
2. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo in individual cNTB test scores (ISLT 
immediate and delayed recall, OCL, Identification, Detection, 
OBK) at Weeks 4, 13, and 26 and over 26 weeks of 
double-blind treatment 
3. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo on the change from baseline in behavioral 
signs and symptoms assessed by the Neuropsychiatric 
Inventory (NPI) scale after 26 weeks of double-blind treatment 
4. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo on sleep variables derived from the PSQI at 
Weeks 4, 13, and 26 and over 26 weeks of double-blind 
treatment 
5. To compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo in ADAS-cog13, ADAS-cog12, and 
ADAS-cog11 score at Weeks 13 and 26 and over 26 weeks of 
double-blind treatment. 
STUDY DESIGN 
 
This is a Phase 2, double-blind, parallel-group, placebo-controlled, 
dose-ranging safety and efficacy study of piromelatine in patients 
with mild dementia due to AD. 
Patients with a documented history of mild dementia due to AD for at 
least 6 months, having an MMSE score of 20 to 27 (inclusive) at 
Screening (a score of 27 is allowed only if accompanied by a score of 
≥ 12 in the ADAS-cog11 portion of the ADAS-cog14 at Screening), 
and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5 or 1 
will be recruited and further screened for eligibility. Caregiver 
commitment for the study is also necessary. 
At Screening (Visit 1), patients will undergo neuropsychiatric 
assessments, psychometric testing, and general medical assessments 
(including 
medical 
history, 
pre-existing 
conditions, 
physical 
examination, vital signs, and ECG). If patients have not had brain 
imaging with findings consistent with the diagnosis of dementia due 
to AD in the last 12 months, a computed tomography (CT) or 
magnetic resonance imaging (MRI) scan will be obtained to rule out 
clinically significant comorbid pathologies. 
Eligible patients will start a 2-week run-in period of placebo (single 
blind), followed by 26 weeks of double-blind treatment comprising 
administration of piromelatine or placebo, for a total treatment 
duration of 28 weeks. During the double-blind period, patients will be 
enrolled in a 1.2:1:1:1 randomization ratio to the 4 trial arms (placebo 
[1.2], and the equal piromelatine treatment arms 5, 20, and 50 mg 
[1:1:1]). 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 10/92 
 
 
 
Intermediate visits will be carried out at 4 weeks (Visit 3) and 
13 weeks (Visit 4) after randomization. A follow-up phone call to 
elicit any safety concerns will be completed 2 weeks after the last 
dose of study medication. Patients who discontinue prior to Visit 5 
(Week 26) will be brought back for a termination visit. 
Assuming an effect size between treatment dose and placebo of 0.35 
over 26 weeks, a significant level (α) of 0.05, and power of 88%, a 
sample size of 143 patients for the placebo arm and 119 patients for 
each of the 3 piromelatine arms is calculated. Assuming a 50% screen 
failure rate and allowing for 15% patient withdrawal, 1150 patients 
should be screened in order to randomly assign 575 patients, of whom 
it is expected 500 will complete the study. 
Piromelatine (5, 20, and 50 mg tablets) and placebo will be 
administered orally, once daily after a meal, before habitual bedtime, 
preferably between 2100h and 2300h. Patients will be required to 
spend at least 2 hours a day exposed to daylight. 
STUDY DURATION 
The study consists of a 2-week run-in period of single-blind placebo 
and a 26-week, randomized, double-blind treatment period comprising 
administration of piromelatine or placebo, for a total treatment 
duration of 28 weeks. 
A follow-up phone call to elicit any safety concerns will be completed 
2 weeks after the last dose of study medication.  
STUDY POPULATION 
 
Male or female patients diagnosed with mild AD dementia who meet 
the core clinical research criteria of the NIA-AA (McKhann et al., 
2011)  
These criteria are clinical in nature and require that patients must 
exhibit impairments in both cognitive and functional domains for 
probable AD with documented evidence of progression of disease to 
be recruited. 
INCLUSION CRITERIA 
1. Patient has a permanent caregiver (participant’s caregiver is not 
expected to change during the course of the study), who will 
accompany the patient to the office, and/or be available by 
telephone at designated times, monitor administration of 
prescribed medications, control the minimum 2-hour daily light 
exposure requirement, and be responsible for the overall care of 
the patient at home. Caregiver must, in the opinion of the 
investigator, have enough contact with the participant to be able 
to perform the duties described above. 
2. Patient and caregiver are willing to take part in the entire study. 
3. Signed informed consent from the patient who is capable to sign 
the consent form as judged by the study investigator and from 
the caregiver as dictated by local legal circumstances. 
4. Patient is a male or female aged 60-85 years (inclusive). 
5. Patient is an outpatient living at home or in an assisted living 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 11/92 
 
 
 
facility with no plans to move or travel during the investigational 
period. 
6. Patient has a clearly documented history either in medical 
records or from an informant of cognitive decline over at least 
6 months. If available, any scale verification of the decline 
should be requested. 
7. Patient has mild probable AD as consistent with criteria 
established by the NIA-AA (McKhann et al., 2011). 
8. Patient has MRI or CT scan, performed within 12 months before 
Screening, with findings consistent with the diagnosis of 
dementia due to AD without any other clinically significant 
comorbid pathologies. If this MRI or CT scan is unavailable or 
occurred more than 12 months before Screening, this assessment 
should be completed and the findings confirmed prior to Visit 2 
(copy of the report will be available at the study site). 
9. Patient has an MMSE score of 20-27 (inclusive) at Screening (a 
score of 27 is allowed only if accompanied by a score of ≥ 12 in 
the ADAS-cog11 portion of the ADAS-cog14 at Screening; 
patients with an MMSE score of 19 may be rescreened once after 
1 month). 
10. Patient has a CDR-GS of 0.5-1 (mild dementia) at Screening. 
11. Patients taking acetylcholinesterase inhibitors for the treatment of 
AD may be enrolled if the patient has been taking such 
medication for at least 6 months before Visit 2 (Baseline), and is 
stable on any dose for the last 4 months prior to Baseline, and if 
the dose is not expected to change during study participation. 
12. Patients not receiving acetylcholinesterase inhibitors may be 
enrolled but must be agreeable to not starting throughout the 
study. 
13. Patients who stopped receiving acetylcholinesterase inhibitors 
must be stable off acetylcholinesterase inhibitors for 6 months 
before Baseline and must be agreeable to not restarting 
throughout the study. 
14. Patient has a negative drug screen (benzodiazepines or opiates) 
at Screening. 
15. Female patients must have had last natural menstruation 
≥ 24 months before Screening OR be surgically sterile. 
16. Male patients and their female spouse/partners who are of 
childbearing potential must agree to use highly effective methods 
of contraception, consisting of 2 forms of birth control (at least 
one of which must be a barrier method) starting at Screening, 
throughout the study and for 90 days post-last dose, OR be 
surgically sterile. 
17. Patients who are taking medications for non-excluded concurrent 
medical conditions should be on a stable dose for at least 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 12/92 
 
 
 
4 weeks 
before 
Screening. 
Patients 
taking 
allowed 
antidepressants or memantine (see Section 12.9) should be on a 
stable dose for at least 3 months before Screening and 
throughout the study. 
18. Patients who are taking vitamin B12 should be on a stable dose 
for at least 3 months before Screening and throughout the study. 
19. Patient is able to ingest oral medication and participate in all 
scheduled evaluations. 
20. Patient has ability and commitment to spend at least 2 hours per 
day exposed to daylight (preferably outside but can be next to a 
window if weather or personal situation does not permit). 
21. Patient and caregiver have the ability to read and write in 
English (or Spanish if using Spanish materials) and have hearing, 
vision, and physical abilities adequate to perform assessments 
(corrective aids allowed). 
EXCLUSION CRITERIA 
Potential patients who meet any of the following criteria will be 
excluded from participating in the study: 
1. Patient has an alternative cause for dementia other than AD. 
2. A past or recent CT or MRI scan or report indicating brain 
pathology that is associated with cognitive impairment or 
incompatible with a diagnosis of probable AD (e.g., any cortical 
infarct defined as > 1.5 cm3; more than 2 lacunar infracts defined 
as ≤ 1.5 cm3; diffuse white matter disease). The medical monitor 
should be contacted when there are questions about eligibility. 
3. Patient 
has 
evidence 
of 
any 
clinically 
significant 
neurodegenerative disease, or other serious neurological 
disorders other than AD, including but not limited to: 
a) Frontotemporal dementia, dementia with Lewy bodies, 
or vascular dementia documented by clinical history 
b) History or presence of any stroke with clinical 
symptoms ≤ 2 years before Screening 
c) Epilepsy or history of seizures, except for simple 
childhood febrile seizures or alcohol withdrawal seizures 
d) History of clinically relevant head trauma with 
neurological sequelae 
e) Parkinson’s disease 
f) Multiple sclerosis 
g) Amyotrophic lateral sclerosis 
h) Myasthenia gravis 
i) Moderate to severe sleep apnea (Apnea Hypopnea Index 
[AHI] ≥ 15); use of continuous positive airway pressure 
(CPAP) or other sleep-related devices for sleep apnea 
j) Narcolepsy 
4. Patient has been diagnosed with the following Axis I disorders 
(Diagnostic and Statistical Manual of Mental Disorders, 5th 
edition [DSM-V] criteria): 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 13/92 
 
 
 
a) Schizophrenia spectrum and other psychotic disorders 
(not related to dementia) 
b) Bipolar and related disorders 
c) Substance use disorders within the past 2 years 
5. Patient has a history of uncontrolled or untreated cardiovascular, 
endocrine, 
gastrointestinal, 
respiratory, 
or 
rheumatologic 
disorders within the past 5 years. 
6. Patient has a history of severe agitation. 
7. Patient has a known history of human immunodeficiency virus 
(HIV). 
8. Patient has a history of serious infectious disease including: 
a) Neurosyphilis 
b) Meningitis 
c) Encephalitis 
9. Patient has a history of a primary or recurrent malignant disease 
that has not been in remission for > 5 years prior to the 
Screening visit, with the exceptions of excised cutaneous 
squamous cell carcinoma in situ, basal cell carcinoma without 
recurrences; and history of intraductal breast cancer, cervical 
carcinoma in situ, or in situ prostate cancer resected over 5 years 
previously. (For resected in situ prostate cancer, i.e., high-grade 
intraepithelial neoplasia, the patient must have a normal 
prostate-specific antigen [PSA] prior to Screening and no 
increase in PSA since his resection surgery). 
10. Patient has severe pain that is likely to interfere with sleep (in the 
opinion of the investigator). 
11. Patient has any concomitant documented progressive disease 
likely to interfere with the conduct of the study, particularly: 
a) Liver disease with aspartate aminotransferase (AST), 
alanine 
aminotransferase 
(ALT) 
or 
gamma-glutamyltransferase (GGT) > 3 times the upper 
limits of normal (ULN) 
b) Total bilirubin > 3 times the ULN 
c) Mean corpuscular volume > 95 µ3 if due to chronic 
alcoholism 
d) Renal failure with creatinine > 150 µmol/L  
12. Patient is unable to adequately perform the computerized testing 
as judged by the study investigator or investigator designee at the 
practice session during Screening. 
13. Continuous use of benzodiazepines or other sedative-hypnotics 
during the 2 weeks before Screening (see Section 12.9). 
14. Patient has a history of chronic use and abuse of benzodiazepines 
or other sedative-hypnotics. 
15. Use of any kind of melatonin/melatonin agonist during the 
2 weeks before Screening (see Section 12.9). 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 14/92 
 
 
 
16. Patient has known or suspected hypersensitivity to exogenous 
melatonin or melatonin receptor agonists. 
17. Patient has clinically significant abnormal laboratory findings 
that have not been approved by the study safety officer. 
18. Patient has persistent bradycardia (heart beat < 50 bpm) or 
tachycardia (heart beat > 100 bpm). 
19. Patient has atrioventricular block (type II/Mobitz II and type III), 
congenital long QT syndrome, sinus node dysfunction or a 
marked prolongation of QTc interval (repeated demonstration in 
ECGs of QTc interval > 450 msec for males and > 470 msec for 
females using Fridericia’s formula: QTc = QT/cube root of RR). 
20. Patient has other serious diseases that could interfere with patient 
assessment, in the opinion of the investigator. 
21. Patient has untreated B12 and/or folic acid deficiency. 
22. Patient has participated in a clinical trial with any investigational 
agent within 3 months before Screening. Participants in any 
former monoclonal antibody clinical trial for AD are not eligible 
until 6 months after the last visit of the previous study. Patients 
who have received active vaccine for AD in the past will be 
excluded. 
23. Patient with a body mass index (BMI) above 35 or below 18. 
24. Lifestyle exclusions: 
a) Patients unwilling to limit alcohol intake to less than 
30 g of pure alcohol per day (see Appendix 1) and to 
abstain after 2000h throughout the study 
b) Patients unwilling to be exposed to at least 2 hours of 
daylight each day 
c) Divergence from the accepted level of study medication 
compliance (70%-130% of expected consumption) as 
verified at Visit 2 (see Section 12.10) 
d) Patients consuming more than 7 cups of tea or coffee (or 
equivalent amount of caffeine [650 mg] in other 
caffeinated beverages) per day 
e) Patients with an irregular lifestyle or life pattern (eg, 
shift workers, patients likely to be jet lagged) 
25. Administrative exclusion: 
a) Patient and/or caregiver unable to contact the 
investigator by phone in case of an emergency 
26. Patients with evidence of serious risk of suicide based on the 
Sheehan Suicidality Tracking Scale (Sheehan-STS); ie, a score 
of 3 or 4 on question 2 or 13 and a score of 2 or higher on 
questions 1a, 3 through 12, and 14 or who, in the opinion of the 
investigator, present a serious risk of suicide. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 15/92 
 
 
 
EFFICACY PARAMETERS 
Primary parameter 
 
Global composite score of the cNTB 
Secondary parameters 
- 
CGIC 
- 
ADCS-MCI-ADL 
- 
ADAS-cog14 
- 
Global composite score of the cNTB 
- 
Episodic memory domain of the cNTB 
- 
Attention domain of the cNTB 
- 
Executive function domain 
Exploratory parameters 
- 
MMSE 
- 
cNTB individual scores 
- 
NPI 
- 
PSQI 
- 
ADAS-cog13, ADAS-cog12, and ADAS-cog11 
SAFETY PARAMETERS 
Vital signs measurements (heart rate and blood pressure), reported 
AEs or SAEs, physical examinations, clinical laboratory evaluations 
(hematology, 
biochemistry, 
and 
urinalysis), 
12-lead 
ECGs, 
Sheehan-STS 
PRIMARY EFFICACY 
STATISTICAL ANALYSIS 
 
The cNTB global composite score (ISLT immediate and delayed 
recall, OCL, identification, detection, and OBK) will be summarized 
at baseline and after 4, 13, and 26 weeks of double-blind treatment 
(actual and change from baseline) for each treatment group using 
descriptive 
statistics 
(n, mean, 
SD, 
median, 
minimum, 
and 
maximum). The primary efficacy analysis will be carried out using an 
analysis of covariance (ANCOVA) model with treatment and study 
site as the main effects and baseline cNTB global z-score as the 
covariate. To evaluate the effect of missing cNTB items, multiple 
imputations will be used for the calculation of cNTB composite scores 
in the case of 1 or 2 missing cNTB items. 
Secondary efficacy analyses will be carried out using a mixed-effects 
maximum likelihood repeated measures (MMRM) model utilizing all 
baseline and postbaseline data to assess any differences in treatment 
effects over time. The model shall include fixed effects of treatment, 
study site, visit, and treatment by visit interaction, with baseline score 
as a covariate, and a baseline by visit interaction. The global treatment 
effect estimates will be reported, with 95% confidence intervals and 
P values. 
SECONDARY EFFICACY 
STATISTICAL ANALYSIS  
The same aforementioned ANCOVA model will be used to analyze 
all 
secondary 
efficacy 
endpoints: 
CGIC, 
ADCS-MCI-ADL, 
ADAS-cog14, cNTB global composite score, cNTB episodic memory 
domain composite score (ISLT and OCL), cNTB attention domain 
composite score (identification and detection), and executive function 
composite score (COWAT and CFT). The MMRM model also will be 
used for the analysis of ADCS-MCI-ADL, cNTB various domains 
composite score (identification and detection) and executive function 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 16/92 
 
 
 
composite score. 
EXPLORATORY 
EFFICACY STATISTICAL 
ANALYSIS  
The same aforementioned ANCOVA model will be used to analyze 
the exploratory efficacy endpoints: MMSE, individual cNTB scores, 
NPI, PSQI (global score and individual components), and 
ADAS-cog13, ADAS-cog12, and ADAS-cog11 scores. 
Additionally, the MMRM model will be used for the analysis of 
individual cNTB scores and the PSQI global and individual 
component scores.  
SAFETY ANALYSIS 
Descriptive statistics will be provided for AEs, change in physical 
examination parameters, and vital signs. The number of patients 
taking concomitant medications during the 28-week treatment period 
(2-week single-blind placebo run-in period followed by 26-week 
double-blind treatment period) will be summarized by WHO drug 
classification code for each treatment group. The number of patients 
withdrawing during the treatment periods will be summarized by 
primary reason for withdrawal for each treatment group. 
The number of patients reporting AEs will be summarized during the 
28-week treatment period by body system and preferred term for each 
treatment group. 
The change in laboratory parameters from baseline (end of the first 
week) to the end of the 28-week treatment period will be summarized 
using shift tables showing the number of patients having values 
below, within, and above the normal range at each assessment for 
each treatment group separately. Data will not be carried forward for 
patients withdrawing due to treatment failure. 
The change in physical examination parameters from baseline to the 
end of the 28-week treatment period will be summarized as the 
number of patients who have a normal or abnormal examination at 
each assessment for each treatment group separately. Data will not be 
carried forward for patients withdrawing due to treatment failure. 
Vital signs will be summarized at baseline and at the end of the 
28-week treatment period (actual and change from baseline) using 
descriptive statistics (n, mean, SD, median, minimum, and 
maximum). 
The number of patients withdrawing during the 28-week treatment 
period will be summarized by primary reason for withdrawal for each 
treatment group. 
No formal statistical testing will be performed on the safety data. 
These safety parameters will be assessed using the safety analysis set. 
PLANNED TRIAL DATES 
First patient in: 
15 November 2015 
Last patient out: 
01 March 2019 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 17/92 
 
 
 
4. 
TABLE OF CONTENTS 
2. 
APPROVAL SIGNATURES ......................................................................................... 2 
3. 
SUMMARY/SYNOPSIS OF PROTOCOL .................................................................. 4 
4. 
TABLE OF CONTENTS ............................................................................................. 17 
5. 
ETHICS ......................................................................................................................... 20 
5.1 
REGULATORY AND ETHICAL APPROVALS ................................................. 20 
5.2 
ETHICAL CONDUCT OF THE STUDY .............................................................. 20 
5.3 
PATIENT INFORMATION AND CONSENT ...................................................... 20 
6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ................ 21 
7. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 22 
8. 
INTRODUCTION......................................................................................................... 25 
9. 
OBJECTIVES OF THE STUDY ................................................................................. 27 
9.1 
PRIMARY OBJECTIVE ........................................................................................ 27 
9.2 
SECONDARY OBJECTIVES................................................................................ 28 
9.2.1 
Key Secondary Objectives ...................................................................................... 28 
9.2.2 
Other Secondary Objectives ................................................................................... 28 
9.2.3 
Exploratory Objectives ........................................................................................... 28 
10. 
INVESTIGATIONAL PLAN ...................................................................................... 30 
10.1 
OVERALL STUDY DESIGN AND PLAN ........................................................... 30 
10.2 
DISCUSSION OF STUDY DESIGN ..................................................................... 34 
10.3. 
SAFETY MONITORING AND DATA AND SAFETY MONITORING BOARD34 
11. 
METHODOLOGY ....................................................................................................... 36 
11.1 
SELECTION OF STUDY POPULATION ............................................................ 36 
11.1.1 
Number of Patients Screened, Entered and Completing ......................................... 36 
11.1.2 
Inclusion Criteria .................................................................................................... 36 
11.1.3 
Exclusion Criteria ................................................................................................... 37 
11.1.4 
Patient Eligibility Review ....................................................................................... 40 
11.1.5 
Removal of Patients from Therapy or Assessments ............................................... 40 
11.2 
TIMINGS THROUGHOUT THE STUDY ............................................................ 41 
11.2.1 
Overall Study Schedule........................................................................................... 41 
12. 
TREATMENTS............................................................................................................. 42 
12.1 
TREATMENTS ADMINISTERED ....................................................................... 42 
12.2 
IDENTITY OF INVESTIGATIONAL PRODUCTS ............................................. 42 
12.2.1 
Piromelatine ............................................................................................................ 42 
12.2.2 
Placebo .................................................................................................................... 43 
12.2.3 
Labelling Information ............................................................................................. 43 
12.3 
SELECTION OF DOSE IN THE STUDY ............................................................. 43 
12.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS............... 43 
12.5 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT .......................... 43 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 18/92 
 
 
 
12.6 
DOSE ADJUSTMENT CRITERIA ....................................................................... 44 
12.7 
BLINDING ............................................................................................................. 44 
12.8 
GENETIC TESTING FOR APOE4 STATUS ....................................................... 44 
12.9 
PRIOR AND CONCOMITANT THERAPY ......................................................... 44 
12.9.1 
Rescue Medication .................................................................................................. 45 
12.10 
TREATMENT COMPLIANCE ............................................................................. 45 
13. 
ASSESSMENTS ............................................................................................................ 46 
13.1 
CLINICAL EFFICACY PARAMETERS .............................................................. 51 
13.1.1 
Primary Efficacy Parameter .................................................................................... 51 
13.1.2 
Secondary Efficacy Parameters .............................................................................. 52 
13.1.3 
Exploratory Efficacy Parameters ............................................................................ 54 
13.2 
APPROPRIATENESS AND CONSISTENCY OF MEASUREMENTS .............. 55 
13.3 
CLINICAL SAFETY PARAMETERS .................................................................. 55 
13.3.1 
Routine Laboratory Procedures .............................................................................. 55 
13.3.2 
Adverse Events ....................................................................................................... 56 
13.3.3 
Suicidal Ideation ..................................................................................................... 57 
14. 
SERIOUS ADVERSE EVENTS .................................................................................. 58 
14.1 
DEFINITION OF A SERIOUS ADVERSE EVENT ............................................. 58 
14.2 
DEFINITION OF AN UNEXPECTED ADVERSE EVENT ................................ 58 
14.3 
REPORTING OF SERIOUS ADVERSE EVENTS .............................................. 58 
14.4 
MEDICAL ASSISTANCE ..................................................................................... 59 
14.5 
REGULATORY RESPONSIBILITY .................................................................... 60 
15. 
STUDY TERMINATION CRITERIA ....................................................................... 61 
16. 
DATA COLLECTION AND ENTRY ........................................................................ 62 
17. 
STATISTICAL ANALYSIS ........................................................................................ 63 
17.1 
DETERMINATION OF SAMPLE SIZE ............................................................... 63 
17.2 
POPULATIONS FOR ANALYSIS ........................................................................ 63 
17.3 
ANALYTICAL MEASURES ................................................................................ 63 
17.3.1 
Analysis of Demographics and Baseline Characteristics ........................................ 63 
17.3.2  
Analysis of Primary Efficacy Parameter................................................................. 63 
17.3.3  
Analysis of Secondary Efficacy Parameters ........................................................... 64 
17.3.4  
Analysis of Exploratory Efficacy Parameters ......................................................... 64 
17.3.5 
General Considerations ........................................................................................... 64 
17.3.6 
Analysis of Safety ................................................................................................... 65 
17.3.7 
Subgroup Analysis .................................................................................................. 65 
18. 
INSTITUTIONAL REVIEW BOARD APPROVAL ................................................ 65 
19. 
INFORMED CONSENT .............................................................................................. 67 
20. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ............. 68 
21. 
RECORDS AND SUPPLIES ....................................................................................... 69 
21.1 
DRUG ACCOUNTABILITY ................................................................................. 69 
21.2 
ELECTRONIC CASE REPORT FORMS ............................................................. 69 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 19/92 
 
 
 
21.3 
CRITICAL DOCUMENTS .................................................................................... 69 
21.4 
INSURANCE .......................................................................................................... 69 
21.5 
INVESTIGATOR INFORMATION ...................................................................... 69 
21.6 
FINAL REPORT SIGNATURE ............................................................................. 70 
22. 
REPORTING AND PUBLICATION, INCLUDING RECORD RETENTION ..... 71 
23. 
APPENDIX 1 ................................................................................................................. 72 
24. 
APPENDIX 2 ................................................................................................................. 73 
25. 
REFERENCES .............................................................................................................. 88 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 20/92 
 
 
 
5. 
ETHICS 
5.1 
REGULATORY AND ETHICAL APPROVALS 
The regulatory permission to perform the study will be obtained in accordance with applicable 
regulatory requirements. The institutional review board (IRB) will approve this protocol, the 
patient informed consent form (ICF), the caregiver ICF, and their updates. The regulatory and 
ethical approvals must be available before a patient is exposed to any study-related procedure, 
including screening tests to determine eligibility for the study. 
5.2 
ETHICAL CONDUCT OF THE STUDY 
The study will be conducted in accordance with the following: 
 Principles of the Declaration of Helsinki (revised version of Seoul, Korea, October of 
2008). 
 Good Clinical Practice (GCP) guidelines, as defined by The International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use Tripartite Guideline for Good Clinical Practice: E6(R1) (ICH E6), the 
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) – Protection of 
Human Subjects and Part 56 (21CFR56) – IRBs. 
 IRBs, Health Insurance Portability and Accountability Act (HIPAA), and all other 
applicable local regulatory requirements and laws. 
5.3 
PATIENT INFORMATION AND CONSENT 
The investigator will obtain a freely given written consent from each patient and caregiver after 
an appropriate explanation of the aims, methods, anticipated benefits, potential hazards, and any 
other aspect of the study that is relevant to his/her decision to participate. The patient must be 
capable to sign the consent form as judged by the study investigator and as dictated by local legal 
circumstances. The consent form will be signed and dated by the patient/caregiver before he/she 
is exposed to any study-related procedure, including screening tests for eligibility. Each patient 
will authorize in writing that his/her source records may be reviewed by a monitor, an auditor, or 
a regulatory inspector, in accordance with applicable regulatory requirements. Patients who are 
willing to participate in the apolipoprotein-E (ApoE4) genotyping will sign a separate applicable 
ICF. 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 21/92 
 
 
 
6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
This study will be a multicenter study conducted in the United States (US). 
 
Study CRO 
 
INC Research, LLC 
 
 
 
 
 
3201 Beechleaf Court, Suite 600 
Raleigh, North Carolina 27604 
USA 
 
Study Statistician 
INC Research, LLC 
 
 
 
Central Laboratory 
Covance Central Laboratory Services LP 
 
 
 
 
Safety Officer 
Tali Nir, DVM 
VP, Clinical and Regulatory Affairs 
Neurim Pharmaceuticals (1991) Ltd 
 
27 Habarzel St 
Tel Aviv 69710, ISRAEL 
 
Phone: 972-3-7684902 
Fax:     972-3-6494568 
e-mail: talin@neurim.com 
 
 
Sponsor Representative 
 
 
Amnon Katz, PhD 
VP, Clinical Development 
Neurim Pharmaceuticals (1991) Ltd 
 
27 Habarzel St 
Tel Aviv 69710, ISRAEL 
 
Phone: 972-3-7684906 
Fax:     972-3-6494568 
e-mail: amnonk@neurim.com 
 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 22/92 
 
 
 
7. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATIONS 
21CFR50 
United States Code of Federal Regulations, Title 21, Part 50 – 
Protection of Human Subjects 
21CFR56 
United States Code of Federal Regulations, Title 21, Part 56 – 
IRBs 
Aβ 
β-amyloid peptide 
AD 
Alzheimer's disease 
ADAS-cog14 
Alzheimer’s Disease Assessment Scale – cognitive subscale (also 
related: ADAS-cog13, ADAS-cog12, and ADAS-cog11) 
ADCS-MCI-ADL 
Alzheimer's Disease Cooperative Study/Activities of Daily Living 
scale adapted for MCI patients 
ADL 
Activities of Daily Living 
AE 
adverse event 
AHI 
Apnea Hypopnea Index 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
APOE4 
apolipoprotein-E (gene) 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CDR 
Clinical Dementia Rating 
CDR-GS 
Clinical Dementia Rating Global Score 
CFT 
Categorical Fluency Test 
CGIC 
Clinical Global Impression of Change 
cNTB 
computerized Neuropsychological Test Battery 
COWAT 
Controlled Oral Word Association Test 
CPAP 
continuous positive airway pressure 
CSF 
cerebrospinal fluid 
CSSRS 
Columbia Suicide Severity Rating Scale 
CT 
computed tomography 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 5th 
edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EEG 
electroencephalogram 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 23/92 
 
 
 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICH E3 
International Conference on Harmonisation Tripartite Guideline 
E3: Structure and Content of Clinical Study Reports 
ICH E6 
International Conference on Harmonisation Tripartite Guideline 
E6(R1): Good Clinical Practice 
ISLT 
International Shopping List Test 
IRB 
institutional review board 
IWRS 
interactive web response system 
MCI 
mild cognitive impairment 
MMRM 
mixed-effects maximum likelihood repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NIA-AA 
National Institute on Aging-Alzheimer's Association 
NPI 
Neuropsychiatric Inventory 
NREM 
non-rapid eye movement 
NTB 
Neuropsychological Test Battery 
OBK 
One Back Card 
OCL 
One Card Learning 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
PSA 
prostate-specific antigen 
PSG 
polysomnography 
PSQI 
Pittsburgh Sleep Quality Index 
SAE 
serious adverse event 
Sheehan-STS 
Sheehan Suicidality Tracking Scale 
SUSAR 
suspected unexpected serious adverse reaction 
SWS 
slow wave sleep 
ULN 
upper limits of normal 
US 
United States 
WASO 
wake after sleep onset 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 24/92 
 
 
 
 
DEFINITION OF TERMS 
 
Safety analysis set 
All patients randomized to treatment 
who have taken at least 1 dose of 
study medication 
Full analysis set 
All patients in the safety analysis set 
who satisfy all entry criteria and 
who have efficacy data for the 
primary parameter recorded for 
baseline and at least 1 postbaseline 
period assessment 
Per protocol set 
All patients in the full analysis set 
who have no major protocol 
violations 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 25/92 
 
 
 
8. 
INTRODUCTION 
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the leading cause of 
dementia in the elderly population. People progressing to AD develop distressing changes in 
memory, thought, function, and behavior, which worsen over time. These changes increasingly 
impact the person's daily life and reduce their independence until ultimately these patients are 
entirely dependent on others (Querfurth and LaFerla, 2010). Worldwide, it is estimated that 
about 36 million people have dementia. Alzheimer’s disease accounts for 50% to 80% of these 
patients (Duthey, 2013). At early-stage AD, the episodic memory is the most noticeable 
impairment (Gold and Budson, 2008). With the shift towards an increasingly elderly population, 
it is predicted that the number of people affected by early-stage AD that will progress to 
dementia will almost double every 20 years, and by the year 2050, 115 million people will have 
the condition (Duthey, 2013). Effective treatments for the devastating disease are urgently 
needed as the world’s population continues to age. 
The diagnosis of AD is generally based on consensus diagnostic criteria developed by the 
National Institute on Aging-Alzheimer's Association (NIA-AA) (McKhann et al., 2011). These 
criteria are clinical in nature and require that patients must exhibit impairments in both cognitive 
and functional domains. In the earliest clinical stages of AD, subtle cognitive deficits may be 
evident only through use of sensitive measures of neuropsychological performance. Thereafter, 
but before developing overt dementia, patients proceed through a clinical phase where cognition 
becomes increasingly affected and relatively mild but detectable impairments in some functional 
abilities emerge as well. 
The hallmark pathological feature of AD is the presence of brain plaques, consisting primarily of 
β-amyloid peptide (Aβ) aggregates (Selkoe, 2002). Accordingly, the abnormal production and 
aggregation of Aβ, associated particularly with late-stage disease, has been the principal target of 
many drug development efforts. However, 3 trials of Aβ lowering agents involving patients with 
overt dementia failed to show improvements in cognition. A leading theory posits that the 
attempts at intervention may have been made too late in the progression of disease, at a stage 
when neuronal damage had become too widespread, and therefore more trials now focus on 
patients in whom overt dementia seems imminent. An ideal drug for such patients will improve 
neuropsychological performance and functional abilities, slow down Aβ buildup, and promote 
neuroprotection and neurogenesis. 
The 
investigational 
compound, 
N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-
carboxamide (piromelatine) is a novel melatonin MT1, 2, and 3 and serotonin 5-HT-1A and -1D 
receptors agonist with a different proposed mechanism of action than currently available AD 
medications. Through this unique molecular mode of action, piromelatine demonstrated in 
preclinical studies in rodents neuroprotective (Buendia et al., 2014, Tang et al., 2012), memory 
enhancing (He et al., 2013, Tian et al., 2010), sleep promoting (Liu et al., 2014), and 
neurogeneration enhancing capabilities (Tian et al., 2015 unpublished) with relevance to AD risk 
factors, comorbidities, and symptoms. The 5HT-1a agonists have demonstrated neuroprotective 
effects (Kline et al., 2004) by increasing both cell proliferation and neurogenesis in the 
hippocampal subgranular zone of the dentate gyrus and the subventricular zone (Banasr et al., 
2004, Islam et al., 2014) and increase slow wave sleep (SWS) specifically by inhibition of 
hypothalamic orexin neurons and the dorsal raphe nuclei that act as wake promoting centers 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 26/92 
 
 
 
(Muraki et al., 2004, Tabuchi et al., 2013). Simultaneous activation of melatonergic and 5HT-1a 
receptors may synergistically promote neurogenesis (Fava et al., 2012). 
The sleep enhancing capacities of piromelatine may also be relevant to the therapeutic potential. 
Recent clinical and biochemical evidence has identified an interesting link between sleep, Aβ, 
cognitive dysfunction, and AD. In mice, Aβ clearance through the glymphatic system (the 
biomolecule clearance system operating the convective flow between the cerebrospinal fluid 
[CSF] and interstitial fluid to remove toxic metabolites) is strongly stimulated by sleep 
(Mendelsohn and Larrick, 2013, Xie et al., 2013). Bidirectional relationships between sleep and 
Aβ production have been demonstrated in mice overexpressing Aβ (Roh et al., 2012). In humans, 
normal soluble Aβ concentrations in the CSF fluctuate with the sleep-wake cycle with 6 hours 
delay (Huang et al., 2012). Disruption of non-rapid eye movement (NREM) SWS resulted in 
impaired overnight consolidation of long-term memory in healthy older adults (Mander et al., 
2015). Since Aβ production is highest at times of neural activity such as during wakefulness and 
lowest at times of decreased neural activity such as during SWS, sleep disturbances accompanied 
by loss of SWS may lead to an increase in production of soluble CSF Aβ, increased Aβ 
aggregation, and attenuation of the Aβ diurnal pattern characterizing AD (Lucey and Bateman, 
2014). Bidirectional relations between Aβ pathology and NREM sleep physiology were observed 
also in patients with mild cognitive impairment (MCI) and AD. In MCI patients the reduction in 
SWS was associated with deficits in sleep dependent memory consolidation (Pace-Schott and 
Spencer, 2015). Moreover, MCI patients had modified sleep structure characterized by shorter 
and disrupted SWS and lower ∆ and Θ power as compared to controls (Westerberg et al., 2012). 
In AD patients, higher SWS was positively associated with retrieval of recent autobiographical 
memories (Rauchs et al., 2013). 
Indeed, 63% of the patients with subtle cognitive deficits (also termed MCIs) (McKinnon et al., 
2014) and 44% of the patients diagnosed with AD (Vitiello and Borson, 2001) demonstrate sleep 
disturbances as determined using the Pittsburgh Sleep Quality Index (PSQI). More recently, 
neuropathological analyses revealed a positive correlation between total sleep time, sleep quality, 
and sleep onset latency in demented and nondemented older adults with higher Aβ burden in 
specific brain areas that are linked to early AD (Spira et al., 2013). Accordingly, deterioration in 
cognition from healthy controls through MCI to AD patients was associated with parallel 
deterioration in sleep (Economou et al., 2013). The presence of insomnia may thus help identify 
patients with early signs of AD who are at a greater risk of deteriorating to dementia. 
The relation becomes evident as poor sleep is directly associated with cognitive decline in 
healthy (Miyata et al., 2013) cognitively impaired (McKinnon et al., 2014), and demented adult 
populations (Vitiello et al., 1990), including AD (Carpenter et al., 1996, McCurry et al., 1999). 
Further exploration of interventions that promote NREM SWS and minimize the progression of 
neurodegeneration and the cognitive dysfunction associated with Aβ pathology is needed 
(Mander et al., 2015). 
Importantly, the mechanism of sleep induction appears to be of key importance for the sought 
cognitive effects. Long-term use of benzodiazepine is associated with an increased risk of 
dementia (Billioti de Gage et al., 2012) and AD (Billioti de Gage et al., 2014, Yaffe and 
Boustani, 2014), presumably because of the known suppression of NREM SWS by 
benzodiazepines and nonbenzodiazepine hypnotics (Arbon et al., 2015). Treatment of patients 
with AD suffering from sleep disturbances with traditional hypnotics is associated with increased 
risk for a wide range of injuries (Chung et al., 2013, Diem et al., 2014) and may actually worsen 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 27/92 
 
 
 
their cognition and memory (Hall-Porter et al., 2014). In contrast, melatonin receptor agonism, 
which maintains the NREM SWS (Arbon et al., 2015), appears beneficial for cognition and 
functioning in mild to moderate AD patients (Wade et al., 2014). 
In a Phase 1 study in healthy volunteers, piromelatine (2, 5, 20, 50, and 200 mg) was found to be 
safe and well tolerated with no serious adverse events (SAEs) and showed a favorable, 
dose-proportional pharmacokinetic (PK) profile following oral intake. In addition, piromelatine 
intake was associated with increase in fatigue and total sleep time in the volunteers in a 
dose-dependent manner (Yalkinoglu et al., 2010). In a Phase 1b multiple ascending dose study in 
insomnia patients, piromelatine (2, 5, 20, and 50 mg) had a favorable PK profile without any sign 
of accumulation. This study also suggested dose-dependent beneficial effects of piromelatine on 
sleep continuity measures. Importantly, in this study piromelatine administered for 5 days to 
nondemented patients with insomnia had no detrimental nor beneficial effect on learning and 
memory as measured using the word-pair association task (Laudon et al., 2012). In a Phase 2, 
randomized, placebo-controlled, sleep laboratory study in insomnia patients (aged 18-80), 
piromelatine (20 mg and 50 mg daily for 1 month) enhanced sleep maintenance (wake after sleep 
onset [WASO]) measured by polysomnography (PSG) significantly in comparison to placebo 
(Neurim press release, 2013). Piromelatine enhanced NREM ∆ power (NREM SWS) and 
decreased NREM β power, a fast electroencephalogram (EEG) activity that is considered to be 
related to the hyperarousal state experienced by insomniac patients (Merica et al., 1998). Both 
effects may be beneficial for early AD and AD patients to enhance Aβ clearance from the brain 
(Grandy, 2013). Overall, piromelatine was generally safe and well tolerated. There were no 
SAEs during the conduct of this study. Adverse event rates during double-blind treatment with 
study medication were low (6.7% in the piromelatine 20 mg group, 0% in the piromelatine 50 
mg and placebo groups). Laboratory values were within normal ranges. No clinically meaningful 
changes in vital signs, electrocardiograms (ECGs), or physical examinations were observed. No 
suicidal behavior or suicidal ideation (Columbia Suicide Severity Rating Scale [CSSRS]) was 
recorded at any time during the study. 
Altogether, through its action at melatonin receptors, piromelatine may improve sleep, circadian 
rhythms control, and, subsequently, cognition in the patients (Wade et al., 2014). Through the 
serotonergic mechanism, piromelatine may improve memory and mood (Rodríguez et al., 2012), 
enhance SWS, and reduce wakefulness (Bjorvatn and Ursin, 1998, Monti and Monti, 2000). 
Through the combined activation of melatonergic and 5HT-1a receptors, piromelatine may act 
synergistically to increase neurogenesis (Fava et al., 2012). 
This study is a Phase 2, randomized, placebo-controlled, dose-ranging study of piromelatine (5, 
20, and 50 mg daily for 6 months) versus placebo to determine an effective dose to take forward 
to Phase 3 studies based on efficacy (cognitive performance), safety, and tolerability in patients 
with mild dementia due to AD. 
9. 
OBJECTIVES OF THE STUDY 
9.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to compare the effect of piromelatine (5, 20, and 50 mg) to 
that of placebo in the change from baseline in global composite score of the computerized 
Neuropsychological Test Battery (cNTB) after 26 weeks of double-blind treatment. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 28/92 
 
 
 
The global composite score includes the International Shopping List Test (ISLT; immediate and 
delayed recall), One Card Learning (OCL), Identification, Detection, and One Back Card (OBK). 
9.2 
SECONDARY OBJECTIVES 
9.2.1 Key Secondary Objectives 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on global 
impression assessed by the Clinical Global Impression of Change (CGIC) after 26 weeks 
of double-blind treatment 
2. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in the 
Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for MCI 
patients (ADCS-MCI-ADL) at Weeks 13 and 26 and over 26 weeks of double-blind 
treatment 
9.2.2 Other Secondary Objectives 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in 
Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog14) at Weeks 13 
and 26 and over 26 weeks of double-blind treatment 
2. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in the change 
from baseline in global composite score of the cNTB at Weeks 4 and 13 and over 
26 weeks of double-blind treatment 
3. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on the 
episodic memory domain* composite score of the cNTB at Weeks 4, 13, and 26 and 
over 26 weeks of double-blind treatment 
* episodic domain tests: ISLT (immediate and delayed recall) and OCL 
4. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on the 
attention domain* composite score of the cNTB at Weeks 4, 13, and 26 and over 
26 weeks of double-blind treatment 
* attention domain tests: Identification and Detection 
5. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on the 
executive function* composite score of the Neuropsychological Test Battery (NTB) at 
Weeks 4, 13, and 26 and over 26 weeks of double-blind treatment 
* executive function domain tests: OBK, Controlled Oral Word Association Test 
(COWAT) and Categorical Fluency Test (CFT) 
6. To compare the safety and tolerability of piromelatine (5, 20, and 50 mg) to that of 
placebo 
9.2.3 Exploratory Objectives 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on cognitive 
aspects of mental function assessed by the Mini-Mental State Examination (MMSE) after 
2 weeks of run-in single-blind placebo followed by 26 weeks of double-blind treatment 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 29/92 
 
 
 
2. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in individual 
cNTB test scores (ISLT immediate and delayed recall, OCL, Identification, Detection, 
OBK) at Weeks 4, 13, and 26 and over 26 weeks of double-blind treatment 
3. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on the 
change from baseline in behavioral signs and symptoms assessed by the 
Neuropsychiatric Inventory (NPI) scale after 26 weeks of double-blind treatment 
4. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on sleep 
variables derived from the PSQI at Weeks 4, 13, and 26 and over 26 weeks of 
double-blind treatment 
5. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in 
ADAS-cog13, ADAS-cog12, and ADAS-cog11 score at Weeks 13 and 26, and over 
26 weeks of double-blind treatment. 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 30/92 
 
 
 
10. 
INVESTIGATIONAL PLAN 
10.1 
OVERALL STUDY DESIGN AND PLAN 
This is a Phase 2, double-blind, parallel-group, placebo-controlled, dose ranging safety and 
efficacy study of piromelatine in patients with mild dementia due to AD. 
Following informed consent, patients with a documented history of mild dementia due to AD for 
at least 6 months, having an MMSE score of 20 to 27 (inclusive) at Screening (a score of 27 is 
allowed only if accompanied by a score of ≥ 12 in the ADAS-cog11 portion of the ADAS-cog14 
at Screening) and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5 or 1 will be 
recruited and further screened for eligibility. Caregiver commitment for the study is also 
necessary (defined as someone who is not expected to change during the course of the study, and 
is responsible for the overall care of the patient at home). 
At Screening (Visit 1), patients will undergo neuropsychiatric assessments, psychometric testing 
and general medical assessments (including medical history, pre-existing conditions, physical 
examination, vital signs, and ECG). A computed tomography (CT) or magnetic resonance 
imaging (MRI) scan will be obtained to rule out clinically significant comorbid pathologies for 
patients who did not have this scan in the last 12 months before Screening. Patients who had a 
past (more than 12 months or less than 12 months before) CT or MRI scan indicating 
incompatibility with a diagnosis of probable AD should not be screened. The medical monitor 
should be contacted when there are questions about eligibility. Rescreening will be allowed on 
specific cases following a decision by the medical monitor.  
Potentially eligible patients will be given a bottle of run-in placebo (single blind) with 
instructions not to begin taking the doses until they receive a phone call from the site staff. Site 
staff will send MMSE, Clinical Dementia Rating (CDR), ADAS-cog, and documented history of 
cognitive deterioration of these potential eligible patients to be centrally reviewed. After 
confirmation of eligibility from the central reviewer, eligible patients will start a 2-week run-in 
period of placebo (single blind), followed by 26 weeks of double-blind treatment comprising 
administration of piromelatine or placebo, for a total treatment duration of 28 weeks. During the 
double-blind period, patients will be enrolled in a 1.2:1:1:1 randomization ratio to the 4 trial 
arms (placebo [1.2], and the equal piromelatine treatment arms 5, 20, and 50 mg [1:1:1]).  
Intermediate visits will be carried out at 4 weeks (Visit 3) and 13 weeks (Visit 4) after 
randomization. A follow-up phone call to elicit any safety concerns will be completed 2 weeks 
after the last dose of study medication. Patients who discontinue prior to Visit 5 (Week 26) will 
be brought back for a termination visit. 
Piromelatine will be administered orally, once daily, after a meal, before habitual bedtime, 
preferably between 2100h and 2300h. Patients will be required to spend at least 2 hours a day 
exposed to daylight. 
Overall study design is shown in Figure 10.1.  


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 31/92 
 
 
 
Figure 10.1: Overall Study Design 
 
 
Single-Blind Run-in 
Double-Blind Treatment 
 
Period 
Screening 
Run-in 
Randomization 
 
Follow-up 
Phone call 
Week 
 
–2 
0 
4 
13 
26 
28 
Visit 
1 
 
2 
3 
4 
5 
 
Treatment 
 
Placebo 
Piromelatine 5, 20, or 50 mg 
or Placebo 
N/A 
 
The Schedule of Assessments is presented in Table 10.1. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 32/92 
 
 
 
Table 10.1: Schedule of Assessments 
Period 
Single-Blind  
Run-in 
Double-Blind Treatment Follow-up a 
Premature 
Discontinuation 
Visit 
Visit 
1 b 
2 
3 
4 
5 
 
 
Study Day 
–25 to 14 
0 ± 3* 
28 ± 3 
91 ± 5 182 ± 5 
196 
 
Study Week 
 
0 
4 
13 
26 
28 
 
Explanation of the study 
X 
 
 
 
 
 
 
Informed consent - patient 
X 
 
 
 
 
 
 
Informed 
consent - caregiver 
X 
 
 
 
 
 
 
Screening number assigned 
X 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
MMSE 
X 
 
 
 
X 
 
 
CDR 
X 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
CT/MRI c 
X 
 
 
 
 
 
 
PET/CSF data collection d 
X 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Physical examination 
X 
 
 
X 
X 
 
X 
Vital signs  
X 
X 
X 
X 
X 
 
X 
BMI 
X 
 
 
 
X e 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
 
X 
12-lead ECG 
X 
 
 
X 
X 
 
X 
Hematology/biochemistry/ 
urinalysis 
X 
 
 
X 
X 
 
X 
Hormonal testing f 
X 
 
 
 
X 
 
X 
Blood sampling for ApoE4 
genotyping g 
 
 
 
 
X 
 
 
Urine drug screen (BZDs 
and opiates) 
X 
 
 
X h 
 
 
 
Recording of adverse events 
 
X 
X 
X 
X 
X 
X 
Sheehan-STS  
X 
 
 
X 
X 
 
X 
Compliance verification 
 
X 
X 
X 
X 
 
 
Computerized NTB 
X i 
X j 
X 
X 
X 
 
 
ADAS-cog14 
X i 
X 
 
X 
X 
 
 
CGIC 
 
X 
 
X 
X 
 
 
ADCS-MCI-ADL 
 
X 
 
X 
X 
 
 
Executive function 
(COWAT, CFT) 
X i 
X 
X 
X 
X 
 
 
NPI  
 
X 
 
 
X 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 33/92 
 
 
 
Period 
Single-Blind  
Run-in 
Double-Blind Treatment Follow-up a 
Premature 
Discontinuation 
Visit 
Visit 
1 b 
2 
3 
4 
5 
 
 
Study Day 
–25 to 14 
0 ± 3* 
28 ± 3 
91 ± 5 182 ± 5 
196 
 
Study Week 
 
0 
4 
13 
26 
28 
 
PSQI  
 
X 
X 
X 
X 
 
 
MMSE, CDR, ADAS-cog, 
and documented history of 
cognitive deterioration for 
central review 
X 
 
 
 
 
 
 
Study medication dispensed 
X 
X 
X 
X 
 
 
 
Collection of unused study 
medication and used packs 
since last visit 
 
X 
X 
X 
X 
 
X 
Run-in phone call k 
X 
 
 
 
 
 
 
Compliance phone call 
(every week between 
Visits 2-5) l 
On Days (±3) 7, 14, 21, 35, 42, 49, 56, 
63, 70, 77, and 84 
On Days (±5) 98, 105, 112, 119, 126, 
133, 140, 147, 154, 161, 168, and 175 
 
 
Key: 
ADAS-cog14 = Alzheimer’s 
Disease 
Assessment 
Scale 
(cognitive 
subscale);  
ADCS-MCI-ADL = Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for MCI 
patients;  ApoE4 = apolipoprotein-E (gene);  BMI = body mass index;  BZD = benzodiazepine;  CDR = Clinical 
Dementia Rating;  CFT = Categorical Fluency Test;  CGIC = Clinical Global Impression of Change;  
COWAT = Controlled Oral Word Association Test;  CSF = cerebrospinal fluid;  CT = computed tomography;  
ECG = electrocardiogram;  MMSE = Mini-Mental State Examination;  MRI = magnetic resonance imaging;  
NPI = Neuropsychiatric Inventory;  NTB = Neuropsychological Test Battery;  PET = positron emission 
tomography;  PSQI = Pittsburgh Sleep Quality Index; Sheehan-STS = Sheehan Suicidality Tracking Scale. 
a 
The Follow-up visit consists of a phone call to the caregiver to elicit any safety concerns 2 weeks after the last 
dose of study medication. 
b 
Only if a CT or MRI scan was not performed in the past or if available scan with findings consistent with the 
diagnosis of dementia due to AD without any other clinically significant comorbid pathologies was performed 
more than 12 months before Screening. The scan should be performed and diagnosis confirmed prior to Visit 2. 
c 
Only for patients who have this information available. 
d 
Blood samples should be drawn in the morning. If the blood sample at Visit 1 is drawn in the afternoon, then 
the Visit 5 sample should also be drawn in the afternoon. 
e 
Retrospective genetic information could be used. 
f 
To be repeated randomly in some patients during the study. 
g 
Practice session. 
h 
There are 2 administrations of the computerized NTB at Visit 2, performed 15 minutes apart. 
i 
On Day –14, after eligibility by central reviewer. 
j 
The caregiver will be called by study personnel for follow-up and safety and compliance verification purposes 
(eg, study medication compliance, daylight exposure compliance, and adverse event/concomitant medication 
checks). 
k 
Only weight. 
l 
Visit 1 may be completed over 2 consecutive days (no Friday/Monday visits) at the discretion of the 
investigator. Both the patient and caregiver must be present both days, and the following screening procedures 
should be completed on the indicated day: Screening Day 1: MMSE, ADAS-cog, cNTB; Screening Day 2: 
COWAT/CFT, CDR, Sheehan-STS. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 34/92 
 
 
 
10.2 
DISCUSSION OF STUDY DESIGN 
Piromelatine proposed mode of action and previous studies suggest that this molecule may 
improve cognitive performance via its effects on sleep and neuroprotective pathways. Sleep 
effects were demonstrated after 4 weeks of treatment in a Phase 2 sleep laboratory study. 
Cognition effects are expected to be seen after 26 weeks of treatment as has been shown 
previously with melatonin administered to a similar population of patients (Wade et al., 2014). 
The cognitive outcome measure mostly used in AD clinical trials, the ADAS-cog, is a scale 
based on a series of items that assess different aspects of cognitive function known to be relevant 
to the cognitive dysfunction that characterizes AD (Greenberg et al., 2013). However, over the 
past 10 years the ADAS-cog has been shown to have poor sensitivity in discerning cognitive 
change in patients with MCI and early AD (Gold, 2007; Greenberg et al., 2013; Grundman et al., 
2004; Sevigny et al., 2010). Given the importance of formal neuropsychological approaches to 
the diagnosis and management of AD in patients with mild and moderate AD, several 
neuropsychological tests have been combined to construct a Neuropsychological Test Battery 
(NTB) (Harrison et al., 2007). In accord with the approaches to constructing the NTB for clinical 
trials in AD, the tests to be used in the NTB for this study have been selected on the basis of the 
following: 
a) demonstrated validity for the target cognitive domain 
b) demonstrated acceptability in patients with some diminished intellectual function due to 
AD 
c) acceptable estimates of test-retest reliability in patients with AD 
d) demonstrated sensitivity to cognitive change in AD (eg, related to drug effects or disease 
progression) 
Dosage specification was made on the basis of previous studies and the relative affinity to the 
melatonin and serotonin receptors. 
The parallel dosing regimen maximizes the ability to make direct comparison between the active 
treatment groups and placebo. 
The use of placebo allows for a blinded, thus minimally biased, study. The placebo group is a 
comparator group for efficacy and safety assessment. 
Within-subject variation in psychometric test scores is common in AD patients. This could be the 
result of measurement error or reflection of the fluctuation in the patient’s condition. Both cases 
may influence the final score. The first problem of rater errors will be addressed by employing 
strict rater training and by vigorous real-time monitoring of rater performances. In addition, in 
order to avoid habituation problems, all patients will receive a practice assessment prior to their 
baseline measurements (NTB and ADAS-cog14). 
10.3. SAFETY MONITORING AND DATA AND SAFETY MONITORING BOARD 
Safety data will be reviewed on an ongoing basis by the sponsor (Neurim Pharmaceuticals 
[1991] Ltd) and the medical monitor. Safety data will also be reviewed on an ongoing basis by 
an independent Data and Safety Monitoring Board (DSMB). The DSMB will be assembled to 
review safety and tolerability data collected during the study. Based on its ongoing assessment of 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 35/92 
 
 
 
the safety and tolerability of piromelatine, the DSMB will provide recommendations to the 
sponsor for modifying, stopping, or continuing the study as planned. Details on the safety 
assessments, frequency of review and meeting schedules are outlined in the DSMB Charter and 
in the Statistical Analysis Plan. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 36/92 
 
 
 
11. 
METHODOLOGY 
11.1 
SELECTION OF STUDY POPULATION 
11.1.1 Number of Patients Screened, Entered and Completing 
Male and female patients between the ages of 60 and 85 (inclusive) with mild AD will be 
screened for the study after having given their written informed consent. After the 2-week 
single-blind, placebo run-in period, eligible patients at Visit 2 will be randomized and treated 
with piromelatine (5, 20, or 50 mg) or placebo as a double-blind treatment for 26 weeks. 
Assuming a 50% screen failure rate and allowing for 15% patient withdrawal, 1150 patients 
should be screened in order to randomly assign 575 patients, of whom it is expected 500 will 
complete the study. 
11.1.2 Inclusion Criteria 
1. Patient has a permanent caregiver (participant’s caregiver is not expected to change 
during the course of the study) who will, accompany the patient to the office and/or be 
available by telephone at designated times, monitor administration of prescribed 
medications, control the minimum 2-hour daily light exposure requirement, and be 
responsible for the overall care of the patient at home. Caregiver must, in the opinion of 
the investigator, have enough contact with the participant to be able to perform the duties 
described above. 
2. Patient and caregiver are willing to take part in the entire study. 
3. Signed informed consent from the patient who is capable to sign the consent form as 
judged by the study investigator and from the caregiver as dictated by local legal 
circumstances. 
4. Patient is a male or female aged 60-85 years (inclusive). 
5. Patient is an outpatient living at home or in an assisted living facility with no plans to 
move or travel during the investigational period. 
6. Patient has a clearly documented history either in medical records or from an informant 
of cognitive decline over at least 6 months. If available, any scale verification of the 
decline should be requested. 
7. Patient has mild probable AD as consistent with criteria established by the NIA-AA 
(McKhann et al., 2011). 
8. Patient has MRI or CT scan, performed within 12 months before Screening, with 
findings consistent with the diagnosis of dementia due to AD without any other 
clinically significant comorbid pathologies. If this MRI or CT scan is unavailable, or 
occurred more than 12 months before Screening this assessment should be completed 
and the findings confirmed prior to Visit 2 (copy of the report will be available at the 
study site). 
9. Patient has an MMSE score of 20-27 (inclusive) at Screening (a score of 27 is allowed 
only if accompanied by a score of ≥ 12 in the ADAS-cog11 portion of the ADAS-cog14 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 37/92 
 
 
 
at Screening; patients with an MMSE score of 19 may be rescreened once after 
1 month). 
10. Patient has a CDR-GS of 0.5-1 (mild dementia) at Screening. 
11. Patients taking acetylcholinesterase inhibitors for the treatment of AD may be enrolled if 
the patient has been taking such medication for at least 6 months before Visit 2 
(Baseline), and is stable on any dose for the last 4 months prior to Baseline, and if the 
dose is not expected to change during study participation. 
12. Patients not receiving acetylcholinesterase inhibitors must be agreeable to not starting 
throughout the study. 
13. Patients who stopped receiving acetylcholinesterase inhibitors must be stable off 
acetylcholinesterase inhibitors for 6 months before Visit 2 (Baseline) and must be 
agreeable to not restarting throughout the study. 
14. Patient has a negative drug screen (benzodiazepines or opiates) at Screening. 
15. Female patients must have had last natural menstruation ≥ 24 months before Screening, 
OR be surgically sterile. 
16. Male patients and their female spouse/partners who are of childbearing potential must 
agree to use highly effective methods of contraception, consisting of 2 forms of birth 
control (at least one of which must be a barrier method) starting at Screening, throughout 
the study and for 90 days post-last dose, OR be surgically sterile. 
17. Patients who are taking medications for nonexcluded concurrent medical conditions 
should be on a stable dose for at least 4 weeks before Screening. Patients taking allowed 
antidepressants or memantine (see Section 12.9) should be on a stable dose for at least 3 
months before Screening and throughout the study. 
18. Patients who are taking vitamin B12 should be on a stable dose for at least 3 months 
before Screening and throughout the study. 
19. Patient is able to ingest oral medication and participate in all scheduled evaluations. 
20. Patient has ability and commitment to spend at least 2 hours per day exposed to daylight 
(preferably outside but can be next to a window if weather or personal situation does not 
permit). 
21. Patient and caregiver have the ability to read and write in English (or Spanish if using 
Spanish materials) and have hearing, vision, and physical abilities adequate to perform 
assessments (corrective aids allowed). 
11.1.3 Exclusion Criteria 
Potential patients who meet any of the following criteria will be excluded from participating 
in the study: 
1. Patient has an alternative cause for dementia other than AD. 
2. A past or recent CT or MRI scan or report indicating brain pathology that is associated 
with cognitive impairment or incompatible with a diagnosis of probable AD (e.g., any 
cortical infarct defined as > 1.5 cm3; more than 2 lacunar infracts defined as ≤ 1.5 cm3; 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 38/92 
 
 
 
diffuse white matter disease). The medical monitor should be contacted when there are 
questions about eligibility. 
3. Patient has evidence of any clinically significant neurodegenerative disease, or other 
serious neurological disorders other than AD, including but not limited to: 
a) Frontotemporal dementia, dementia with Lewy bodies, or vascular dementia 
documented by clinical history 
b) History or presence of any stroke with clinical symptoms ≤ 2 years before 
Screening 
c) Epilepsy or history of seizures, except for simple childhood febrile seizures or 
alcohol withdrawal seizures 
d) History of clinically relevant head trauma with neurological sequelae 
e) Parkinson’s disease 
f) Multiple sclerosis 
g) Amyotrophic lateral sclerosis 
h) Myasthenia gravis 
i) Moderate to severe sleep apnea (Apnea Hypopnea Index [AHI] ≥ 15); use of 
continuous positive airway pressure (CPAP) or other sleep-related devices for 
sleep apnea 
j) Narcolepsy 
4. Patient has been diagnosed with the following Axis I disorders (Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition [DSM-V] criteria): 
a) Schizophrenia spectrum and other psychotic disorders (not related to dementia) 
b) Bipolar and related disorders 
c) Substance use disorders within the past 2 years 
5. Patient has a history of uncontrolled or untreated cardiovascular, endocrine, 
gastrointestinal, respiratory, or rheumatologic disorders within the past 5 years. 
6. Patient has a history of severe agitation. 
7. Patient has a known history of human immunodeficiency virus (HIV). 
8. Patient has a history of serious infectious disease including: 
a) Neurosyphilis 
b) Meningitis 
c) Encephalitis 
9. Patient has a history of a primary or recurrent malignant disease that has not been in 
remission for > 5 years prior to the Screening visit, with the exceptions of excised 
cutaneous squamous cell carcinoma in situ, basal cell carcinoma without recurrences; 
and history of intraductal breast cancer, cervical carcinoma in situ, or in situ prostate 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 39/92 
 
 
 
cancer resected over 5 years previously. (For resected in situ prostate cancer, i.e., high 
grade intraepithelial neoplasia, the patient must have a normal prostate-specific antigen 
[PSA] prior to Screening and no increase in PSA since his resection surgery). 
10. Patient has severe pain that is likely to interfere with sleep (in the opinion of the 
investigator). 
11. Patient has any concomitant documented progressive disease likely to interfere with the 
conduct of the study, particularly: 
a) Liver disease with aspartate aminotransferase (AST), alanine aminotransferase 
(ALT) or gamma-glutamyltransferase (GGT) > 3 times the upper limits of normal 
(ULN) 
b) Total bilirubin > 3 times the ULN 
c) Mean corpuscular volume > 95 µ3 if due to chronic alcoholism 
d) Renal failure with creatinine > 150 µmol/L 
12. Patient is unable to adequately perform the computerized testing as judged by the study 
investigator or investigator designee at the practice session during Screening. 
13. Continuous use of benzodiazepines or other sedative-hypnotics during the 2 weeks 
before Screening (see Section 12.9). 
14. Patient has a history of chronic use and abuse of benzodiazepines or other 
sedative-hypnotics. 
15. Use of any kind of melatonin/melatonin agonist during the 2 weeks before Screening 
(see Section 12.9). 
16. Patient has known or suspected hypersensitivity to exogenous melatonin or melatonin 
receptor agonists. 
17. Patient has clinically significant abnormal laboratory findings that have not been 
approved by the study safety officer. 
18. Patient has persistent bradycardia (heart beat < 50 bpm) or tachycardia (heart 
beat > 100 bpm). 
19. Patient has atrioventricular block (type II/Mobitz II and type III), congenital long QT 
syndrome, sinus node dysfunction or a marked prolongation of QTc interval (repeated 
demonstration in ECGs of QTc interval > 450 msec for males and > 470 msec for 
females using Fridericia’s formula: QTc = QT/cube root of RR). 
20. Patient has other serious diseases that could interfere with patient assessment, in the 
opinion of the investigator. 
21. Patient has untreated B12 and/or folic acid deficiency. 
22. Patient has participated in a clinical trial with any investigational agent within 3 months 
before Screening. Participants in any former monoclonal antibody clinical trial for AD 
are not eligible until 6 months after the last visit of the previous study. Patients who have 
received active vaccine for AD in the past will be excluded. 
23. Patient with a body mass index (BMI) above 35 or below 18. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 40/92 
 
 
 
24. Lifestyle exclusions: 
a) Patients unwilling to limit alcohol intake to less than 30 g of pure alcohol per day 
(see Appendix 1) and to abstain after 2000h throughout the study 
b) Patients unwilling to be exposed to at least 2 hours of daylight each day 
c) Divergence from the accepted level of study medication compliance (70%-130% 
of expected consumption) as verified at Visit 2 (see Section 12.10) 
d) Patients consuming more than 7 cups of tea or coffee (or equivalent amount of 
caffeine [650 mg] in other caffeinated beverages) per day 
e) Patients with an irregular lifestyle or life pattern (eg, shift workers, patients likely 
to be jet lagged) 
25. Administrative exclusion 
a) Patient and/or caregiver unable to contact the investigator by phone in case of an 
emergency 
26. Patients with evidence of serious risk of suicide based on the Sheehan Suicidality 
Tracking Scale (Sheehan-STS); ie, a score of 3 or 4 question 2 or 13 and a score of 2 or 
higher on questions 1a, 3 through 12 and 14, or who, in the opinion of the investigator, 
present a serious risk of suicide. 
11.1.4 Patient Eligibility Review 
One of the keys to study success is validation of appropriate patient selection. Clinical review for 
patient eligibility and appropriate symptom severity level confirmation can enhance the subject 
selection process and optimize clinical trial outcomes. The mere presence of surveillance 
improves the integrity of subject selection given that sites are aware that a site-independent body 
is monitoring subject eligibility data. 
For patients found eligible by the sites, records of the MMSE, CDR, and documentation of 
cognitive decline complaint over at least 6 months by patient will be reviewed. The results of the 
ADAS-cog14 administered as a practice session during Screening will be reviewed as well. The 
ADAS-cog11 portion of the ADAS-cog14 will be part of the eligibility approval only in cases 
where the MMSE score is 27. MMSE, CDR, and ADAS review will also include audio capture 
and review of the interviews. 
These records will be reviewed by a team of independent certified clinicians who will approve 
eligibility. In cases where issues are identified, the investigator will be contacted to discuss 
patient eligibility on a peer-to-peer basis. The discussion will include the relevant data, the 
possible exclusionary finding, and any new data the investigator may have gathered. A decision 
to enroll a patient will be made by the investigator after consultation with the reviewing 
clinician. All communication regarding subject eligibility will be documented and filed. 
11.1.5 Removal of Patients from Therapy or Assessments 
Patients who fail to fulfill the enrollment criteria at the Visit 1 screening evaluation will be 
withdrawn from the study prior to receipt of any study medication. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 41/92 
 
 
 
Patients withdrawn from the study prior to randomization would be considered as “screen 
failure.” 
Patients withdrawn from the study after randomization would be considered as “drop-out.” 
Patients may withdraw their consent at any time during the study or may be withdrawn by the 
investigator at any time. Neurim Pharmaceuticals (1991) Ltd reserves the right to withdraw 
patients from the study on the grounds that a serious protocol violation has occurred. In case of 
dispute, the principal investigator’s opinion will prevail. 
The date and reason for withdrawal as well as the data collected up to that time should be 
recorded in the electronic case report form (eCRF). 
Patients who withdraw from the study after receiving any study medication will be required to 
return to the study site for a Premature Discontinuation Visit for safety assessments to be 
performed. Once a patient has been withdrawn, he/she may not re-enter the study, and the 
medication that was designated for this patient cannot be given to any other patient. 
11.2 
TIMINGS THROUGHOUT THE STUDY 
11.2.1 Overall Study Schedule 
It is intended to have an 18-month recruitment period. Each patient will undergo a 2-week, 
single-blind, run-in period and a 26-week, randomized, double-blind treatment period, for a total 
of 28 weeks. Two weeks after last dosing of study medication, the caregiver will receive a 
follow-up phone call. The duration of the study is expected to be approximately 40 months from 
first patient screened to final patient completing the randomized treatment. 
An integrated clinical study report in the format of the International Conference on 
Harmonisation Tripartite Guideline E3: Structure and Content of Clinical Study Reports 
(ICH E3) will be written within 3 months of the last patient completing the study. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 42/92 
 
 
 
12. 
TREATMENTS 
12.1 
TREATMENTS ADMINISTERED 
Throughout the study, all study medication is to be administered orally, 1 tablet daily, taken 
before going to bed, preferably between 2100h and 2300h, and after food consumption. 
Upon completion of the 2-week, single-blind run-in period, patients will be randomly assigned in 
a 1.2:1:1:1 ratio to placebo (1.2) or to 1 of 3 active treatment arms (1:1:1) as follows: 
Active Medication 
Piromelatine 5, 20, or 50 mg tablets 
Placebo Medication 
Matched placebo tablets, with identical features to the piromelatine tablets, will be used as 
control treatment 
At the end of the study, each investigator will forward all unused medication packs together with 
any study medication that has not been allocated to the clinical supply vendor for destruction. 
Piromelatine tablets are pink and oval shaped. Tablets will be packaged in polyethylene 
terephthalate bottles containing 35 tablets. Patients will receive sufficient medication at the 
randomization visit (Visit 2) to provide enough tablets for the period of treatment between visits 
to allow for loss of tablets and for arrival at the scheduled visit up to 3 days after the scheduled 
date. For the period between Visit 2 (randomization) and Visit 3 (Week 4), each patient will 
receive 1 bottle with 35 tablets. For the period between Visit 3 (Week 4) and Visit 4 (Week 13), 
each patient will receive 2 bottles containing 35 tablets each (total of 70 tablets). For the period 
between Visit 4 (Week 13) and Visit 5 (Week 26), each patient will receive 3 bottles containing 
35 tablets each (total of 105 tablets). 
12.2 
IDENTITY OF INVESTIGATIONAL PRODUCTS 
12.2.1 Piromelatine 
Generic name:  
piromelatine 
Chemical name: 
(N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2- 
carboxamide) 
Formulation:  
Microcrystalline cellulose 
Starch 
Colloidal silicon dioxide 
Magnesium stearate 
Opadry II 85F140041 Pink 
The microcrystalline cellulose serves as a filler, starch is used as a binder, colloidal silicon 
dioxide is used as glidant, magnesium stearate serves as a lubricant, and pink Opadry II serves 
for film coating. 
The study medication will be securely stored in the medical center's local pharmacy or in the 
investigator's office, separate from other drugs. It should not be exposed to sources of heat and is 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 43/92 
 
 
 
to be kept at room temperature (15°C-25°C, or 59°F-77°F). The study medication may not be 
used for any purpose other than the present study; the insurance coverage shall otherwise become 
null and void. 
12.2.2 Placebo 
The placebo is of identical appearance and formulation to the active piromelatine tablet but 
contains no active piromelatine. 
12.2.3 Labelling Information 
The study medication bottles will be labeled according to US Food and Drug Administration 
(FDA) requirements. The labeling on all bottles of study medication will include the following: 
name of sponsor, pharmaceutical dosage form, route of administration, quantity of dosage units, 
batch numbers, bottle number, study number, patient ID number, directions for use, “for clinical 
trial use only”, investigator name, storage method, the statement “keep out of reach of children,” 
and “Caution: New Drug – Limited by Federal Law (US) to investigational use.” 
12.3 
SELECTION OF DOSE IN THE STUDY 
The choice of doses (5, 20, and 50 mg) to be orally administered in AD patients is defined 
according to the following clinical data. 
In a Phase 1 study in healthy volunteers, piromelatine (2, 5, 20, 50, and 200 mg) was found to be 
safe and well tolerated with no SAEs and showed a favorable, dose-proportional PK profile 
following oral intake. In addition, piromelatine intake was associated with increase in total sleep 
time in the volunteers in a dose-dependent manner (Yalkinoglu et al., 2010). In a Phase 1b 
multiple ascending dose study in insomnia patients, piromelatine (2, 5, 20, and 50 mg) had a 
favorable PK profile without any sign of accumulation. This study also showed that piromelatine 
had some beneficial effects on sleep continuity measures and did not have an adverse effect on 
memory (Laudon et al., 2012). In a Phase 2, randomized, placebo-controlled, sleep laboratory 
study in insomnia patients (aged 18-80 years), piromelatine (20 and 50 mg daily for 1 month) 
enhanced sleep maintenance (WASO) measured by PSG significantly in comparison to placebo 
(Neurim press release, 2013). Piromelatine enhanced NREM ∆ power (deep sleep) and decreased 
NREM β power, a fast EEG activity that is considered to be related to the hyperarousal state 
experienced by insomniac patients (Merica et al., 1998). Both effects may be beneficial for AD 
patients to enhance Aβ clearance from the brain. 
12.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
Commencing at Visit 1, all patients will be assigned an identification number. This identification 
number and the patient’s 3 initials must appear on all patient-related documents submitted to 
Neurim Pharmaceuticals. When qualified for enrollment at Visit 2, the patient will be randomly 
assigned to 1 of 4 trial arms. 
12.5 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT 
Upon completion of eligibility review, the caregiver will be instructed via telephone call to begin 
administration of study medication. The patient will take the first dose of placebo that evening. 
After 2 weeks of single-blind placebo run-in, the patient will be randomly assigned to receive 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 44/92 
 
 
 
either piromelatine (5, 20, or 50 mg) or placebo. The patient will take the first dose of 
piromelatine/placebo in the evening of Visit 2. The dose of medication will be 1 tablet daily in 
the evening after meals, before going to bed, preferably between 2100h and 2300h. 
12.6 
DOSE ADJUSTMENT CRITERIA 
The dose will not change throughout the 26-week randomized double-blind treatment period. 
12.7 
BLINDING 
The initial 2-week run-in period of this study is designed as single blind, with the patient blinded 
to the medication he/she is receiving. All patients will receive placebo during the run-in period. 
The run-in will be followed by 26 weeks of double-blind treatment, where the investigators, 
staff, and patients will be unaware of the allocated treatment. 
The blinding will not be broken (unless in an emergency) until all completed eCRFs have been 
received by data management and the database is locked. 
In case of an emergency, the investigator may access patient treatment assignment through the 
interactive web response system (IWRS). This will be done only when the investigator decides 
that knowledge of the treatment arm is required. Except in emergency cases, treatment 
assignment should not be accessed without discussion with the sponsor's safety officer. The date 
and reasons for accessing treatment assignment must be fully documented, and a statement that 
the correct procedure was followed should be documented in the trial master file. 
12.8 
GENETIC TESTING FOR APOE4 STATUS 
Genetic testing for apolipoprotein E (APOE4) status is voluntary. Retrospective genetic 
information could be used. Patients requiring a blood test for APOE4 status must sign a separate 
ICF. The test should be performed during the patient’s last visit. 
12.9 
PRIOR AND CONCOMITANT THERAPY 
Patients receiving acetylcholinesterase inhibitors for the treatment of AD must have been taking 
the medication for at least 6 months before Baseline (Visit 2), the daily dose must have remained 
unchanged for 4 months prior to Baseline, and the dose must not be expected to change during 
study participation. 
Patients who stopped receiving acetylcholinesterase inhibitors before enrollment must be stable 
off acetylcholinesterase inhibitors for 6 months before Baseline and must be agreeable to not 
restarting throughout the study. 
Patients not receiving acetylcholinesterase inhibitors must be agreeable to not starting it 
throughout the study. 
Patients taking memantine (with or without acetylcholinesterase inhibitors) must be on a stable 
dose for at least 3 months before Baseline and plan to continue throughout the study. 
Patients taking antidepressants should be on a stable dose for at least 3 months before the 
Screening visit (Visit 1) and throughout the study. 
The following medications are not allowed during the study or during the 5 weeks before the 
Screening visit (Visit 1): 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 45/92 
 
 
 
 
Fluvoxamine 
 
Mirtazapine 
 
Trazodone 
 
Insulin  
A full list of prohibited medication is listed in Section 24, APPENDIX 2 “PROHIBITED 
AND RESTRICTED MEDICATIONS.” 
Patients 
taking 
alternative 
pharmacotherapy 
for 
dementia 
(eg, 
Souvenaid, 
DHA 
[docosahexaenoic acid], phosphatidylserine, omega-3 fatty acids, ginkgo biloba, ginseng, 
Huperzia serrata, vitamin B, vitamin D, vitamin E, or any other supplement to improve cognitive 
function) should be on a stable dose for at least 3 months before the Screening visit (Visit 1). 
Other necessary and permitted concomitant treatment should not be altered if it has been 
established and equilibrated for at least 4 weeks prior to study enrollment, unless the 
investigator(s) consider(s) that a change is necessary. This should first be discussed with the 
sponsor's safety officer who will assess whether the patient is to be withdrawn. 
Continuous use of sedative-hypnotics or treatments used as a hypnotic (eg, all benzodiazepines, 
zopiclone, zolpidem and zaleplon, barbiturates, buspirone and hydroxyzine, melatonin or 
melatonin agonists [ramelteon]) is not allowed during the study or during the 2 weeks before the 
Screening visit (Visit 1). 
12.9.1 Rescue Medication 
Intermittent use of short to medium-acting benzodiazepines, melatonin (up to 3 mg), ramelteon 
(up to 8 mg), eszopiclone (up to 2 mg), zaleplon (up to 5 mg) or zolpidem tartrate (≤ 6.25 mg 
controlled release and ≤ 10 mg tablet) is allowed when absolutely necessary for intermittent 
sleep disturbances. Intermittent use is defined as no more than 2 times a week. However, these 
medications cannot be used within 3 days of any study visit. 
12.10 TREATMENT COMPLIANCE 
Treatment compliance will be calculated at each study visit by the investigator counting returned 
tablets and using the formula: 
Compliance (%) = 
number of tablets actually taken 
 100 
 
number of days since last visit 
Compliance between Visit 1 and Visit 2 should be calculated using number of days since start of 
run-in. 
Any divergence from the accepted level of compliance (70%-130% of expected consumption) is 
to be investigated by the investigator and should lead to withdrawal of the patient from the study. 
Treatment compliance will be recorded in the eCRF by the investigator. 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 46/92 
 
 
 
13. 
ASSESSMENTS 
The table in Section 10.1 presents the assessments that are planned to be conducted throughout the 
study. 
Prescreening (telephone call) 
Investigators should clarify to potential patients the requirements of concomitant medications as 
specified in Section 12.9. 
Visit 1 - Screening (Day –25 to -14) 
 Explanation of the study 
 Patient and caregiver will both be given an ICF to read and sign. Legally authorized 
representatives will not be allowed in this protocol unless the ICF has been signed by 
them in addition to the patient as dictated by legal circumstances. 
 Allocation of screening number 
 Eligibility screening: 
1. MMSE completed by the investigator or investigator designee with the patient 
2. CDR completed by the investigator or investigator designee with the patient and 
caregiver 
3. Recording of demographic data (date of birth, sex, tobacco and alcohol use, 
substance abuse) 
4. Detailed medical and surgical history 
5. Physical examination and vital signs measurements, including 12-lead ECG 
6. Examination of CT/MRI scans 
7. Examination of positron emission tomography (PET)/CSF data (for patients who 
have this information) 
8. Inclusion and exclusion criteria 
 Collection of blood and urine samples for urinalysis, hematology, biochemistry, and 
hormonal tests 
 Urine drug screen for benzodiazepines and opiates 
 Recording of concomitant medication(s) 
 Sheehan-STS 
 Practice session with cNTB 
 Practice session with ADAS-cog14 (score of ≥ 12 in the ADAS-cog11 portion of the 
scale is required and should recorded if MMSE score is 27) 
 Practice session with executive function measurements (COWAT, CFT) 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 47/92 
 
 
 
 Uploading MMSE, CDR, ADAS-cog, and documented history of cognitive deterioration 
for central review 
 Dispensing of study medication (placebo) – caregiver will be instructed via telephone 
call to open the bottle and start the run-in period upon confirmation of eligibility. The 
patient will be asked to bring all medication packs, including empty packs, with him/her 
to Visit 2. 
Visit 1 may be completed over 2 consecutive days (no Friday/Monday visits) at the discretion of 
the investigator. Both the patient and caregiver must be present both days, and the following 
screening procedures should be completed on the indicated day: 
 Screening Day 1: MMSE, ADAS-cog, cNTB 
 Screening Day 2: COWAT/CFT, CDR, Sheehan-STS 
Post Visit 1 (–14) - This time point becomes Day –14 regardless of the time it took to reach it 
Upon completion of eligibility review, the caregiver will be instructed via telephone call to open 
the bottle and start the run-in period. Should eligibility review and/or laboratory results show that 
a patient can no longer be considered eligible, the unopened run-in bottle will be collected from 
the patient. Ineligible patients who accidently open run-in bottles and consume run-in placebo 
tablets will be invited to a premature discontinuation visit (see below). 
Visit 2 - Baseline (Day 0  3 days [from the end of run-in]) 
 Vital signs measurements 
 Verification of relevant inclusion/exclusion criteria (see Section 11.1.2 and 
Section 11.1.3) 
 Recording of concomitant medication(s) 
 Recording of adverse events (AEs) (see Section 13.3.2) 
 Review of Visit 1 clinical laboratory results 
 Compliance verification 
 Allocation of randomization number 
 Collection of all unused study medication and used bottles since last visit 
 cNTB (ISLT immediate and delayed recall, OCL, identification, detection, OBK) 
completed by the patient WITH the investigator or investigator designee 
 CGIC completed by an investigator designee (should not be completed by the principal 
investigator) with the patient and caregiver; the CGIC assessor must be blinded to all 
other data for the patient after Visit 2 
 ADCS-MCI-ADL completed by the investigator or investigator designee with the 
caregiver 
 ADAS-cog14 completed by the investigator or investigator designee with the patient 
 Executive function measurements (COWAT, CFT) completed by the investigator or 
investigator designee with the patient 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 48/92 
 
 
 
 NPI completed by the investigator or investigator designee with the caregiver 
 Patient PSQI completed by the investigator or investigator designee with the patient and 
caregiver 
 Dispensing of study medication 
 The patient will be asked to bring all medication packs, including empty packs, with 
him/her to Visit 3. 
Pre-Visit 3 
On Days 7 ± 3, 14 ± 3, and 21 ± 3, the caregiver will be called by study personnel for follow-up 
and for safety and compliance verification purposes (eg, study medication compliance, daylight 
exposure compliance, and AE/concomitant medication checks). 
Visit 3 - Week 4 (Day 28  3 days) 
 Vital signs measurements 
 Recording of concomitant medication(s) 
 Recording of AEs 
 Compliance verification 
 cNTB (ISLT immediate and delayed recall, OCL, identification, detection, OBK) 
completed by the patient WITH the investigator or investigator designee 
 Executive function measurements (COWAT, CFT) completed by the investigator or 
investigator designee with the patient 
 Patient PSQI completed by the investigator or investigator designee with the patient and 
caregiver 
 Collection of all unused study medication and used bottles since last visit 
 Dispensing of study medication 
 The patient will be asked to bring all medication packs, including empty packs, with 
him/her to Visit 4 
Pre-Visit 4 
On Days 35 ± 3, 42 ± 3, 49 ± 3, 56 ± 3, 63 ± 3, 70 ± 3, 77 ± 3, and 84 ± 3, the caregiver will be 
called by study personnel for follow-up and for safety and compliance verification purposes (eg, 
study medication compliance, daylight exposure compliance, and AE/concomitant medication 
checks). 
Visit 4 - Week 13 (Day 91  5 days) 
 Physical examination and vital signs measurements, including 12-lead ECG 
 Recording of concomitant medication(s) 
 Recording of AEs (see Section 13.3.2) 
 Collection of blood and urine samples for urinalysis, hematology and biochemistry tests 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 49/92 
 
 
 
 Urine drug screen for benzodiazepines and opiates (to be repeated randomly in some 
patients during the study) 
 Sheehan-STS 
 Compliance verification 
 cNTB (ISLT immediate and delayed recall, OCL, identification, detection, OBK) 
completed by the patient WITH the investigator or investigator designee 
 ADAS-cog14 completed by the investigator or investigator designee with the patient 
 CGIC completed by an investigator designee (should not be completed by the principal 
investigator) with the patient and caregiver; the CGIC assessor must be blinded to all 
other data for the patient after Visit 2 
 ADCS-MCI-ADL completed by the investigator or investigator designee with the 
caregiver 
 Executive function measurements (COWAT, CFT) completed by the investigator or 
investigator designee with the patient 
 Patient PSQI completed by the investigator or investigator designee with the patient and 
caregiver 
 Collection of all unused study medication and used bottles since last visit 
 Dispensing of study medication 
 The patient will be asked to bring all medication packs, including empty packs, with 
him/her to Visit 5 
Pre-Visit 5 
On Days 98 ± 5, 105 ± 5, 112 ± 5, 119 ± 5, 126 ± 5, 133 ± 5, 140 ± 5, 147 ± 5, 154 ± 5, 161 ± 5, 
168 ± 5, and 175 ± 5 the caregiver will be called by study personnel for follow-up and for safety 
and compliance verification purposes (eg, study medication compliance, daylight exposure 
compliance, and AE/concomitant medication checks). 
Visit 5 – Week 26 (Day 182  5 days) 
 Physical examination and vital signs measurements, including 12-lead ECG 
 Recording of concomitant medication(s) 
 Recording of AEs (see Section 13.3.2) 
 Collection of blood and urine samples for urinalysis, hematology, biochemistry, and 
hormonal tests 
 Collection of blood samples for ApoE4 genotyping (for those patients who agree to sign 
separate ICF for genetic testing) 
 Body weight measurement 
 Sheehan-STS 
 Compliance verification 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 50/92 
 
 
 
 cNTB (ISLT immediate and delayed recall, OCL, identification, detection, OBK) 
completed by the patient WITH the investigator or investigator designee 
 MMSE completed by the investigator or investigator designee with the patient 
 CGIC completed by investigator designee (should not be completed by the principal 
investigator) with the patient and caregiver; the CGIC assessor must be blinded to all 
other data for the patient after Visit 2 
 ADCS-MCI-ADL completed by the investigator or investigator designee with the 
caregiver 
 ADAS-cog14 completed by the investigator or investigator designee with the patient 
 Executive function measurements (COWAT, CFT) completed by the investigator or 
investigator designee with the patient 
 NPI completed by the investigator or investigator designee with the caregiver 
 Patient PSQI completed by the investigator or investigator designee with the patient and 
caregiver 
 Collection of all unused study medication and used bottles since last visit 
 
Order of scale administration 
For each study visit, it is recommended that the scales be conducted in the following order. 
Patient: 
Visit 1: MMSE, ADAS-cog, cNTB, COWAT/CFT, CDR, Sheehan-STS 
Visit 2: cNTB (×2), ADAS-cog, COWAT/CFT, CGIC, PSQI 
Visit 3: cNTB, COWAT/CFT, PSQI 
Visit 4: cNTB, ADAS-cog, COWAT/CFT, CGIC, PSQI, Sheehan-STS 
Visit 5: cNTB, ADAS-cog, COWAT/CFT, CGIC, MMSE, PSQI, Sheehan-STS 
Caregiver: 
Visit 1: CDR 
Visit 2: CGIC, ADCS-ADL, PSQI (with patient), NPI 
Visit 3: PSQI (with patient) 
Visit 4: CGIC, ADCS-ADL, PSQI (with patient) 
Visit 5: CGIC, ADCS-ADL, PSQI (with patient) NPI 
 
IMPORTANT NOTE: The investigator or investigator designee must be present 
throughout the entire session to assist the patient in completing all of the computerized 
NTB subtests (ISLT immediate and delayed recall, OCL, identification, detection, OBK). 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 51/92 
 
 
 
Investigator or investigator designee will have to confirm by signing that he/she was 
present throughout the entire session. 
*Please note that only raters with a “Qualified” status (in the Site Status Memo that each 
site receive occasionally from Bracket) are permitted to rate the associated scales including 
the Clinical History form in the study. 
 
Safety Follow-up 
Two weeks after the last dose of study medication, a telephone call will be made to the caregiver 
to elicit any safety concerns for the purpose of recording AEs. 
Premature Discontinuation Visit 
The investigator will order the patient a laboratory test request (hematology, biochemistry and 
urinalysis), the results of which should be recorded by the investigator when they become 
available. This visit also includes: 
 Collection of all unused study medication and used bottles since last visit 
 Physical examination and vital signs measurements, including 12-lead ECG 
 Collection of blood and urine samples for urinalysis, hematology, biochemistry, and 
hormonal tests 
 Recording of concomitant medication(s) 
 Recording of AEs 
 Sheehan-STS 
Premature Discontinuation Visit prior to Randomization 
Ineligible patients who accidently open run-in bottles and consume run-in placebo tablets will be 
invited to a premature discontinuation visit, which will include: 
 Collection of accidentally used run-in bottle 
 Physical examination and vital signs measurements 
 Recording of AEs 
13.1 
CLINICAL EFFICACY PARAMETERS 
13.1.1 Primary Efficacy Parameter 
The primary efficacy parameter is the cNTB (global composite of 5 test scores): 
1. Visual recognition learning task (OCL): The OCL task is a continuous visual recognition 
learning task that assesses visual learning within a pattern separation model. Theoretical 
models of the pattern separation model specify that information is organized in 
orthogonal and distinct nonoverlapping representations so that new memories can be 
stored rapidly without interference. The OCL has been shown to be a valid test of 
learning and memory in MCI and AD. In this task, the patient must attend to the card in 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 52/92 
 
 
 
the center of the screen and respond to the question, “Have you seen this card before in 
this task?” If the answer is yes, patients are instructed to press the “YES” button, and the 
“NO” button if the answer is no. Normal playing cards are displayed (without joker 
cards). In this task, 4 cards are drawn at random from the deck and are repeated 
throughout the task. These 4 cards are interspersed with distractors (nonrepeating cards). 
The task ends after 80 trials, without rescheduling for postanticipatory correct trials. The 
primary performance measure for this task is the proportion of correct answers 
(accuracy), which is normalized using an arcsine square root transformation. 
2. Verbal Learning Task (ISLT – immediate and delayed): The ISLT is a 
computer-controlled verbal learning test. In this test, patients are read a list of 12 words. 
Each word is a concrete noun and describes an item of food that is found commonly in 
the culture/society in which testing is occurring. The examiner asks the patient “I am 
going to read to you a list of items I want you to get from the 
supermarket/store/market/shop etc.” After the 12 words have been read, the patient is 
asked to recall as many of the words as he/she can. If he/she can recall no more words, 
the same list is read a second time with the words in the same order after the same 
instruction. The process of reading the list and waiting for responses occurs 3 times. At 
the completion of the computerized battery, the patient is asked to recall as many of the 
items as he/she can from the shopping list. This provides a measure of delayed recall. 
The primary performance measure for this task is the total number of correct words 
recalled. 
3. Detection task: The Cogstate Detection task is a measure of simple reaction time and has 
been shown to provide a valid assessment of psychomotor function in healthy adults and 
in adults with MCI and AD. For this test, the patient must press a “YES” response key as 
soon as he/she detects an event (ie, a card turning face up presented in the center of the 
computer screen). The software measures the response time to detect each event. 
4. Identification task: The Cogstate Identification task is a measure of choice reaction time 
and has been shown to provide a valid assessment of visual attention in MCI and AD. In 
this task an event (a card turning face up) occurs in the center of the computer screen and 
the patient must decide “YES” or “NO” as to whether this event meets a predefined and 
unchanging criterion (eg, is the color of the card red?). The software measures the speed 
and accuracy of each response. 
5. Computerized One Back Working Memory task (OBK): The Cogstate One Back 
memory task is a valid measure of working memory in MCI and AD. On this task the 
patient is shown a single stimulus in the center of the computer screen (a card turns face 
up). The patient must decide “YES” or “NO” as to whether the current card matches the 
card that had been seen on the immediately previous trial. The software measures the 
speed and accuracy of each response. 
13.1.2 Secondary Efficacy Parameters 
CGIC 
The ADCS-CGIC is a systematic method for assessing clinically significant change in a clinical 
trial as viewed by an independent skilled and experienced clinician. The ADCS-CGIC focuses on 
clinicians' observations of change in the patient's cognitive, functional, and behavioral 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 53/92 
 
 
 
performance since the beginning of a trial. It relies on both direct examination of the patient and 
interview of informants. Unlike a targeted symptom scale, it takes into account a patient's overall 
function in the cognitive, behavioral, and functional activity domains. Scoring is based on an 
interview with the caregiver and examination of the patient by an independent evaluator, without 
consulting other information such as cognitive test results. The ADCS-CGIC requires the 
assessor to consider a number of cognitive, functional, and behavioral areas prior to providing an 
overall "global" assessment of clinical change (Schneider et al., 1997; Schneider et al., 2006). 
The ADCS-CGIC assessor must be blinded to all other data for the patient after Visit 2. 
Daily living activity (ADCS-MCI-ADL) 
The ADCS-MCI-ADL is one out of several available measurements of the Activities of Daily 
Living (ADL) in the targeted study population (Gold, 2012), and it is based on the work of the 
ADCS operating in the US (Galasko et al., 2006). The ADCS-MCI-ADL is an 18-item 
interview–based assessment (questions 19-24 are not to be completed), and its ratings will be 
based on an interview of the patient’s best (closest) informant by a rater from the clinic. Scale 
administration duration will be about 15-30 minutes. 
ADAS-cog14 
The ADAS was designed to measure the severity of the most important symptoms of AD. Its 
subscale, ADAS-cog, is the most popular cognitive testing instrument used in clinical trials. It 
consists of 11 tasks measuring the disturbances of memory, language, praxis, attention, and other 
cognitive abilities that are often referred to as the core symptoms of AD. The test comprises 
11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe 
impairment. A negative change indicates an improvement from baseline. The addition of delayed 
recall, number cancelation, and maze tasks – and thus turning ADAS-cog into a 12-, 13-, and 
14-item scale respectively – has increased the ability to detect changes in patients in the early 
stages of the disease (Sano et al., 2011). 
Global Composite Score of the cNTB (composite of 5 test scores) 
The global composite score of the cNTB is a composite score of the ISLT (immediate and 
delayed recall), OCL, Identification, Detection, and OBK tests. For more details on the 
individual tests, please refer to Section 13.1.1. 
Episodic Memory Domain of the cNTB (composite of 2 test scores) 
The episodic memory domain of the cNTB is a composite score of the ISLT (immediate and 
delayed recall) and OCL tests. 
Attention Domain of the cNTB (composite of 2 test scores) 
The attention domain of the cNTB is a composite score of the Identification and Detection tests. 
Executive Function Domain (composite of 3 test scores) 
1. Computerized One Back Working Memory task (OBK) 
2. Category Fluency Test (CFT): In this task, the patient is given a category and is 
instructed to provide as many items as he/she can that belong to this category in 
60 seconds. The score on this test is the total number of correct words provided for each 
category. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 54/92 
 
 
 
3. Controlled Oral Words Association Test (COWAT): The COWAT is a cognitive test of 
verbal processing ability used to assess brain impairment. Verbal processing ability and 
verbal fluency are considered executive functions. The emphasis on these tests focuses 
on the degree of discrepancy (as opposed to consistency) between current functioning 
and an estimated pre-impairment functioning. The COWAT assesses the patient’s ability 
to spontaneously produce words that begin with specific letters within a certain time 
limit. In particular, the test uses the letters F, A, and S. 
13.1.3 Exploratory Efficacy Parameters 
MMSE 
The MMSE is a brief assessment instrument used to assess cognitive function in elderly patients. 
The MMSE can be used to screen for cognitive impairment and as a measurement of cognition 
over time and with pharmacologic treatment. The instrument is divided into 2 sections. The first 
section measures orientation, memory, and attention: the maximum score is 21. The second 
section tests the ability of the patient to name objects, follow verbal and written commands, write 
a sentence, and copy figures: the maximum score is 9. The scoring range for the MMSE is 0-30. 
The MMSE was shown to be both reliable and valid in a group of elderly subjects, including 
those with dementia, depression with cognitive impairment, depression, and “normal” elderly 
patients. The MMSE has been shown to possess sensitivity and specificity in various 
populations. Although the MMSE alone is unable to provide diagnostic information, the data on 
its sensitivity and specificity in cognitively impaired patients demonstrates its utility as a 
screening instrument. 
cNTB – Individual Scores 
The individual scores of the cNTB include ISLT (immediate and delayed recall), OCL, 
Identification, Detection, and OBK. 
NPI 
The scale consists of 12 domains that are rated for both frequency (range 1-4) and severity 
(range 1-3). A composite score for each domain is calculated (frequency × severity), which 
ranges from 1 to 12. There is a leading question for each item. If the symptom is not present then 
the frequency, severity, and distress scores are not completed. In this case, the score is 0 for the 
item. The sum of the composite scores yields the NPI-12 total score (range 0-144). A negative 
change in score indicates an improvement from baseline (symptom reduction) (Cummings et al., 
1994). 
PSQI 
The PSQI is an effective instrument used to measure the quality and patterns of sleep in the older 
adult. It differentiates “poor” from “good” sleep by measuring 7 areas: subjective sleep quality, 
sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medication, and daytime dysfunction over the last month. The investigator with the patient and 
caregiver rate each of these 7 areas of sleep. In cases of discrepancies, the caregiver answers 
prevail. Scoring of answers is based on a 0 to 3 scale, whereby a score of 3 reflects the negative 
extreme on the Likert Scale. A global sum of 5 or greater indicates a “poor” sleeper (Buysse et 
al., 1989). 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 55/92 
 
 
 
ADAS-cog13, ADAS-cog12, and ADAS-cog11 
The ADAS was designed to measure the severity of the most important symptoms of AD. Its 
subscale, ADAS-cog, is the most popular cognitive testing instrument used in clinical trials. It 
consists of 11 tasks measuring the disturbances of memory, language, praxis, attention, and other 
cognitive abilities that are often referred to as the core symptoms of AD. The test comprises 
11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe 
impairment. A negative change indicates an improvement from baseline. The addition of delayed 
recall, number cancelation, and maze tasks – and thus turning ADAS-cog into a 12-, 13-, and 
14-item scale respectively – has increased the ability to detect changes in patients in the early 
stages of the disease (Sano et al., 2011). 
Sheehan Suicidality Tracking Scale 
The Sheehan-STS is a prospective rating scale that tracks both treatment-emergent suicidal 
ideation and behaviors. The Sheehan-STS is a 22-item scale that can be administered by either a 
clinician or patient through self-report. 
13.2 
APPROPRIATENESS AND CONSISTENCY OF MEASUREMENTS 
These efficacy measurements have been used in other studies in elderly patients and AD patients. 
13.3 
CLINICAL SAFETY PARAMETERS 
The safety parameters assessed at each visit will include spontaneously reported AEs or SAEs, 
vital signs measurements (heart rate and blood pressure), physical examination, body weight, and 
clinical laboratory tests (hematology, biochemistry, and urinalysis). A 12-lead ECG will be 
performed at Visit 1 (Screening), Visit 4 (Week 13), and Visit 5 (Week 26; end-of-study visit). 
The Sheehan-STS will also be rated at Visit 1 (Screening), Visit 4 (Week 13), and Visit 5 (Week 
26; end-of-study visit). 
13.3.1 Routine Laboratory Procedures 
All blood and urine samples will be analyzed using a central laboratory. An operating manual 
specifying all the steps for the urine and blood sampling will be given to the person in charge of 
the sampling. 
The sampling will be performed at the site at Visits 1 (Screening), 4, and 5 and as soon as 
possible following the Premature Discontinuation Visit (if applicable). 
The following parameters will be measured for hematology: hemoglobin, hematocrit, red blood 
cells, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin 
concentration, white blood cells, lymphocytes, monocytes, neutrophils, eosinophils, basophils, 
and platelets. 
The following parameters will be measured for biochemistry: creatinine, uric acid, urea, AST, 
ALT, albumin, GGT, total protein, sodium, potassium, chloride, calcium, phosphorus, glucose, 
alkaline phosphatase, and total bilirubin. 
Prolactin and testosterone levels will be measured from blood samples collected at Visits 1 and 
5. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 56/92 
 
 
 
13.3.2 Adverse Events 
The recording of AEs is an important aspect of study documentation. Detailed guidelines are set 
out below. 
Eliciting and Documenting Adverse Events 
It is the responsibility of the investigator to document all AEs that occur during the study. An AE 
includes any noxious, pathological, or unintended change in anatomical, physiological, or 
metabolic functions as indicated by physical signs, symptoms, and/or laboratory changes, 
whether associated with the study medication and whether or not considered drug related. This 
includes an exacerbation of pre-existing conditions or events, intercurrent illnesses, drug 
interaction, or the significant worsening of the indication under investigation that is not recorded 
elsewhere in the eCRF under specific efficacy assessments. Anticipated day-to-day fluctuations 
of pre-existing conditions, including the disease under study, which do not represent a clinically 
significant exacerbation or worsening, need not be considered AEs. 
Patient entry into the study is defined as the time at which informed consent is obtained (this 
must be before any protocol-specific diagnostic procedures or interventions are performed). All 
AEs subsequent to Visit 1 must be reported regardless of whether or not they are considered drug 
related. 
Adverse events will be elicited by asking the patient a nonleading question, for example “Have 
you experienced or are you experiencing any new or changed symptoms since we last 
asked/since your last visit?.” Adverse events should be reported on the appropriate page of the 
eCRF. 
Assessment of Severity 
Each AE will be assigned a category as follows: 
Mild:  
 
The AE was not sufficiently intense to result in discontinuation of the drug. 
Symptomatic treatment may have been given. 
Moderate:  
The AE was sufficiently intense to result in discontinuation of the drug. 
Symptomatic treatment may have been given. 
Severe: 
 
Severe is more intense than moderate; moreover the AE interferes significantly 
with ability to do work or usual activity. 
If there is a change in severity of an AE, it must be recorded as a separate event. 
Assessment of Frequency 
Frequency should be assessed using the following categories: 
 unique 
 intermittent 
 continued 
Assessment of Outcome 
Outcome should be assessed using the following categories: 
 recovered 
 recovered with sequelae 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 57/92 
 
 
 
 not recovered 
 unknown 
Assessment of Causality 
Every effort should be made by the investigator to explain each AE and assess its relationship, if 
any, to study medication treatment. Causality should be assessed using the following categories: 
 not related 
 unlikely to be related 
 possibly related 
 probably related 
 definitely related 
Follow-up of Adverse Events 
All investigators should follow-up with patients on AEs until the event is resolved or until, in the 
opinion of the investigator, the event is stabilized or determined to be chronic. Details of AE 
resolution must be documented in the eCRF. 
13.3.3 Suicidal Ideation 
Suicidal ideation will be rated at Visit 1 (Screening), at Visit 4 (Week 13), and at Visit 5 
(Week 26; end-of-study visit) using the Sheehan-STS. At Screening, patients with evidence of 
serious risk of suicide based on the Sheehan-STS with a score of 3 or 4 on question 2 or 13 and a 
score of 2 or higher on questions 1a, 3 through 12, and 14 should be excluded from the study. 
During the study (at Visit 4), patients should be discontinued from the study if they score 3 or 4 
on any one question 2 through 8 or 13, or score 2 or higher on any one question 1a, 9 through 12, 
or 20, or if, in the opinion of the investigator, the patient present a serious risk of suicide. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 58/92 
 
 
 
14. 
SERIOUS ADVERSE EVENTS 
14.1 
DEFINITION OF A SERIOUS ADVERSE EVENT 
An SAE is any event that is: 
1. Fatal 
2. Life threatening 
An AE is life threatening if the patient was at immediate risk of death from the event as 
it occurred; ie, it does not include a reaction that might have caused death if it had 
occurred in a more serious form. 
3. Disabling or incapacitating 
An AE is incapacitating or disabling if it results in a substantial and/or permanent 
disruption of the patient’s ability to carry out normal life functions. 
4. Results in hospitalization or prolongs a hospital stay 
Complications occurring during hospitalization are AEs and are SAEs if they cause 
prolongation of the current hospitalization. Hospitalization for elective treatment of a 
pre-existing, nonworsening condition is not, however, considered an AE. The details of 
such hospitalizations must be recorded on the medical history/physical examination 
page of the eCRF. 
5. In addition, medical and scientific judgment is required to decide if prompt notification 
is required in other situations; ie, any event which the investigator regards as serious that 
did not strictly meet the criteria above but may have jeopardized the patient or required 
intervention to prevent one of the outcomes listed above, or which would suggest any 
significant hazard, contraindication, side effect, or precaution that may be associated 
with the use of the drug. 
14.2 
DEFINITION OF AN UNEXPECTED ADVERSE EVENT 
An unexpected AE is defined as any AE that is not expected, ie, one that has not been reported as 
expected in this protocol or in the investigator’s brochure, either from previous clinical or 
preclinical studies. 
14.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any SAE must be reported by the investigator if it occurs during the clinical study or within 
30 days of receiving the study medication, whether or not the SAE is related to the study 
medication. An SAE report consists of the SAE form, the AE form, and the concomitant 
medication form. A copy of these forms must be faxed within 24 hours following knowledge of 
the event by the investigator for the attention of the medical monitor at: 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 59/92 
 
 
 
Name: Enrique Comesaña, MD, MBA 
Title: Executive Medical Director 
Company: INC Research, LLC 
Email: enrique.comesana@incresearch.com 
Office: (737) 484-3304 
Mobile: (512) 367-0592 
Fax: (737) 209-7302 
 
INC Research will inform Neurim Pharmaceuticals of any deaths, life-threatening SAEs, or 
drug-related SAEs within 1 working day and within 2 working days for all other SAEs. The 
sponsor’s safety officer will inform the qualified person in pharmacovigilance of any suspected 
unexpected serious adverse reaction (SUSAR) within 24 hours of receipt. The safety officer will 
inform the qualified person in pharmacovigilance immediately of any developing safety concern. 
The investigator should not wait to receive additional information to fully document the event 
before notifying of an SAE, though additional information may be requested. Where applicable, 
information from relevant laboratory results, hospital case records, and autopsy reports should be 
obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the investigator at any 
time after cessation of study medication and linked by the investigator to this study, should be 
reported to the study monitor immediately. 
14.4 
MEDICAL ASSISTANCE 
If there is a need to discuss any medical issues concerning an SAE, then the medical monitor for 
the study can be contacted at: 
Name: Enrique Comesaña, MD, MBA 
Title: Executive Medical Director 
Company: INC Research, LLC 
Email: enrique.comesana@incresearch.com 
Office: (737) 484-3304 
Mobile: (512) 367-0592 
Fax: (737) 209-7302 
 
In addition, the sponsor's safety officer can be contacted at: 
Name: Tali Nir, DVM 
Title: VP, Clinical and Regulatory Affairs 
Company: Neurim Pharmaceuticals (1991) Ltd 
Mail: talin@neurim.com 
Tel: 972-3-7684902 
Fax: 972-3-6494568 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 60/92 
 
 
 
14.5 
REGULATORY RESPONSIBILITY 
INC Research, on behalf of Neurim Pharmaceuticals, has a responsibility to notify the regulatory 
authorities about the safety of a new drug and will also inform all participating investigators of 
serious and/or unexpected drug-related events associated with the use of this drug. Therefore, 
prompt notification of SAEs is required by the investigator so that reporting timelines can be 
met, and also to ensure ethical responsibilities towards the safety of other patients are met. The 
investigators must adhere to local requirements of the IRBs and independent ethics committees 
with regard to reporting these events locally. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 61/92 
 
 
 
15. 
STUDY TERMINATION CRITERIA 
Neurim Pharmaceuticals reserves the right to discontinue the study at any time. The reasons will 
be discussed with the investigators. A study site may also be discontinued by Neurim 
Pharmaceuticals for significant deviations from the protocol or due to insurmountable difficulties 
experienced in running the study at that center. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 62/92 
 
 
 
16. 
DATA COLLECTION AND ENTRY 
The study will be monitored at regular intervals during the enrollment and follow-up period. 
There will be a monitoring visit or telephone call approximately every 8 weeks. The frequency of 
monitoring visits will be determined by the rate of patient recruitment. 
The following will be reviewed at these visits: 
 Compliance with the protocol 
 Consent procedure 
 Source document verification (see below) 
 AE procedures 
 Storage and accountability of materials 
It is the responsibility of the investigator to maintain adequate and accurate eCRFs, which have 
been designed to record all observations and other data pertinent to the clinical investigation. All 
eCRFs should be completed in their entirety. 
The purpose of source document verification is to verify, so far as is possible, that the 
information in the eCRF reflects the data recorded in the patient’s medical notes (see Section 
21.2 for details). Source document verification will be performed with due regard for patient 
confidentiality and will be undertaken on an ongoing basis as part of the monitoring visits. Direct 
access to the source documents will be required. The monitor will make a direct comparison with 
data entered in the eCRFs. 
The investigator must permit the monitor, the sponsor’s internal auditors, and representatives 
from the regulatory authorities, IRB, and ethics committees to inspect all study-related 
documents and pertinent medical records for confirmation of data contained within the eCRFs. 
INC Research will be responsible for activities associated with the Statistical Analysis Plan and 
for data management of this study. This will include producing an eCRF and setting up a 
relevant database and data transfer mechanisms, along with appropriate validation of data and 
production of queries. 
Automated checks will be made against the data to ensure completeness and consistency. The 
database and check programs will be validated prior to implementation. Missing or inconsistent 
data will be queried in writing to the investigator for clarification. Subsequent modifications in 
the database will be documented. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 63/92 
 
 
 
17. 
STATISTICAL ANALYSIS 
Further details of the planned statistical analysis will be provided in the Statistical Analysis Plan. 
17.1 
DETERMINATION OF SAMPLE SIZE 
Eligible patients will be enrolled equally in a 1.2:1:1:1 randomization ratio to the 4 trial arms 
(placebo [1.2] and the equal piromelatine treatment arms 5 mg, 20 mg, and 50 mg [1:1:1]). 
Assuming an effect size between treatment dose and placebo of 0.35 over 26 weeks, a significant 
level (α) of 0.05, and power of 88%, a sample size of 143 patients for the placebo arm and 119 
for each of the 3 piromelatine arms is calculated. Assuming a 50% screen failure rate and 
allowing for 15% patient withdrawal, 1150 patients should be screened in order to randomly 
assign 575 patients, of whom it is expected 500 will complete the study. 
17.2 
POPULATIONS FOR ANALYSIS 
All patients randomized to treatment who have taken at least 1 dose of study medication will be 
included in the safety analysis set for the evaluation of safety. 
The evaluation of efficacy will be based on 2 analysis sets, the full analysis set and the 
per-protocol set. The full analysis set is the primary population and will include all patients in the 
safety analysis set who satisfy all entry criteria and who have efficacy data for the primary 
parameter recorded for baseline and at least 1 postbaseline period assessment. The per-protocol 
set will include all patients in the full analysis set who have no major protocol violations. 
17.3 
ANALYTICAL MEASURES 
Statistical testing will be one-tailed at the 5% level of significance. The justification for this 
follows. When conducting placebo-controlled trials, it is imperative that the study medication be 
demonstrated to be superior in efficacy to placebo, since equivalent or worse efficacy than 
placebo will preclude approvability. Consequently, a one-sided test for efficacy is required. The 
null hypothesis is that the drug is equal or worse than placebo. The alternative hypothesis is that 
the drug has greater efficacy than placebo. A Type I error occurs only when it is concluded that a 
study medication is effective when in fact it is not. This can occur in only one tail of the 
distribution of the treatment difference. 
17.3.1 Analysis of Demographics and Baseline Characteristics 
Demographic data (age, gender, BMI), education (years), duration of AD, severity of disease as 
expressed by MMSE score, and ApoE4 genotyping will be summarized by treatment group for 
the full analysis set using descriptive statistics. 
Prior medication, compliance, and medical and surgical history will be summarized by treatment 
group for the full analysis set using descriptive statistics. 
No formal statistical testing will be performed on these data. 
17.3.2  Analysis of Primary Efficacy Parameter 
The cNTB global composite score (ISLT immediate and delayed recall, OCL, identification, 
detection, and OBK) will be summarized at baseline and after 4, 13, and 26 weeks of 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 64/92 
 
 
 
double-blind treatment (actual and change from baseline) for each treatment group using 
descriptive statistics (n, mean, SD, median, minimum, and maximum). The primary efficacy 
analysis will be carried out using an analysis of covariance (ANCOVA) model with treatment 
and study site as the main effects and baseline cNTB global z-score as the covariate. To evaluate 
the effect of missing cNTB items, multiple imputations will be used for the calculation of cNTB 
composite scores in the case of 1 or 2 missing cNTB items. 
Secondary efficacy analyses will be carried out using a mixed-effects maximum likelihood 
repeated measures (MMRM) model utilizing all baseline and postbaseline data to assess any 
differences in treatment effects over time. The model shall include fixed effects of treatment, 
study site, visit, and treatment by visit interaction, with baseline score as a covariate, and a 
baseline by visit interaction. The global treatment effect estimates will be reported, with 95% 
confidence intervals and P values. 
17.3.3  Analysis of Secondary Efficacy Parameters 
The same aforementioned ANCOVA model will be used to analyze all secondary efficacy 
endpoints: CGIC, ADCS-MCI-ADL, ADAS-cog14, cNTB global composite score, cNTB 
episodic memory domain composite score (ISLT and OCL), cNTB attention domain composite 
score (identification and detection), and executive function composite score (OBK, COWAT and 
CFT). The MMRM model also will be used for the analysis of ADCS-MCI-ADL, cNTB various 
domains composite score (identification and detection) and executive function composite score. 
17.3.4  Analysis of Exploratory Efficacy Parameters 
The same aforementioned ANCOVA model will be used to analyze the exploratory efficacy 
endpoints: MMSE, individual cNTB scores, NPI, PSQI (global score and individual 
components), and ADAS-cog13, ADAS-cog12, and ADAS-cog11 scores. 
Additionally, the MMRM model will be used for the analysis of individual cNTB scores and the 
PSQI global and individual component scores. 
17.3.5 General Considerations 
For all ANCOVA and MMRM models, data collected from investigators who enrolled fewer 
than 3 patients in any 1 treatment group will be combined prior to analysis. If this combination 
still results in a treatment group having fewer than 3 patients in any 1 treatment group, then this 
group of patients will be combined with the next fewest-enrolling investigator. In the event that 
there is a tie for fewest-enrolling investigator, one of these will be chosen at random by a 
random-number generator. 
The inherent assumption of normally distributed data will be evaluated by generating output for 
the residuals from the full ANCOVA and MMRM models, which include the interaction term, 
and by testing for normality using the Shapiro-Wilk test. In the event that the data are 
predominantly non-normally distributed, analyses will also be conducted on the ranked data. 
This rank transformation will be applied by ranking all the data for a particular variable, across 
all investigators and treatments, from lowest to highest. Integer ranks will be assigned starting at 
1; mean ranks will be assigned when ties occur. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 65/92 
 
 
 
17.3.6 Analysis of Safety 
Descriptive statistics will be provided for AEs, change in physical examination parameters, and 
vital signs. The number of patients taking concomitant medications during the 28-week treatment 
period (2-week single-blind, placebo run-in period followed by 26-week double-blind, treatment 
period) will be summarized by WHO drug classification code for each treatment group. The 
number of patients withdrawing during the treatment periods will be summarized by primary 
reason for withdrawal for each treatment group. 
The number of patients reporting AEs will be summarized during the 28-week treatment period 
by body system and preferred term for each treatment group. 
The change in laboratory parameters from baseline (end of the first week) to the end of the 
28-week treatment period will be summarized using shift tables showing the number of patients 
having values below, within, and above the normal range at each assessment for each treatment 
group separately. Data will not be carried forward for patients withdrawing due to treatment 
failure. 
The change in physical examination parameters from baseline to the end of the 28-week 
treatment period will be summarized as the number of patients who have a normal or abnormal 
examination at each assessment for each treatment group separately. Data will not be carried 
forward for patients withdrawing due to treatment failure. 
Vital signs will be summarized at baseline and at the end of the 28-week treatment period (actual 
and change from baseline) using descriptive statistics (n, mean, SD, median, minimum, and 
maximum). 
The number of patients withdrawing during the 28-week treatment period will be summarized by 
primary reason for withdrawal for each treatment group. 
No formal statistical testing will be performed on the safety data. These safety parameters will be 
assessed using the safety analysis set. 
17.3.7 Subgroup Analysis 
The effect of age, gender, origin, baseline disease severity as measured by MMSE, ApoE4, 
baseline insomnia severity, and patient education level upon efficacy will be evaluated if sample 
sizes are sufficient to warrant such analyses. For example, if all patients are Caucasian, then 
there is no need to evaluate the co-factor origin. The ANCOVA and MMRM models described 
above will be supplemented with terms for the main effect and interaction with treatment. Each 
co-factor will be analyzed in separate models. The test for treatment-by-subgroup interaction will 
address whether the response to piromelatine, compared with placebo, is different or consistent 
between levels of the co-factor. 
18. 
INSTITUTIONAL REVIEW BOARD APPROVAL 
This study will be conducted in accordance with the provisions of the Declaration of Helsinki 
(latest revision, Fortaleza 2013). In addition, this study will be undertaken in accordance with the 
protocol and GCP on the conducting and monitoring of clinical studies. The IRB must be 
constituted according to the International Council for Harmonisation (ICH) guidelines on GCP 
and local laws. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 66/92 
 
 
 
The investigator will submit the protocol, patient information, and consent forms to the local 
and/or central IRB through INC Research and its written unconditional approval will be obtained 
and submitted to the sponsor before the start of the study. 
Neurim Pharmaceuticals will ensure an investigator’s brochure is available. The investigator will 
submit the investigator’s brochure and protocol to the IRB through INC Research for the 
protocol’s review and approval. Verification of the IRB unconditional approval of the protocol 
and patient information and consent forms will be transmitted to INC Research and thence to 
Neurim Pharmaceuticals, prior to the start of the study. This approval must refer to the study by 
exact protocol title and number, identify the documents reviewed and state the date of review. 
The IRB must be informed by the investigator through INC Research of all subsequent protocol 
amendments and of unexpected SAEs occurring during the study, which are likely to affect the 
safety of the patients or the conduct of the study. 
The investigator should provide the IRB with all relevant amendments or updates of the protocol 
and investigator’s brochure through INC Research. Also, the investigator should provide written 
reports to the IRB annually or more frequently if requested on any changes significantly 
affecting the conduct of the trial and/or increasing risk to the patients. A final report of study 
outcome, if required, should also be submitted by the investigator through INC Research to the 
IRB. 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 67/92 
 
 
 
19. 
INFORMED CONSENT 
The principles of informed consent in the Declaration of Helsinki and Guidelines on GCP should 
be implemented in this clinical study before protocol-specified procedures are carried out. 
Information should be given in both oral and written form whenever possible and deemed 
appropriate by the IRB. Patients and/or their relatives must be given ample opportunity to inquire 
about details of the study. The patient must be capable to sign the consent form as judged by the 
study investigator. The legal representative will be allowed to sign only as dictated by local legal 
circumstances. 
The written consent document will embody the elements of informed consent as described in the 
Declaration of Helsinki and Guidelines on GCP and will also comply with local regulations. 
Consent forms must be in a language fully comprehensible to the prospective patient. Informed 
consent will be documented by the use of a written consent form approved by the IRB and 
signed by the patient and the investigator obtaining the consent. The ICF will also be annotated 
with the study patient or screening number. The signature confirms the consent is based on 
information that has been understood. Each patient’s signed ICF must be kept on file by the 
investigator for possible inspection by regulatory authorities, Neurim Pharmaceuticals, or INC 
Research. 
Patients who are willing to participate in the ApoE4 genotyping will be asked to sign a separate 
applicable ICF. 
The consent form will include a statement by which the patients allow the sponsor’s duly 
authorized personnel to have access to source data which support the data on the eCRF (eg, 
medical records, appointment books, original laboratory records). These personnel will not 
disclose any of the patient’s personal medical information. 
Each caregiver will be given an informed consent form (ICF) to read and sign. This ICF will 
comply with the Declaration of Helsinki and Guidelines on GCP, as well as local regulations. 
Informed consent forms must be in a language fully comprehensible to the prospective caregiver. 
Informed consent will be documented by the use of a written information sheet approved by the 
IRB and signed by the caregiver. The signature confirms the consent is based on information that 
has been understood. Each caregiver’s signed information sheet must be kept on file by the 
investigator for possible inspection by regulatory authorities, Neurim Pharmaceuticals, or INC 
Research personnel. 
 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 68/92 
 
 
 
20. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
To ensure both the safety of participants in the study, and the collection of accurate, complete, 
and reliable data, Neurim Pharmaceuticals or its representatives will perform the following 
activities: 
 Provide instructional material to the study sites, as appropriate. 
 Sponsor a start-up training session to instruct the investigators and study coordinators. 
This session will give instruction on the protocol, the completion of the clinical report 
forms, and study procedures. 
 Make periodic visits to the study site. 
 Be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax. 
 Review and evaluate clinical report form data and use standard computer edits to detect 
errors in data collection. 
To ensure the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the investigator will do the following: 
 Keep records of laboratory tests, clinical notes, and patient medical records in the patient 
files as original source documents for the study. 
Neurim Pharmaceuticals or its representatives may periodically check a sample of the patient 
data recorded against source documents at the study site. The study may be audited by Neurim 
Pharmaceuticals and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 69/92 
 
 
 
21. 
RECORDS AND SUPPLIES 
21.1 
DRUG ACCOUNTABILITY 
Upon receipt of study medication, the investigator (or investigator’s designee) will conduct an 
inventory of the supplies and complete a supplies receipt. The investigator will retain a copy of 
this receipt at the site and return the original receipt to the study monitor. 
It is the responsibility of the study monitor to ensure that the investigator (or investigator’s 
designee) has correctly documented the dispensing and return of study medication on the 
dispensing log, which will be provided. The study monitor will arrange regular collection of 
unused study medication returned by the patient. The study monitor will also perform an 
inventory of study medication at the close-out visit to the site. All discrepancies must be 
accounted for and documented. 
21.2 
ELECTRONIC CASE REPORT FORMS 
In accordance with GCP and ICH Guidelines, the study monitor will carry out source document 
verification to ensure that the data collected in the eCRF are accurate and reliable. Source 
document verification involves cross-referencing data in the eCRF with those recorded in any 
source document (eg, patients’ medical notes, nurses’ notes, appointment diaries, laboratory 
reports). 
All key trial information must be recorded in the patient’s medical notes. This includes: 
confirmation of diagnosis, date of informed consent given and of study entry, visit dates, start 
and stop dates of study medication, changes to concomitant medication, and AEs. Study 
procedures will be fully documented in the eCRFs and signed by the investigator. For data 
required to be transcribed into the eCRF, a check on accuracy will be performed by the 
investigator. The investigator will check relevant laboratory reports for accuracy, will annotate 
the laboratory report for values of clinical significance and out of range values, and then will 
sign and date such reports. 
21.3 
CRITICAL DOCUMENTS 
The investigator must permit the monitor, the sponsor’s internal auditors, IRB, independent 
ethics committees, and representatives from the regulatory authorities to have direct access to all 
study-related documents and pertinent hospital or medical records for confirmation of data 
contained within the eCRFs. 
21.4 
INSURANCE 
Insurance for this study will be arranged and financed by the sponsor of the study according to 
applicable laws. 
21.5 
INVESTIGATOR INFORMATION 
The name, title, and institution of the investigators are to be listed on the “Investigator” page 
provided in Section 2 of this protocol. If the investigator is changed after the study has been 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 70/92 
 
 
 
approved by an IRB, or a regulatory agency, or by Neurim Pharmaceuticals, this addition will 
not be considered a change to the protocol. However, the “Investigator” page will be updated to 
provide the new information. 
21.6 
FINAL REPORT SIGNATURE 
The study chair will sign the final clinical study report for this study, indicating agreement with 
the analyses, results, and conclusions of the report. 
The investigator who will serve as the study chair will be named by the sponsor of the study. 
 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 71/92 
 
 
 
22. 
REPORTING AND PUBLICATION, INCLUDING RECORD 
RETENTION 
After completion of the study, all documents and data relating to the study will be kept in an 
orderly manner by the investigator in a secure study file. This file will be available for inspection 
by the sponsor or their representatives. Essential documents must be retained for 2 years after the 
final marketing approval in an ICH region or at least 2 years have elapsed since the 
discontinuation of clinical development of the investigational product. The investigator must 
contact the sponsor before destroying any trial-related documentation. In addition, all patient 
medical records and other source documentation will be kept for the maximum time permitted by 
the hospital, institution, or medical practice. 
Neurim Pharmaceuticals has the ownership of all data and results collected during this study. In 
consequence, Neurim Pharmaceuticals reserves the right to use the data of the present study, 
either in the form of eCRFs (or copies of these), or in the form of a report, with or without 
comments and with or without analysis, in order to submit them to the health authorities of any 
country. Furthermore, in the event that the clinical research leads to patentable results, the 
investigator (or entity acting on his behalf following local requirements) shall refrain from filing 
patent(s) application which will be filed by Neurim Pharmaceuticals or any other entity 
delegated by Neurim Pharmaceuticals. 
Presentations and/or publications will be considered as joint scientific efforts between the 
investigators, INC Research, and Neurim Pharmaceuticals. They will be prepared and signed by 
authors of each party. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 72/92 
 
 
 
23. 
APPENDIX 1 
ALCOHOL EQUIVALENTS 
 
Average degrees of alcohol (in grams of alcohol) in the most commonly found drinks: 
 
Drinks 
Degrees 
Volume (mL) 
Beer (draught) 
3-4 
250 
Beer (bottled) 
5-6 
250 or 330 
Cider 
5-6 
200-250 (1 glass) 
Wine 
10-12 
100-150 (glass) 
Fortified wine 
18-20 
50 
Pastis 
45 
25 
Whisky 
10-45 
25 
Strong liqueurs 
40-60 
25 
* Alcohol consumption in mL = degrees × volume (mL) ÷ 100 
* Alcohol consumption in g = alcohol consumption (mL) × 0.8 
 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 73/92 
 
 
 
24. 
APPENDIX 2 
PROHIBITED AND RESTRICTED MEDICATIONS 
The washout window for prohibited medications is 5 days or 5 half-lives, whichever is longer, 
after ICF signature. 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Atropine  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Benztropine  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Benztropine Mesilate 
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Biperiden  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Chlorpheniramine  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Diphenhydramine  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Diphenhydramine 
Hydrochloride 
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Ipratropium  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Ipratropium Bromide 
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Orphenadrine 
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Oxitropium  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Tolterodine  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Tiotropium  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Tiotropium Bromide 
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Trihexyphenidyl  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Trihexyphenidyl Hydrochloride 
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Muscarinic 
agents  
Scopolamine  
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 74/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
ANTICHOLINERGIC 
AGENTS 
 
Anti-Nicotinic agents  Dextromethorphan  
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Nicotinic agents  Dextromethorphan 
Hydrobromide 
PROHIBITED 
ANTICHOLINERGIC 
AGENTS 
Anti-Nicotinic agents  Dextromethorphan 
W/Paracetamol/ 
Phenylephrine 
PROHIBITED 
NOOTROPIC 
SUPPLEMENT 
AchEI 
Huperzine 
Prohibited  
(added 25 Nov 
2015) 
ANTIDEPRESSANTS  
Other (NaSSA) 
Mirtazapine  
PROHIBITED 
ANTIDEPRESSANTS  
Other (NRIs) 
Atomoxetine  
Prohibited 
even if not 
formally a CNS 
stimulant 
ANTIDEPRESSANTS  
Other (NS) 
Agomelatine  
Prohibited 
(revised 25 
Nov 2015) 
ANTIDEPRESSANTS  
Other (SARIs) 
Trazodone  
PROHIBITED 
ANTIDEPRESSANTS  
Other (SARIs) 
Trazodone Hydrochloride 
PROHIBITED 
ANTIDEPRESSANTS  
Other (SSRIs) 
Fluvoxamine 
PROHIBITED 
ANTIDEPRESSANTS  
Other (SSRIs) 
Fluvoxamine Maleate 
PROHIBITED 
ANTIDEPRESSANTS  
Other (TAAR1 
agonists) 
Amphetamine 
PROHIBITED 
ANTIDEPRESSANTS  
Other (TAAR1 
agonists) 
Dextroamphetamine 
PROHIBITED 
ANTIDEPRESSANTS  
Other (TAAR1 
agonists) 
Dextromethampheta-mine 
PROHIBITED 
ANTIDEPRESSANTS  
Other (TAAR1 
agonists) 
Lisdexamfetamine  
PROHIBITED 
ANTIDEPRESSANTS  
Other (TeCAs) 
Amoxapine  
PROHIBITED 
ANTIDEPRESSANTS  
Other (TeCAs) 
Mirtazapine  
PROHIBITED 
ANTIDEPRESSANTS  
MAOI (Irreversible) 
Isocarboxazid 
PROHIBITED 
ANTIDEPRESSANTS 
 
MAOI (Irreversible) 
Phenelzine  
PROHIBITED 
ANTIDEPRESSANTS 
 
MAOI (Irreversible) 
Selegiline 
PROHIBITED 
ANTIDEPRESSANTS 
 
MAOI (Irreversible) 
Tranylcypromine  
PROHIBITED 
ANTIDEPRESSANTS 
 
MAOI (Reversible) 
Moclobemide 
PROHIBITED 
ANTIDEPRESSANTS 
MAOI (Reversible) 
Pirlindole 
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 75/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
 
ANTIDEPRESSANTS 
 
MAOI (Reversible) 
Pirazidol 
PROHIBITED 
ANTIDEPRESSANTS 
SSRIs 
Sertraline, Paroxetine, 
Fluoxetine 
RESTRICTED 
(must be 
under stable 
dose for at 
least 3 months 
prior to 
screening) 
ANTIDEPRESSANTS 
SNRIs 
Venlafaxine, Duloxetine  
RESTRICTED 
(must be 
under stable 
dose for at 
least 3 months 
prior to 
screening) 
ANTIDEPRESSANTS 
Dopamine/ 
Norepinephrine RIs 
Bupropion hydrochloride 
Prohibited 
(revised 25 
Nov 2015) 
ANTIDEPRESSANTS 
Tricyclic 
antidepressants 
Amitriptyline  
PROHIBITED 
ANTIDEPRESSANTS 
Tricyclic 
antidepressants 
Amitriptyline Hydrochloride 
PROHIBITED 
(TAC with high 
sedative/ 
anticholinergic 
action) 
ANTIDEPRESSANTS 
Tricyclic 
antidepressants 
Amitriptylinoxide  
PROHIBITED 
(TAC with high 
sedative/ 
anticholinergic 
action) 
ANTIDEPRESSANTS 
Tricyclic 
antidepressants 
Clomipramine  
PROHIBITED 
(TAC with high 
sedative/ 
anticholinergic 
action) 
ANTIDEPRESSANTS 
Tricyclic 
antidepressants 
Clomipramine Hydrochloride 
PROHIBITED 
(TAC with high 
sedative/ 
anticholinergic 
action) 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 76/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
ANTIDEPRESSANTS 
Tricyclic 
antidepressants 
Doxepin  
PROHIBITED 
(TAC with high 
sedative/ 
anticholinergic 
action) 
 
ANTIDEPRESSANTS 
Tricyclic 
antidepressants 
Nortriptyline 
RESTRICTED 
(must be 
under stable 
dose for at 
least 3 months 
prior to 
screening) 
ATYPICAL 
ANTIPSYCHOTICS + 
Combination 
products 
Olanzapine/Fluoxetine 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Aripiprazole  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Asenapine  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Asenapine Maleate 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Iloperidone 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Olanzapine  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Olanzapine Embonate 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Paliperidone  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Paliperidone Palmitate 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Quetiapine  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Quetiapine Fumarate 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Risperidone 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Ziprasidone  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Ziprasidone Hydrochloride 
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 77/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Lurasidone  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Lurasidone Hydrochloride 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
 
Atypical  
Zotepine  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Amisulpride 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Sulpiride 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Clozapine 
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Bifeprunox  
PROHIBITED 
ATYPICAL 
ANTIPSYCHOTICS 
Atypical  
Brexpiprazole 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Alprazolam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Bretazenil  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Bromazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Brotizolam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Chlordiazepoxide  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Cinolazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Clonazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Clorazepate 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Clotiazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Cloxazolam 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Delorazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Diazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Estazolam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Etizolam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Flunitrazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Flurazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Flurazepam Hydrochloride 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Flutoprazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Halazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Ketazolam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Loprazolam 
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 78/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
ANXIOLITICS 
Benzodiazepines 
Lorazepam and other 
medium-acting 
benzodiazepines 
Prohibited in 
regular dose 
prior to 
screening. 
Restricted as 
per protocol 
section 12.9.1 
Rescue 
Medication 
during trial 
ANXIOLITICS 
Benzodiazepines 
Lormetazepam 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Medazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Midazolam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Midazolam Hydrochloride 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Midazolam Maleate 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Nimetazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Nitrazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Nordazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Oxazepam 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Phenazepam 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Pinazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Prazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Premazepam 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Pyrazolam 
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Quazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Temazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Tetrazepam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Triazolam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
Clobazam  
PROHIBITED 
ANXIOLITICS 
Benzodiazepines 
DMCM 
PROHIBITED 
HYPNOTICS 
Z- drugs 
Eszopiclone  
PROHIBITED 
HYPNOTICS 
Z- drugs 
Zaleplon 
PROHIBITED 
HYPNOTICS 
Z- drugs 
Zolpidem 
PROHIBITED 
HYPNOTICS 
Z- drugs 
Zolpidem Tartrate 
PROHIBITED 
HYPNOTICS 
Z- drugs 
Zopiclone 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Adderall 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Obetrol 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Amphetamine 
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 79/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
CNS STIMULANTS 
Substituted 
phenethylamines 
Dexmethylphenidate 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Dextroamphetamine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Dextromethampheta-mine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
 
Lisdexamfetamine  
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Methylphenidate 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Methylphenidate 
hydrochloride 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Mixed amphetamine salts 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Benzedrine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Bupropion 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Bupropion hydrochloride 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Cathinone 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Ecstasy 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Methamphetamine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Ephedrine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
MDMA 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
MDPV 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Caffeine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Catha edulis 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Cocaine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Khat  
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 80/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
CNS STIMULANTS 
Substituted 
phenethylamines 
Mephedrone 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Methylenedioxypyro-valerone 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Methylone 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
 
Phenylpropanolamine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Propylhexadrine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Pseudoephedrine 
PROHIBITED 
CNS STIMULANTS 
Substituted 
phenethylamines 
Pseudoephedrine 
Hydrochloride 
PROHIBITED 
CNS STIMULANTS 
Eugeroics 
Adrafinil  
PROHIBITED 
CNS STIMULANTS 
Eugeroics 
Armodafinil 
PROHIBITED 
CNS STIMULANTS 
Eugeroics 
Modafinil 
PROHIBITED 
CNS STIMULANTS 
Nicotine therapy 
Varenicline tartrate 
PROHIBITED 
INSULIN REPLACEMENT 
THERAPY 
Insulin and analogs 
Insulin (any source), 
Lispro,Aspart,Degludec+Aspart, 
combinations 
PROHIBITED 
IMMUNOSUPPRESSANTS CORTICOSTEROIDS 
(at 
immunosuppresive 
dose) 
Prednisone 
PROHIBITED 
IMMUNOSUPPRESSANTS CORTICOSTEROIDS 
(at 
immunosuppresive 
dose) 
Prednisolone 
PROHIBITED 
IMMUNOSUPPRESSANTS CORTICOSTEROIDS 
(at 
immunosuppresive 
dose) 
Dexamethasone 
PROHIBITED 
IMMUNOSUPPRESSANTS CYTOTOXIC AGENTS 
Cyclophosphamide 
PROHIBITED 
IMMUNOSUPPRESSANTS CYTOTOXIC AGENTS 
Methotrexate 
PROHIBITED 
IMMUNOSUPPRESSANTS CYTOTOXIC AGENTS 
Azathiprine 
PROHIBITED 
IMMUNOSUPPRESSANTS T-CELL SUPPRESIVE 
AGENTS 
Cyclosporine 
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 81/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
IMMUNOSUPPRESSANTS T-CELL SUPPRESIVE 
AGENTS 
Tacrolimus 
PROHIBITED 
Melatonin agonists 
melatonin receptor 
agonists 
Melatonin,Ramelteon 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Carbamazepine 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Divalproex sodium  
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Lamotrigine 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Oxcarbazepine 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Sodium valproate  
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Valproate sodium 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Valproate magnesium 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Valproate semisodium 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Topiramate 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Acetazolamide 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Valproic acid  
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Primadone 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Phenytoin 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Ergenyl chrono 
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Phenobarbital 
PROHIBITED 
MOOD STABILIZERS 
MINERAL 
Lithium  
PROHIBITED 
MOOD STABILIZERS 
ANTIEPILEPTICS 
Gabapentin 
PROHIBITED 
MOOD STABILIZERS 
MINERAL 
Lithium carbonate 
PROHIBITED 
DIETARY SUPPLEMENTS 
NUTRACEUTICALS 
Souvenaid, DHA 
[DOCOSAHEXAENOIC ACID], 
Phosphatidylserine, Omega-3, 
Ginkgo biloba, Ginseng, 
Huperzia serrata, Vitamin B, 
Vitamin D, Vitamin E 
RESTRICTED 
(must be 
under stable 
dose for at 
least 3 months 
prior to 
screening) 
OPIOIDS 
Allosteric modulators Cannabidiol  
PROHIBITED 
OPIOIDS 
Allosteric modulators Tetrahydrocannabinol  
PROHIBITED 
OPIOIDS 
Benzomorphan 
derivatives 
Dezocine 
PROHIBITED 
OPIOIDS 
Benzomorphan 
derivatives 
Pentazocine  
PROHIBITED 
OPIOIDS 
Benzomorphan 
derivatives 
Phenazocine  
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Bezitramide  
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Dextromoramide  
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 82/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Dextropropoxyphene 
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Difenoxin  
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Diphenoxylate 
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Dipipanone  
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
LAAM 
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Levomethadyl Acetate  
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Loperamide  
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Methadone  
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Piritramide  
PROHIBITED 
OPIOIDS 
Diphenylpropylamine 
derivatives 
Propoxyphene  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Acetylpropionyl-morphine  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Desomorphine 
PROHIBITED 
OPIOIDS 
Esters of morphine 
Diacetyldihydro-morphine  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Diacetylmorphine  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Dibenzoylmorphine  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Dipropanoylmorphine 
PROHIBITED 
OPIOIDS 
Esters of morphine 
Heroin  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Methyldesorphine  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Morphine diacetate  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Morphine dinicotinate  
PROHIBITED 
OPIOIDS 
Esters of morphine 
Morphine dipropionate 
PROHIBITED 
OPIOIDS 
Esters of morphine 
Morphine sulfate 
PROHIBITED 
OPIOIDS 
Esters of morphine 
Nicomorphine 
PROHIBITED 
OPIOIDS 
Ethers of morphine 
Dihydrocodeine 
PROHIBITED 
OPIOIDS 
Ethers of morphine 
Ethylmorphine 
PROHIBITED 
OPIOIDS 
Ethers of morphine 
Heterocodeine  
PROHIBITED 
OPIOIDS 
Morphinan 
derivatives 
Butorphanol  
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 83/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
OPIOIDS 
Morphinan 
derivatives 
Levomethorphan 
PROHIBITED 
OPIOIDS 
Morphinan 
derivatives 
Levorphanol  
PROHIBITED 
OPIOIDS 
Morphinan 
derivatives 
Nalbuphine  
PROHIBITED 
OPIOIDS 
Opioid antagonists: 
Nalmefene 
PROHIBITED 
OPIOIDS 
Opioid antagonists: 
Naloxone  
PROHIBITED 
OPIOIDS 
Opioid antagonists: 
Naltrexone 
PROHIBITED 
OPIOIDS 
Opium alkaloids  
Codeine 
PROHIBITED 
OPIOIDS 
Opium alkaloids  
Morphine 
PROHIBITED 
OPIOIDS 
Opium alkaloids  
Oripavine  
PROHIBITED 
OPIOIDS 
Opium alkaloids  
Papaveretum 
PROHIBITED 
OPIOIDS 
Opium alkaloids  
Thebaine  
PROHIBITED 
OPIOIDS 
Oripavine derivatives  Buprenorphine 
PROHIBITED 
OPIOIDS 
Oripavine derivatives  Dihydroetorphine  
PROHIBITED 
OPIOIDS 
Oripavine derivatives  Etorphine  
PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Buprenorphine  
PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Etorphine  
PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Hydrocodone  
PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Hydromorphone  
PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Hydromorphone Hydrochloride PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Vicodin 
PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Oxycocet 
PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Oxycodone 
PROHIBITED 
OPIOIDS 
Semi-synthetic 
alkaloid derivatives 
Oxymorphone  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Anilidopiperidines 
Alfentanil  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Anilidopiperidines 
Alphamethylfentanyl  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Anilidopiperidines 
Carfentanyl  
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 84/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
OPIOIDS 
Synthetic opioids: 
Anilidopiperidines 
Fentanyl  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Anilidopiperidines 
Ohmefentanyl 
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Anilidopiperidines 
Remifentanil  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Anilidopiperidines 
Sufentanil  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
Allylprodine 
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
Ketobemidone  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
meperidine  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
MPPP  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
PEPAP 
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
Pethidine  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
Prodine  
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
Panadeine CO 
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
Nuprofen Plus 
PROHIBITED 
OPIOIDS 
Synthetic opioids: 
Phenylpiperidines 
Nembudeine 
PROHIBITED 
OPIOIDS 
Other 
Tapentadol 
PROHIBITED 
OPIOIDS 
Other 
Tramadol  
PROHIBITED 
OPIOIDS 
Other 
Tramadol Hydrochloride 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Chlorpromazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Chlorpromazine Hydrochloride 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Chlorprothixene  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Clopenthixol  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Cyamemazine  
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 85/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Dixyrazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Flupentixol  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Flupentixol Decanoate 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Fluphenazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Fluphenazine Hydrochloride 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Fluphenazine Decanoate 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Levomepromazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Levomepromazine Maleate 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Mesoridazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Perazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Perazine Dunakinate 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Pericyazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Perphenazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Pipotiazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Prochlorperazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Promazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Promethazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Prothipendyl  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Thioproperazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Thioridazine  
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 86/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Thioxanthenes 
  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Tiotixene  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Trifluoperazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Trifluoperazine Hydrochloride 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
 
Phenothiazines 
Triflupromazine  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Zuclopenthixol  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Zuclopenthixol Acetate 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Phenothiazines 
Zuclopenthixol Decanoate 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Benperidol 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Bromperidol  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Diphenylbutylpiper-idine 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Droperidol  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Fluspirilene 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Haloperidol  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Haloperidol Decanoate 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Moperone 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Penfluridol  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Pimozide  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Pipamperone  
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Pipamperone Hydrochloride 
PROHIBITED 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 87/92 
 
 
 
Drug Category 
Drug Subcategory 
Medication-PT 
Status 
TYPICAL 
ANTIPSYCHOTICS 
Butyrophenones 
Timiperone 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Conventional 
Clotiapine 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Conventional 
Loxapine 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Neuroleptic 
Tiapride 
PROHIBITED 
TYPICAL 
ANTIPSYCHOTICS 
Neuroleptic 
Sertindole 
PROHIBITED 
 
 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 88/92 
 
 
 
25. 
REFERENCES 
ARBON, E. L., KNUROWSKA, M. & DIJK, D. J. 2015. Randomised clinical trial of the effects 
of prolonged-release melatonin, temazepam and zolpidem on slow-wave activity during 
sleep in healthy people. J Psychopharmacol. 29(7):764-76. 
BANASR, M., HERY, M., PRINTEMPS, R. & DASZUTA, A. 2004. Serotonin-induced 
increases in adult cell proliferation and neurogenesis are mediated through different and 
common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. 
Neuropsychopharmacology. 29(3):450-60. 
BILLIOTI DE GAGE, S., BÉGAUD, B., BAZIN, F., VERDOUX, H., DARTIGUES, J.-F., 
PÉRÈS, K., KURTH, T. & PARIENTE, A. 2012. Benzodiazepine use and risk of 
dementia: prospective population based study. BMJ. 345:1-12. 
BILLIOTI DE GAGE, S., MORIDE, Y., DUCRUET, T., KURTH, T., VERDOUX, H., 
TOURNIER, M., PARIENTE, A. & BÉGAUD, B. 2014. Benzodiazepine use and risk of 
Alzheimer’s disease: case-control study. BMJ. 349:1-10. 
BJORVATN, B. & URSIN, R. 1998. Changes in sleep and wakefulness following 5-HT1A 
ligands given systemically and locally in different brain regions. Rev Neurosci. 
9(4):265-73. 
BUENDIA, I., NAVARRO, E., EGEA, J., PARADA, E., GÓMEZ, V., CASAS, I., LAUDON, 
M., LEÓN, R. & LÓPEZ, M. G. Neuroprotective mechanism of the novel melatonin 
derivative Neu-P11 against oxygen and glucose deprivation in rat hippocampal slices and 
in vivo fotothrombotic stroke model. Spanish congress of pharmacology FARMADRID 
XXIII, 2014 Madrid. 
BUYSSE, D. J., REYNOLDS, C. F., 3RD, MONK, T. H., BERMAN, S. R. & KUPFER, D. J. 
1989. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and 
research. Psychiatry Res. 28(2):193-213. 
CARPENTER, B. D., STRAUSS, M. & PATTERSON, M. B. 1996. Sleep disturbances in 
community-dwelling patients with Alzheimer’s disease. Clin Gerontol. 16(2):35-49. 
CHUNG, S. D., LIN, C. C., WANG, L. H., LIN, H. C. & KANG, J. H. 2013. Zolpidem use and 
the risk of injury: a population-based follow-up study. PLoS One. 8(6):e67459. 
CUMMINGS, J., MEGA, M., GRAY, K., ROSENBERG-THOMPSON, S., CARUSI, D. & 
GORNBEIN, J. 1994. The neuropsychiatric inventory: comprehensive assessment of 
psychopathology in dementia. Neurology. 44(12):2308-14. 
DIEM, S. J., EWING, S. K., STONE, K. L., ANCOLI-ISRAEL, S., REDLINE, S., ENSRUD, K. 
E. & THE OSTEOPOROTIC FRACTURES IN MEN (MrOS) STUDY Group, 2014. Use 
of non-benzodiazepine sedative hypnotics and risk of falls in older men. J Gerontol 
Geriatr Res. 3(3):158. 
DUTHEY, B. 2013. Alzheimer disease and other dementias, EU, Universiteit Utrecht; Boston 
University; World Health Organization. 
ECONOMOU, N., PAPAGEORGIOU, S., BOANAKIS, A., MAESTRI, M., TOGNONI, G. & 
BONANNI, E. 2013. From normal elderly through mild cognitive impairment (MCI) to 
Alzheimer’s disease. A progression based on sleep polysomnographic findings. Sleep 
Medicine. 14:e19-e20. 
FAVA, M., TARGUM, S. D., NIERENBERG, A. A., BLEICHER, L. S., CARTER, T. A., 
WEDEL, P. C., HEN, R., GAGE, F. H. & BARLOW, C. 2012. An exploratory study of 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 89/92 
 
 
 
combination buspirone and melatonin SR in major depressive disorder (MDD): a possible 
role for neurogenesis in drug discovery. J Psychiatr Res. 46:1553-63. 
GALASKO, D., BENNET, D., SANO, M., MARSON, D., KAYE, J. & EDLAND, S. 2006. 
Alzheimer's Disease Cooperative Study. ADCS Prevention Instrument Project: 
assessment of instrumental activities of daily living for community-dwelling elderly 
individuals in dementia prevention clinical trials. Alzheimer Dis Assoc Disord. 
20:s152-69. 
GOLD, C. A. & BUDSON, A. E. 2008. Memory loss in Alzheimer's disease: implications for 
development of therapeutics. Expert Rev Neurother. 8(12):1879-91. 
GOLD, D. A. 2012. An examination of instrumental activities of daily living assessment in older 
adults and mild cognitive impairment. J Clin Exp Neuropsychol. 34(1):11-34. 
GOLD, M. 2007. Study design factors and patient demographics and their effect on the decline 
of placebo-treated subjects in randomized clinical trials in Alzheimer's disease. J Clin 
Psychiatry. 68(3):430-8. 
GRANDY, J. K. 2013. Melatonin: therapeutic intervention in mild cognitive impairment and 
Alzheimer's disease. J Neurol Neurophysiol. 4(2):1000148. 
GREENBERG, B. D., CARRILLO, M. C., RYAN, J. M., GOLD, M., GALLAGHER, K., 
GRUNDMAN, M., BERMAN, R. M., ASHWOOD, T. & SIEMERS, E. R. 2013. 
Improving Alzheimer's disease phase II clinical trials. Alzheimers Dement. 9(1):39-49. 
GRUNDMAN, M., PETERSEN, R. C., FERRIS, S. H., THOMAS, R. G., AISEN, P. S., 
BENNETT, D. A., FOSTER, N. L., JACK, C. R., JR., GALASKO, D. R., DOODY, R., 
KAYE, J., SANO, M., MOHS, R., GAUTHIER, S., KIM, H. T., JIN, S., SCHULTZ, A. 
N., SCHAFER, K., MULNARD, R., VAN DYCK, C. H., MINTZER, J., ZAMRINI, E. 
Y., CAHN-WEINER, D., THAL, L. J. & ALZHEIMER'S DISEASE COOPERATIVE 
STUDY. 2004. Mild cognitive impairment can be distinguished from Alzheimer disease 
and normal aging for clinical trials. Arch Neurol. 61(1):59-66. 
HALL-PORTER, J. M., SCHWEITZER, P. K., EISENSTEIN, R. D., AHMED, H. A. H. & 
WALSH, J. K. 2014. The effect of two benzodiazepine receptor agonist hypnotics on 
sleep-dependent memory consolidation. J Clin Sleep Med. 10:27-34. 
HARRISON, J., MINASSIAN, S., JENKINS, L., BLACK, R.S., KOLLER, M. & 
GRUNDMAN, M. 2007. A neuropsychological test battery for use in Alzheimer disease 
clinical trials. Arch Neurol. 64(9):1323-29. 
HE, P., OUYANG, X., ZHOU, S., YIN, W., TANG, C., LAUDON, M. & TIAN, S. 2013. A 
novel melatonin agonist Neu-P11 facilitates memory performance and improves 
cognitive impairment in a rat model of Alzheimer' disease. Horm Behav. 64(1):1-7. 
HUANG, Y., POTTER, R., SIGURDSON, W., ET AL. 2012. EFfects of age and amyloid 
deposition on aβ dynamics in the human central nervous system. Arch Neurol. 
69(1):51-58. 
ISLAM, M. R., MORIGUCHI, S., TAGASHIRA, H. & FUKUNAGA, K. 2014. Rivastigmine 
improves hippocampal neurogenesis and depression-like behaviors via 5-HT1A receptor 
stimulation in olfactory bulbectomized mice. Neuroscience. 272:116-30. 
KLINE, A. E., MASSUCCI, J. L., DIXON, C. E., ZAFONTE, R. D. & BOLINGER, B. D. 2004. 
The 
therapeutic 
efficacy 
conferred 
by 
the 
5-HT(1A) 
receptor 
agonist 
8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) after experimental traumatic 
brain injury is not mediated by concomitant hypothermia. J Neurotrauma. 21(2):175-85. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 90/92 
 
 
 
LAUDON, M., KATZ, A., METZGER, D., STANER, L., PROSS, N., CORNETTE, F., 
GUICHARD, N., NIR, T. & ZISAPEL, N. 2012. Tolerability, pharmacokinetic and 
pharmacodynamic evaluation of multiple ascending doses of Neu-P11 in insomnia 
patients. Sleep. 35:A221. 
LIU, Y. Y., YIN, D., CHEN, L., QU, W. M., CHEN, C. R., LAUDON, M., CHENG, N. N., 
URADE, Y. & HUANG, Z. L. 2014. Piromelatine exerts antinociceptive effect via 
melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a 
mouse model of neuropathic pain. Psychopharmacology (Berl). 231(20):3973-85. 
LUCEY, B. P. & BATEMAN, R. J. 2014. Amyloid-β diurnal pattern: possible role of sleep in 
Alzheimer's disease pathogenesis. Neurobiol Aging. 35:S29-34. 
MANDER, B. A., MARKS, S. M., VOGEL, J. W., RAO, V., LU, B., SALETIN, J. M., 
ANCOLI-ISRAEL, S., JAGUST, W. J. & WALKER, M. P. 2015. β-amyloid disrupts 
human NREM slow waves and related hippocampus-dependent memory consolidation. 
Nat Neurosci. 18(7):1051-7. 
MCCURRY, S. M., LOGSDON, R. G., TERI, L., GIBBONS, L. E., KUKULL, W. A., BOWEN, 
J. D., MCCORMICK, W. C. & LARSON, E. B. 1999. Characteristics of sleep 
disturbance in community-dwelling Alzheimer's disease patients. J Geriatr Psychiatry 
Neurol. 12(2):53-9. 
MCKHANN, G. M., KNOPMAN, D. S., CHERTKOW, H., HYMAN, B. T., JACK, C. R., JR., 
KAWAS, C. H., KLUNK, W. E., KOROSHETZ, W. J., MANLY, J. J., MAYEUX, R., 
MOHS, R. C., MORRIS, J. C., ROSSOR, M. N., SCHELTENS, P., CARRILLO, M. C., 
THIES, B., WEINTRAUB, S. & PHELPS, C. H. 2011. The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement. 7(3):263-9. 
MCKINNON, A., TERPENING, Z., HICKIE, I. B., BATCHELOR, J., GRUNSTEIN, R., 
LEWIS, S. J. G. & NAISMITH, S. L. 2014. Prevalence and predictors of poor sleep 
quality in mild cognitive impairment. J Geriatr Psychiatry Neurol. 27(3):204-11. 
MENDELSOHN, A. R. & LARRICK, J. W. 2013. Sleep facilitates clearance of metabolites 
from the brain: glymphatic function in aging and neurodegenerative diseases. 
Rejuvenation Res. 16(6):518-23. 
MERICA, H., BLOIS, R. & GAILLARD, J. M. 1998. Spectral characteristics of sleep EEG in 
chronic insomnia. Eur J Neurosci. 10(5):1826-34. 
MIYATA, S., NODA, A., IWAMOTO, K., KAWANO, N., OKUDA, M. & OZAKI, N. 2013. 
Poor sleep quality impairs cognitive performance in older adults. J Sleep Res. 22:535-41. 
MONTI, J. M. & MONTI, D. 2000. Role of dorsal raphe nucleus serotonin 5-HT1A receptor in 
the regulation of REM sleep. Life Sci. 66(21):1999-2012. 
MURAKI, Y., YAMANAKA, A., TSUJINO, N., KILDUFF, T. S., GOTO, K. & SAKURAI, T. 
2004. Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A 
receptor. J Neurosci. 24(32):7159-66. 
PACE-SCHOTT, E.F. & SPENCER, R.M. 2015. Sleep-dependent memory consolidation in 
healthy aging and mild cognitive impairment. Curr Top Behav Neurosci. 25:307-30. 
QUERFURTH, H. W. & LAFERLA, F. M. 2010. Alzheimer's disease. N Engl J Med. 
362:329-44. 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 91/92 
 
 
 
RAUCHS, G., PIOLINO, P., BERTRAN, F., DE LA SAYETTE, V., VIADER, F., EUSTACHE, 
F. & DESGRANGES, B. 2013. Retrieval of recent autobiographical memories is 
associated with slow-wave sleep in early AD. Front Behav Neurosci. 7:114. 
RODRÍGUEZ, J. J., NORISTANI, H. N. & VERKHRATSKY, A. 2012. The serotonergic 
system in ageing and Alzheimer's disease. Prog Neurobiol. 99(1):15-41. 
ROH, J. H., HUANG, Y., BERO, A. W., KASTEN, T., STEWART, F. R., BATEMAN, R. J. & 
HOLTZMAN, D. M. 2012. Disruption of the sleep-wake cycle and diurnal fluctuation of 
β-amyloid in mice with Alzheimer's disease pathology. Sci Transl Med. 4(150):150ra122. 
SANO, M., RAMAN, R., EMOND, J., THOMAS, R. G., PETERSEN, R., SCHNEIDER, L. S. 
& AISEN, P. S. 2011. Adding delayed recall to the Alzheimer Disease Assessment Scale 
is useful in studies of mild cognitive impairment but not Alzheimer disease. Alzheimer 
Dis Assoc Disord. 25:122-7. 
SCHNEIDER, L.S., OLIN, J.T., DOODY, R.S., CLARK, C.M., MORRIS, J.C., REISBERG, B., 
SCHMITT, F.A., GRUNDMAN, M., THOMAS, R.G. & FERRIS, S.H. 1997. Validity 
and reliability of the Alzheimer's Disease Cooperative Study - Clinical Global Impression 
of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 
11:22-32. 
SCHNEIDER, L. S., CLARK, C. M., DOODY, R., FERRIS, S. H., MORRIS, J. C., RAMAN, 
R., REISBERG, B. & SCHMITT, F. A. 2006. ADCS Prevention Instrument Project: 
ADCS-clinicians' global impression of change scales (ADCS-CGIC), self-rated and study 
partner-rated versions. Alzheimer Dis Assoc Disord. 20:S124-38. 
SELKOE, D. J. 2002. Alzheimer's disease is a synaptic failure. Science. 298(5594):789-91. 
SEVIGNY, J. J., PENG, Y., LIU, L. & LINES, C. R. 2010. Item analysis of ADAS-Cog: effect 
of baseline cognitive impairment in a clinical AD trial. Am J Alzheimers Dis Other 
Demen. 25(2):119-24. 
SPIRA, A. P., GAMALDO, A. A., AN, Y., WU, M. N., SIMONSICK, E. M., BILGEL, M., 
ZHOU, Y., WONG, D. F., FERRUCCI, L. & RESNICK, S. M. 2013. Self-reported sleep 
and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 
70(12):1537-43. 
TABUCHI, S., TSUNEMATSU, T., KILDUFF, T. S., SUGIO, S., XU, M., TANAKA, K. F., 
TAKAHASHI, S., TOMINAGA, M. & YAMANAKA, A. 2013. Influence of inhibitory 
serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and 
wakefulness. Sleep. 36(9):1391-404. 
TANG, S., WANG, L., TIAN, S., DENG, H., LAUDON, M. & QIAO, G. 2012. Effects of 
Neu-P11 on sodium azide induced memory deficit in rats. Journal of Heinan Medical 
University. 9:1166-9. 
TIAN, S. W., LAUDON, M., HAN, L., GAO, J., HUANG, F. L., YANG, Y. F. & DENG, H. F. 
2010. Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in 
rodent models. Acta Pharmacol Sin. 31(7):775-83. 
VITIELLO, M. V. & BORSON, S. 2001. Sleep disturbances in patients with Alzheimer's 
disease: epidemiology, pathophysiology and treatment. CNS Drugs. 15:777-96. 
VITIELLO, M. V., PRINZ, P. N., WILLIAMS, D. E., FROMMLET, M. S. & RIES, R. K. 1990. 
Sleep disturbances in patients with mild-stage Alzheimer's disease. J Gerontol. 
45(4):M131-8. 
WADE, A. G., FARMER, M., HARARI, G., FUND, N., LAUDON, M., NIR, T., 
FRYDMAN-MAROM, A. & ZISAPEL, N. 2014. Add-on prolonged-release melatonin 


Protocol Version 7 
Date: 10 April 2017 
Identification: NEUP11-AD2 
Page 92/92 
 
 
 
for cognitive function and sleep in mild to moderate Alzheimer's disease: a 6-month, 
randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 9:947-61. 
WESTERBERG, C. E., MANDER, B. A., FLORCZAK, S. M., WEINTRAUB, S., MESULAM, 
M. M., ZEE, P. C. & PALLER, K. A. 2012. Concurrent impairments in sleep and 
memory in amnestic mild cognitive impairment. J Int Neuropsychol Soc. 18(3):490-500. 
XIE, L., KANG, H., XU, Q., CHEN, M. J., LIAO, Y., THIYAGARAJAN, M., O’DONNELL, J., 
CHRISTENSEN, D. J., NICHOLSON, C., ILIFF, J. J., TAKANO, T., DEANE, R. & 
NEDERGAARD, M. 2013. Sleep drives metabolite clearance from the adult brain. 
Science. 342(6156):373-7. 
YAFFE, K. & BOUSTANI, M. 2014. Benzodiazepines and risk of Alzheimer’s disease. BMJ. 
9:349. 
YALKINOGLU, Ö., ZISAPEL, N., NIR, T., PIECHATZEK, R., SCHORR-NEUFING, U., 
BITTERLICH, N., OERTEL, R., ALLGAIER, C., KLUGE, A. & LAUDON, M. 2010. 
Phase-I study of the safety, tolerability, pharmacokinetics and sleep promoting activity of 
Neu-P11, a novel putative insomnia drug in healthy humans. Sleep. 33:A220. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 1 of 66 
Document Type: 
Template 
Document ID: 
03.007A.02 
Issue Date:            01 SEP 2015 
Effective Date:    29 SEP 2015 
Sponsor Name: 
Neurim Pharmaceuticals 
Protocol Number and Title: 
 
NEUP11-AD2 
Randomized, double-blind, parallel-group, 
placebo controlled, dose-ranging study of 
piromelatine in patients with mild dementia 
due to Alzheimer’s Disease  
 
Protocol Version and Date: 
V7.0 (10th April 2017) 
Protocol Amendment 
numbers and dates 
V6.0 (14th August 2016) 
V5.0  (25th May 2016) 
V4.0  (16th February 2016) 
V3.0 (13th November 2015) 
V2.0 (11th September, 2015) 
V1.0 (23rd July 2015) 
 
 
INC Research Project Code: 
1006401 
Author(s): 
David White 
Senior Biostatistician 
Philippa Rook 
Biostatistician II 
SAP Version: 
Final 1.0  
SAP Version Date:  
20 May 2019 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Neurim Pharmaceuticals. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
NCT02615002


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 2 of 66 
official of Neurim Pharmaceuticals.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, INC Research should be notified 
promptly. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 3 of 66 
Revision History 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
Draft 
Version 
0.1 
22 Dec 2017 
David White 
Initial Release Version – Draft Version 0.1 
Draft 
Version 
0.2 
01 Oct 2018 
Philippa Rook 
Updated Draft Version 0.2 
Draft 
Version 
0.3 
17 Jan 2019 
Philippa Rook 
Updated Draft Version 0.3 
Draft 
Version 
0.4 
26 Mar 2019 
Philippa Rook 
Updated Draft Version 0.4 
Final 
Version 
1.0 
20 May 2019 
Philippa Rook 
Final Version 1.0 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 4 of 66 
I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
INC Research 
 
 
 
Lead Biostatistician  
Philippa Rook 
Biostatistician II 
 
 
Date (dd-Mmm-yyyy) 
Senior Reviewing Biostatistician 
Georgia Gourgioti 
Manager, Biostatistics 
Date (dd-Mmm-yyyy) 
Neurim Pharmaceuticals 
 
 
 
Sponsor Contact  
Amnon Katz 
VP Clinical Development 
 
Date (dd-Mmm-yyyy) 
 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 5 of 66 
TABLE OF CONTENTS 
CONTENTS 
REVISION HISTORY ................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................. 5 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 9 
2. 
PURPOSE ..................................................................................................... 12 
2.1. 
Responsibilities ................................................................................................................. 12 
2.2. 
Timings of Analyses .......................................................................................................... 12 
3. 
STUDY OBJECTIVES ................................................................................... 13 
3.1. 
Primary Objective .............................................................................................................. 13 
3.2. 
Secondary Objectives ....................................................................................................... 13 
3.3. 
Exploratory Objectives ...................................................................................................... 13 
3.4. 
Brief Description ................................................................................................................ 14 
3.5. 
Subject Selection ............................................................................................................... 15 
3.5.1. 
Inclusion Criteria .............................................................................................................. 15 
3.5.2. 
Exclusion Criteria ............................................................................................................. 15 
3.6. 
Determination of Sample Size .......................................................................................... 15 
3.7. 
Treatment Assignment and Blinding ............................................................................... 16 
3.8. 
Administration of Study Medication ................................................................................ 16 
3.9. 
Study Procedures and Flowchart ..................................................................................... 16 
4. 
ENDPOINTS .................................................................................................. 17 
4.1. 
Primary Efficacy Endpoint ................................................................................................ 17 
4.2. 
Secondary Efficacy Endpoints ......................................................................................... 17 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 6 of 66 
4.3. 
Exploratory Efficacy Endpoints ....................................................................................... 17 
4.4. 
Safety Endpoints ................................................................................................................ 18 
5. 
ANALYSIS SETS .......................................................................................... 19 
5.1. 
Screened Set ...................................................................................................................... 19 
5.2. 
Safety Analysis Set ............................................................................................................ 19 
5.3. 
Full Analysis Set ................................................................................................................ 19 
5.4. 
Per Protocol Set ................................................................................................................. 19 
5.5. 
Protocol Deviations and Violations ................................................................................. 19 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 21 
6.1. 
General Methods ................................................................................................................ 21 
6.2. 
Key Definitions ................................................................................................................... 22 
6.3. 
Missing Data ....................................................................................................................... 22 
6.4. 
Pooling of Centers ............................................................................................................. 22 
6.5. 
Statistical Assumptions .................................................................................................... 23 
6.6. 
Subgroups .......................................................................................................................... 23 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 24 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 24 
7.2. 
Protocol Deviations and Violations ................................................................................. 24 
7.3. 
Demographic and Other Baseline Characteristics ......................................................... 24 
7.4. 
Medical/Surgical History ................................................................................................... 25 
7.5. 
Other Baseline Characteristics ........................................................................................ 25 
7.6. 
Prior and Concomitant Medications ................................................................................ 26 
7.7. 
Scans .................................................................................................................................. 27 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 7 of 66 
8. 
EFFICACY ..................................................................................................... 28 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 28 
8.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 31 
8.2.1. 
Clinical Global Impression of Change ............................................................................. 31 
8.2.2. 
Alzheimer’s Disease Cooperative Study/Activities of Daily Living Scale Adapted for MCI 
Patients ......................................................................................................................................... 31 
8.2.3. 
Alzheimer’s Disease Assessment Scale Cognitive 14 Subscale .................................... 32 
8.2.4. 
Computerized Neuropsychological Test Battery Global Composite Score ..................... 33 
8.3. 
Exploratory Efficacy Endpoints and Analyses ............................................................... 34 
8.3.1. 
Computerized Neuropsychological Test Battery Episodic Memory Domain Composite 
Score 34 
8.3.2. 
Computerized Neuropsychological Test Battery Attention Domain Composite Score.... 34 
8.3.3. 
Executive Function Domain Composite Score ................................................................ 35 
8.3.4. 
Mini Mental State Examination ........................................................................................ 36 
8.3.5. 
Individual Computerized and Paper-Based Neuropsychological Test Battery Score ..... 36 
8.3.6. 
Neuropsychiatric Inventory .............................................................................................. 37 
8.3.7. 
Pittsburgh Sleep Quality Index ........................................................................................ 37 
8.3.8. 
Alzheimer’s Disease Assessment Scale Cognitive 13, 12 and 11 Subscale .................. 38 
8.3.9. 
Computerized Neuropsychological Test Battery Global Composite Score without Paper-
Based Components ...................................................................................................................... 39 
8.3.10. 
Combined Piromelatine Treatment Group 20 mg + 50 mg vs Placebo ...................... 40 
8.3.11. 
ApoE4 Carrier Status .................................................................................................. 40 
8.3.12. 
Insomnia at Baseline ................................................................................................... 40 
8.3.13. 
Alzheimer’s Disease Medications at Baseline ............................................................ 40 
8.3.14 
Clinical Dementia Rating ............................................................................................. 41 
9. 
SAFETY ......................................................................................................... 42 
9.1. 
Extent of Exposure ............................................................................................................ 42 
9.2. 
Treatment Compliance ...................................................................................................... 42 
9.3. 
Adverse Events .................................................................................................................. 42 
9.4. 
Laboratory Evaluations ..................................................................................................... 44 
9.5. 
Vital Signs ........................................................................................................................... 45 
9.6. 
ECG ..................................................................................................................................... 45 
9.7. 
Physical Examination ........................................................................................................ 46 
9.8. 
Other Safety ........................................................................................................................ 46 
10. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 47 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 8 of 66 
11. 
REFERENCE LIST .................................................................................... 49 
12. 
PROGRAMMING CONSIDERATIONS ...................................................... 50 
12.1. 
General Considerations .................................................................................................... 50 
12.2. 
Table, Listing, and Figure Format .................................................................................... 50 
12.2.1. 
General ........................................................................................................................ 50 
12.2.2. 
Headers ....................................................................................................................... 50 
12.2.3. 
Display Titles ............................................................................................................... 51 
12.2.4. 
Column Headers ......................................................................................................... 51 
12.2.5. 
Body of the Data Display ............................................................................................. 52 
12.2.6. 
Footnotes .................................................................................................................... 54 
13. 
QUALITY CONTROL ................................................................................. 55 
14. 
INDEX OF TABLES ................................................................................... 56 
15. 
INDEX OF LISTINGS ................................................................................. 63 
16. 
APPENDICES ............................................................................................ 65 
17. 
MOCK-UPS ................................................................................................ 66 
 
 
 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 9 of 66 
1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AD 
Alzheimer's Disease 
ADAS-cog14 
Alzheimer’s Disease Assessment Scale cognitive subscale 
ADCS-MCI-ADL 
Alzheimer's Disease Cooperative Study/Activities of Daily 
Living scale adapted for MCI patients 
AE 
Adverse Event 
ALAT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ASAT 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BDRM 
Blinded Data Review Meeting 
BMI 
Body Mass Index 
CDR 
Clinical Dementia Rating 
CFT 
Category Fluency Test 
CGIC 
Clinical Global Impression of Change 
CI 
Confidence Interval 
cNTB 
computerized Neuropsychological Test Battery 
COWAT 
Controlled Oral Word Association Test 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBL 
Data Base Lock 
DET 
Detection 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 10 of 66 
Abbreviation 
Description 
GGT 
Gamma-Glutamyltransferase 
ICH 
International Council on Harmonization 
IDN 
Identification 
ISLT 
International Shopping List Test 
IVRS 
Interactive Voice Randomization System 
IWRS 
Interactive Web Randomization System 
LOTE 
Lack of Therapeutic Efficacy 
Max 
Maximum 
MCH 
Mean Corpuscular Hemoglobin 
MCI 
Mild Cognitive Impairment 
MCMC 
Markov Chain Monte Carlo 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
MMRM 
Mixed-effects Maximum likelihood Repeated Measures 
MMSE 
Mini Mental State Examination 
N/A 
Not Applicable 
NA 
Not Applicable 
NCI 
National Cancer Institute 
NPI 
Neuropsychiatric Inventory 
OBK 
One Back Card 
OCL 
One Card Learning 
PPS 
Per Protocol Set 
PSQI 
Pittsburgh Sleep Quality Index 
PT 
Preferred Term 
QC 
Quality Control 
QTc 
Corrected QT Interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 11 of 66 
Abbreviation 
Description 
SD 
Standard Deviation 
SHBG 
Sex Hormone Binding Globulin 
Sheehan-STS 
Sheehan Suicidality Tracking Scale 
SE 
Standard Error 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Analysis Set 
STS 
Suicidality Tracking Scale 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Table, Listing and Figure 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 12 of 66 
2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.   
2.1. 
RESPONSIBILITIES 
INC Research will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings.   
2.2. 
TIMINGS OF ANALYSES 
The primary analysis of safety and efficacy and/or pharmacokinetics is planned after all 
subjects complete the final study visit or terminate early from the study, and database 
is locked after all data related edits and queries are resolved. 
 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 13 of 66 
3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to compare the effect of piromelatine (5, 20, and 
50 mg) to that of placebo in the change from baseline in global composite score of the 
computerized Neuropsychological Test Battery (cNTB) after 26 weeks of double-blind 
treatment. 
The global composite score includes the computerized International Shopping List Test 
(ISLT; immediate and delayed recall), One Card Learning (OCL), Identification (IDN), 
Detection (DET), One Back Card (OBK), and the paper-based Controlled Oral Word 
Association Test (COWAT) and Category Fluency Test (CFT). 
3.2. 
SECONDARY OBJECTIVES 
The key secondary objectives are: 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on 
global impression assessed by the Clinical Global Impression of Change (CGIC) 
after 26 weeks of double-blind treatment.  
2. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in 
the Alzheimer's Disease Cooperative Study/Activities of Daily Living scale 
adapted for MCI patients (ADCS-MCI-ADL) at Weeks 13 and 26 and over 26 weeks 
of double-blind treatment. 
The other secondary objectives are: 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in 
Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog14) at 
Weeks 13 and 26 and over 26 weeks of double-blind treatment. 
2. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in 
the change from baseline in global composite score of the cNTB at Weeks 4 and 
13 and over 26 weeks of double-blind treatment. 
3.3. 
EXPLORATORY OBJECTIVES 
The exploratory objectives are: 
1. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on 
the episodic memory domain* composite score of the cNTB at Weeks 4, 13, and 
26 and over 26 weeks of double-blind treatment. 
* episodic domain tests: ISLT (immediate and delayed recall) and OCL 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 14 of 66 
2. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on 
the attention domain* composite score of the cNTB at Weeks 4, 13, and 26 and 
over 26 weeks of double-blind treatment. 
* Attention domain tests: IDN and DET 
3. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on 
the executive function* composite score of the cNTB at Weeks 4, 13, and 26 and 
over 26 weeks of double-blind treatment. 
* Executive function domain tests: OBK, COWAT and CFT. 
4. To compare the safety and tolerability of piromelatine (5, 20, and 50 mg) to that 
of placebo. 
5. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on 
cognitive aspects of mental function assessed by the Mini Mental State 
Examination (MMSE) after 2 weeks of run-in single-blind placebo and 26 weeks of 
double-blind treatment. 
6. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in 
individual cNTB test scores (ISLT immediate and delayed recall, OCL, IDN, DET, 
OBK, COWAT, and CFT) at Weeks 4, 13, and 26 and over 26 weeks of double-
blind treatment. 
7. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on 
the change from baseline in behavioral signs and symptoms assessed by the 
Neuropsychiatric Inventory (NPI) Scale after 26 weeks of double-blind treatment. 
8. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo on 
sleep variables derived from the Pittsburgh Sleep Quality Index (PSQI) at Weeks 
4, 13, and 26 and over 26 weeks of double-blind treatment. 
9. To compare the effect of piromelatine (5, 20, and 50 mg) to that of placebo in 
ADAS-cog13, ADAS-cog12, and ADAS-cog11 score at Weeks 13 and 26 and over 
26 weeks of double-blind treatment. 
3.4. 
BRIEF DESCRIPTION 
This is a Phase 2, double-blind, parallel group, placebo-controlled, dose ranging safety 
and efficacy study of piromelatine in patients with mild dementia due to Alzheimer's 
disease (AD). 
During the double-blind period, patients will be enrolled in a 1.2:1:1:1 randomization 
ratio to the 4 trial arms (placebo [1.2], and the equal piromelatine treatment arms 5, 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 15 of 66 
20, and 50 mg [1:1:1]). Intermediate visits will be carried out at 4 weeks (Visit 3) and 
13 weeks (Visit 4) after randomization. 
Figure 1: Overall Study Design 
Period 
 
Single-blind Run-in 
Double-blind 
Treatment 
Follow-
up 
Phone 
call 
Screening 
Run-in 
Randomization 
Week 
 
-2 
0 
4 
13 
26 
28 
Visit 
1 
 
2 
3 
4 
5 
 
Treatment 
 
Placebo 
Piromelatine 5, 20, 
or 50 mg 
or 
Placebo 
N/A 
Each patient will undergo a 2-week, single blind run-in period and a 26-week, 
randomized, double-blind treatment period, for a total of 28 weeks. Two weeks after 
last dosing of study medication, the patient will receive a follow-up phone call. The 
duration of the study is expected to be approximately 40 months from first patient 
screened to final patient completing the randomized treatment.  
3.5. 
SUBJECT SELECTION 
Male and female patients between the ages of 60 and 85 (inclusive) with mild AD.  
3.5.1. 
Inclusion Criteria 
The inclusion criteria are defined in Section 11.1.2 of the protocol. 
3.5.2. 
Exclusion Criteria 
The exclusion criteria are defined in Section 11.1.3 of the protocol. 
3.6. 
DETERMINATION OF SAMPLE SIZE 
Eligible patients will be enrolled equally in a 1.2:1:1:1 randomization ratio to the 4 trial 
arms (placebo [1.2] and the equal piromelatine treatment arms 5 mg, 20 mg, and 50 mg 
[1:1:1]). Assuming an effect size between treatment dose and placebo of 0.35 over 26 
weeks, a significant level (α) of 0.05 for one-sided test, and power of 80%, a sample size 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 16 of 66 
of 115 patients for the placebo arm and 95 for each of the 3 piromelatine arms is 
calculated. Assuming a 50% screen failure rate and allowing for 15% patient withdrawal, 
920 patients should be screened in order to randomly assign 460 patients, of whom it is 
expected 400 will complete the study. Enrollment will end on November 30th 2018. 
3.7. 
TREATMENT ASSIGNMENT AND BLINDING 
Patients will be assigned a patient number once written informed consent has been 
obtained. The randomization list will be generated using a computer-based system and 
randomization will be performed using an interactive web response system (IWRS). 
Patients will be randomized, with a ratio of 1.2:1:1:1:1 to each treatment group after 
successful completion of the single-blind run-in period. 
The lead statistician will create a dummy randomization and will be used to provide the 
dry run of Table, Figure and Listing (TFL) outputs before database lock. An independent 
unblinded statistician, who will not communicate with the sponsor or other interested 
party, will create the actual randomization. This will be stored in a restricted folder 
where only the unblinded statistician will have access to.   
Unblinding will occur after database lock. The lead statistician will receive the 
unblinded randomization list from the unblinded team and rerun all the TFL outputs 
using this list. 
3.8. 
ADMINISTRATION OF STUDY MEDICATION 
Piromelatine will be administered orally, once daily, after a meal, before habitual 
bedtime, preferably between 2100h and 2300h.  
3.9. 
STUDY PROCEDURES AND FLOWCHART 
The schedule of assessments can be found in table 10.1 of the protocol. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 17 of 66 
4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is the cNTB global composite score (ISLT immediate and 
delayed recall, OCL, IDN, DET, OBK, COWAT and CFT) over 26 weeks of double blind 
treatment. 
4.2. 
SECONDARY EFFICACY ENDPOINTS 
Efficacy will be further assessed based on the following secondary variables: 
 
CGIC at Weeks 13 and 26 and over 26 weeks of double-blind treatment; 
 
ADCS-MCI-ADL at Weeks 13 and 26 and over 26 weeks of double blind treatment; 
 
ADAS-cog14 at Weeks 13 and 26 and over 26 weeks of double-blind treatment;  
 
cNTB global composite score (ISLT, ISLT-delayed, OCL, IDN, DET, OBK, COWAT, 
and CFT) over 4 and 13 weeks of double blind treatment. 
4.3. 
EXPLORATORY EFFICACY ENDPOINTS  
Efficacy will be further assessed based on the following exploratory variables: 
 
cNTB episodic memory domain composite score (ISLT, ISLT-delayed, and OCL) at 
Weeks 4, 13 and 26 and over 26 weeks of double blind treatment; 
 
cNTB attention domain composite score (IDN and DET) at Weeks 4, 13 and 26 and 
over 26 weeks of double blind treatment; 
 
cNTB executive function composite score (OBK, COWAT and CFT) at Weeks 4, 13 
and 26 and over 26 weeks of double blind treatment. 
 
MMSE after 2 weeks of run-in single-blind placebo and 26 weeks of double-blind 
treatment; 
 
Individual cNTB test scores at Weeks 4, 13, and 26 and over 26 weeks of double-
blind treatment; 
 
NPI scale after 26 weeks of double-blind treatment; 
 
PSQI (global score and individual components) at Weeks 4, 13, and 26 and over 
26 weeks of double-blind treatment; 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 18 of 66 
 
ADAS-cog13, ADAS-cog12, and ADAS-cog11 scores at Weeks 13 and 26 and over 26 
weeks of double-blind treatment; 
 
All of the above primary and secondary cNTB composite global score analyses, 
without the paper-based CFT and COWAT in the executive function domain; 
 
All of the above primary and secondary analyses comparing placebo with the 
combined 20 mg and 50 mg piromelatine treatment group; 
 
All the above primary and secondary efficacy endpoints separated for ApoE4 
carriers and non-carriers (see Section 6.6); 
 
All the above primary and secondary efficacy endpoints separated for insomnia 
and non-insomnia patients (see Section 6.6); 
 
All the above primary and secondary efficacy endpoints separated for naïve 
patients and patients taking AD medications at baseline (see Section 6.6).  
4.4. 
SAFETY ENDPOINTS  
The following variables will be collected for assessment of safety: 
 
Adverse events (including Serious Adverse Events [SAEs]); 
 
Physical examination; 
 
Vital signs; 
 
Concomitant medications; 
 
Laboratory parameters (hematology, biochemistry [including sex hormones], and 
urinalysis); 
 
Electrocardiograms (ECG); 
 
Sheehan Suicidality Tracking Scale (Sheehan-STS). 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 19 of 66 
5. 
ANALYSIS SETS 
All the primary, secondary and exploratory efficacy endpoints will be analyzed using the 
full analysis set. The per protocol set will also be used for the analysis of the primary 
and secondary efficacy endpoints. Safety and tolerability will be analyzed using the 
safety analysis set. 
5.1. 
SCREENED SET 
The screened set will include all patients screened who have given written informed 
consent. Unless specified otherwise, this set will be used for the listing and 
summarization of subject disposition, and for the listing of patient eligibility. 
 
5.2. 
SAFETY ANALYSIS SET  
The safety analysis set (SS) will include all randomized patients who were administered 
at least one dose of study medication. Patients will be analyzed according to treatment 
received. The SS will be used for all analyses of safety endpoints and for the 
presentation of patients in all subject listings, with the exception of disposition and 
eligibility. 
 
5.3. 
FULL ANALYSIS SET  
The full analysis set (FAS) will include all patients in the safety analysis set who have 
efficacy data for the primary parameter recorded for baseline and at least 1 post 
baseline assessment. Patients will be analyzed according to randomized treatment. The 
FAS will be used for all analyses of primary, secondary and exploratory efficacy 
endpoints (including the primary and secondary endpoints analysis of the combined 20 
mg and 50 mg arm versus placebo) and for the summarization of demographics and 
baseline characteristics data. 
5.4. 
PER PROTOCOL SET  
The per protocol set (PPS) will include all patients in the full analysis set who have no 
major protocol violations to be determined at the Blinded Data Review Meeting (BDRM). 
Patients will be analyzed according to randomized treatment. The PPS will be used for 
all analyses of primary and secondary efficacy endpoints.  
 
5.5. 
PROTOCOL DEVIATIONS AND VIOLATIONS 
A protocol deviation is any change or alteration from the procedures stated in the study 
protocol, consent document, recruitment process, or study materials 
(e.g., questionnaires). 
 
A major protocol violation is a deviation that has an impact on subject safety, may 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 20 of 66 
substantially alter risks to subjects, may have an effect on the integrity of the study 
data, or may affect the subject’s willingness to participate in the study. Major protocol 
violations include (but are not limited to): deviation from inclusion/exclusion criteria, 
withdrawal criteria met during the study but subject was not withdrawn, prohibited 
concomitant medications, substantial deviations from the dosing schedule. 
 
A minor protocol violation is a deviation that does not impact subject safety, 
compromise the integrity of the study data, or affect the subject’s willingness to 
participate in the study. 
 
Protocol deviations will be documented during the study period using the IMPACT 
monitoring database and will be assigned into one of the following categories:  
 
Visit schedule; 
 
Concomitant medication; 
 
Dosing; 
 
Laboratory; 
 
Non-compliance; 
 
Visit/procedures requirements; 
 
Other. 
This data will be exported from IMPACT and a listing will be generated with the date of 
occurrence, the category (as above), type of violation, and the reason for the deviation. 
The listing will be reviewed prior to database lock.  
All protocol deviation/violation data will be listed and summarized on the safety 
analysis set. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 21 of 66 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
This section describes analytical analysis issues that relate to all or some of the analytic 
analysis sections that follow. It describes general guidelines for analysis as well as the 
following items:  
 
SAS version 9.4 or higher will be used. 
 
INC Research will be responsible for reporting the demographic, safety, and efficacy 
data including listings of the administration information for collection of samples. 
 
Unless otherwise specified, summaries will be presented for each treatment group 
and dose level and overall.  
 
The total number of patients in the treatment group and dose level will be used as 
the denominator for percentage calculations, unless stated otherwise in the table 
shell.  
 
Continuous variables will be summarized using the number of observations (n), 
mean, standard deviation (SD), median, 25th and 75th percentile, 5th percentile and 
95th percentile, minimum, and maximum. Categorical variables will be summarized 
using number of observations (n), frequency and percentages of patients. 
 
All safety data will be entered in to the patient data listings. All patients entered 
into the database, including screen failures, will be included in the disposition 
listings. Patients who are screened only (who have given signed written informed 
consent) will be presented as a separate group at the end of the appropriate 
listings. 
 
All patients who provide informed consent will be accounted for in this study. 
 
In general, the listings will be sorted by dose level (treatment group), patient 
number, and assessment date (and time) if applicable.  
 
The summary tables will include the total column and columns as follows: 
o Placebo, 5 mg piromelatine, 20 mg piromelatine, 50 mg piromelatine. 
 
Multiple assessments at a given time point (planned, repeat, and unscheduled) will 
not be included in summary tables unless specified otherwise, but will be included 
in the listings. For example if there are multiple laboratory results at a given 
visit/time point, the latest non-missing value within the visit/time point window will 
be used. See the specific sections of the SAP for further descriptions.  
 
See Section 12 for INC standard programming conventions. 
 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 22 of 66 
6.2. 
KEY DEFINITIONS 
For the purposes of this study, the term “study drug” refers to piromelatine or placebo.  
 
The study day is the day relative to the date of first dose of study drug, where day -1 is 
the day before the first dose of study drug and day 1 is the day of first dose of study 
drug (Week 0 (Visit 2)). 
 
The last dose date is defined as the last non-missing date where a nonzero dose of study 
drug was recorded. 
 
Unless otherwise specified, baseline is the last non-missing observation before the start 
of the study treatment, which is expected to be the baseline visit at Week 0, or 
Screening (if existing) if the Week 0 data are not available. 
 
6.3. 
MISSING DATA 
In cases of missing baseline data for cNTB tests, the pre-baseline value will be taken for 
analysis. If the pre-baseline value is missing as well, values from Screening will be taken 
and used for analysis as baseline.  In cases where the baseline value for COWAT, CFT 
and ADAS-cog14 are missing, values obtained at Screening will be taken and used for 
analysis.  
Pattern mixture model imputation will be used to treat missing data for all analyses of 
covariance (ANCOVA) as described in Section 8.1.  In the case of cNTB composite scores 
the imputation will be carried out at the level of the composite score, not at the level 
of individual tests. 
Missing data for AEs where toxicity and relationship to study drug are missing will be 
treated as described in Section 9.3.  
Missing or partial dates for concomitant medications and adverse events will be treated 
as described in Sections 7.6 and 9.3 respectively. 
No other imputation of missing data shall be performed. 
6.4. 
POOLING OF CENTERS 
For all mixed-effects maximum likelihood repeated measures (MMRM) and ANCOVA 
models for the efficacy endpoints, data collected from investigators who enrolled fewer 
than 3 patients in any 1 treatment group will be combined prior to analysis. If this 
combination still results in a treatment group having fewer than 3 patients in any 1 
treatment group, then this group of patients will be combined with the next 
fewest-enrolling investigator. In the event that there is a tie for fewest-enrolling 
investigator, one of these will be chosen at random by a random-number generator. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 23 of 66 
6.5. 
STATISTICAL ASSUMPTIONS 
The inherent assumption of normally distributed data will be evaluated by generating 
output for the residuals from the full MMRM and ANCOVA models, which include the 
interaction term, and by testing for normality using the Shapiro-Wilk test. In the event 
that the data are predominantly non-normally distributed, analyses will also be 
conducted on the ranked data. This rank transformation will be applied by ranking all 
the data for a particular variable, across all investigators and treatments, from lowest 
to highest. Integer ranks will be assigned starting at 1; mean ranks will be assigned 
when ties occur. 
6.6. 
SUBGROUPS 
For the piromelatine treatment, the 20 mg and 50 mg arms will be combined to create 
an active arm subgroup. The active subgroup versus placebo analyses will be applied to 
all primary and secondary endpoints for the FAS using the MMRM. 
Additional subgroups will be determined according to ApoE4 carrier status (the presence 
of ApoE4 allele), baseline insomnia severity (patients being below or above the PSQI 
cutoff score of ≥5) and naïve patients and those taking AD medication 
(acetylcholinesterase inhibitors and/or memantine) at baseline. These evaluations will 
be applied to all primary and secondary efficacy endpoints for the FAS using the MMRM 
model and will include also the calculation of effect size (Cohen’s d). 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 24 of 66 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
The overall number of screened patients who have given written informed consent will 
be summarized for the screened set. 
Patient disposition will be summarized for the screened set. 
The study discontinuation along with the reasons for discontinuation as recorded on the 
eCRF, and the study day of discontinuation will be listed.  
The study disposition summary tables will include the number and percentage of 
patients in each of the analysis sets and the reason for study discontinuation. Patients 
who are screen failures will be included in the all patients column. Flowcharts, similar 
to CONSORT study diagrams, will be created for each analysis set. 
Subject disposition data will be listed on the screened set. 
7.2. 
PROTOCOL DEVIATIONS AND VIOLATIONS 
Protocol deviations will be captured by the clinical monitoring team on an ongoing basis 
throughout the study. These deviations will be discussed in a case-by-case process and 
classified into major and minor violations before the data base lock at the BDRM.  
All protocol deviations will be summarized by major/minor violations (defined within 
the BDRM) and classification for each treatment group for the safety analysis set.  
All protocol deviation/violation data will be listed on the safety analysis set. 
7.3. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Age (years) will be calculated as the number of years between the date of birth and the 
date informed consent was recorded on the eCRF. 
Age at Screening = (informed consent date - date of birth + 1) / 365.25 and truncated to 
complete years. 
 
Age (years) and body mass index (BMI) will be summarized using summary statistics for 
continuous variables. Demography (sex, race, ethnicity, age, and child-bearing 
potential) will be summarized by treatment group for patients in the full analysis set. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 25 of 66 
Sex, race, ethnicity and child bearing potential will be summarized using the summary 
statistics for categorical variables.  
Education status will be summarized using summary statistics for years of education 
achieved. Highest level of education achieved will be summarized using the summary 
statistics for categorical variables. Education status will be summarized by treatment 
group for patients in the full analysis set. 
All demography and education status data will be listed on the safety analysis set.  
7.4. 
MEDICAL/SURGICAL HISTORY  
Medical/surgical history as recorded at Screening (Visit 1) will be summarized using the 
full analysis set by treatment group using the number and percentage of patients 
reporting each system organ class (SOC) and preferred term (PT). Medical/surgical 
history will be sorted by descending overall total by SOC and PT using the Medical 
Dictionary for Regulatory Activities (MedDRA) coding dictionary version 17.1 or later in 
the summary table.  
Medical/surgical history data will be listed on the safety analysis set and sorted by 
treatment group, patient number, onset date, SOC, and PT. 
7.5. 
OTHER BASELINE CHARACTERISTICS 
Duration of AD and severity of insomnia as expressed by PSQI score at baseline will be 
summarized by treatment group using the full analysis set.  
Duration of AD will be calculated as: 
(Date of informed consent – onset date of AD) / 365.25 and displayed to 1 decimal 
place. 
For the calculation 01JAN will be imputed as only onset year of AD is recorded. Duration 
of AD and severity of disease will be summarized using summary statistics for continuous 
variables. 
Duration of AD and severity of insomnia will be summarized using the full analysis set. 
Optional ApoE4 genotyping will be summarized using the full analysis set. Subjects will 
be classified as ApoE4 carriers if they will have one or more copies of the ApoE4 allele. 
That is, subjects of the genotypes e4/e4, e4/e3 and e4/e2. Subjects without the ApoE 
e4 allele will be classified as Non-carriers (i.e., e3/e3, e3/e2, and e2/e2). This 
definition will be used for the subgroup exploratory analysis (Section 8.3.11). 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 26 of 66 
Severity of insomnia will be determined using a score cutoff of ≥5 in PSQI global score 
for insomnia at baseline. This definition will be used for the subgroup analysis (Section 
8.3.12). 
Alzheimer disease medications at baseline will be summarized using the full analysis 
set. Subjects will be classified as naïve if they do not take acetylcholinesterase 
inhibitors and/or memantine at baseline. This definition will be used for the subgroup 
exploratory analysis (Section 8.3.13). 
This will be summarized post data base lock (DBL) once the data is analyzed. 
All data will be listed on the safety analysis set. 
7.6. 
PRIOR AND CONCOMITANT MEDICATIONS 
A summary of medications taken during the course of the study will be presented in 
tabular form using Anatomical Therapeutic Chemical (ATC) classification level 2 and PT 
via the World Health Organization Drug classification Dictionary (WHO-DD) version March 
2012 or later. All medications will be summarized using the full analysis set by 
treatment group and sorted alphabetically by ATC level 2 class and PT. 
Prior medications are those medications taken before the start of treatment in the 
single-blind run-in phase, not including medications ongoing at the start of the run-in. A 
medication is considered concomitant in the single-blind run-in phase if ongoing at or 
taken on or after the start date of treatment in the run-in. A medication is considered 
concomitant in the double-blind treatment phase if ongoing at or taken on or after the 
start date of study treatment. A medication can be concomitant in both the single-blind 
run-in and double-blind treatment phases. Concomitant medications will be summarized 
by the number and percentage of patients taking a particular medication using the 
coding described above by phase. If a patient has taken a medication more than once, 
the patient will be counted only once in the total. Prior medications will be listed only. 
See Section 12.9 of the protocol for more details on the time frame allowed for 
medications. 
All prior and concomitant medications will be listed on the safety analysis set by 
treatment group. 
Medications with incomplete end dates will be considered concomitant, unless an 
incomplete date (e.g. month and year) clearly indicates that the medication started and 
stopped prior to the start of treatment: 
 
Day and month are missing and the year is equal to or after the year of the 
start of treatment in the run-in;  


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 27 of 66 
 
Day is missing and the year is after the year of the start of treatment in the 
run-in;  
 
Day is missing and the year is equal to the year of the start of treatment in 
the run-in and the month is equal to or after the month of the start of the 
run-in; 
 
Year is missing; or 
 
Complete date is missing. 
7.7. 
SCANS 
CT/MRI scans results and PET/CSF results will be recorded at Screening (Visit 1). This 
data will be listed only on the safety analysis set. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 28 of 66 
8. 
EFFICACY 
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy endpoint is the change from baseline over 26 weeks of cNTB global 
composite score. 
The global composite score of the cNTB is a composite score of the ISLT (immediate and 
delayed recall), OCL, IDN, DET, OBK and paper-based COWAT and CFT tests.  
Calculation of scores: for each test listed above a z-score relative to study baseline will 
be calculated.  
𝑧−𝑆𝑐𝑜𝑟𝑒 (𝑧𝑖𝑗𝑡) = (𝑥𝑖𝑗𝑡−𝑥̅1𝑡)
𝜎1𝑡
∗𝑀𝑢𝑙𝑡𝑖𝑝𝑙𝑖𝑐𝑎𝑛𝑑 
Where: 
t = is the test indicator (ISLT, ISLT delayed, OCL, IDN, DET, OBK, COWAT or CFT) 
i = indexes subject i 
j = indexes the jth assessment for subject i (j = 1 means baseline) 
x = cognitive score 
xijt = subject’s score for test t at the current assessment 
x̄1t = mean performance score of the study sample for test t at baseline                    
σ1t = standard deviation of the study sample for test t at baseline 
Multiplicand equals 1 for tests for which a higher score is indicative of better cognitive 
performance (i.e., ISLT, ISLTR, OCL, COWAT, CFT) and -1 for tests where a lower score 
is indicative of better cognitive performance (i.e., IDN, DET, OBK) 
Calculation of composite global score: A z-score for each test will be calculated as 
described above. A mean of all available z-scores for given patient in a given 
assessment will be calculated as the composite global score. For a given patient at a 
given assessment a minimum of 5 valid test scores of the tests listed above will be 
determined, of which at least 1 test are included from each of the domain composites 
as described in Section 3.2. 
cNTB global composite scores and changes from baseline will be summarized (by 
treatment) at Visits 2, 3, 4 and 5. Change in cNTB global composite scores from baseline 
over 26 weeks (Visit 5) will be analyzed using a MMRM model utilizing all baseline and 
postbaseline data to assess any differences in treatment effects over time. The model 
will include fixed effects of treatment, study site, visit, and treatment by visit 
interaction, with baseline score, age, gender and ApoE4 as covariates, and a baseline by 
visit interaction. The global treatment effect estimates will be reported, with 95% 
confidence intervals and P values. Baseline will be the last non-missing observation at 
Visit 2 or before. The standard error of the change from baseline will also be included. 
The adjusted mean difference between treatments versus placebo will be presented 
along with the standard error and a 95% confidence interval. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 29 of 66 
These analyses will be performed by using PROC MIXED in SAS, and adjusted means will 
be obtained by using the LSMEANS statement. 
An effect size calculation will be performed, where Cohen’s d effect size will be 
calculated on the adjusted mean difference of change from baseline of treatment 
versus placebo. The effect size will be derived as the adjusted mean difference divided 
by the pooled standard deviation. The pooled within group variance (standard deviation 
squared) of two treatments is defined as: 
               Pooled Variance = [(n1 – 1)*Var1 + (n2 -1)*Var2]/ (n1 + n2 -2) 
Where: 
n1 = number of subjects with non-missing data for Placebo at Week 26 
Var1 = variance for Placebo 
n2 = number of subjects with non-missing data for active treatment at Week 26 
Var2 = variance for active treatment 
These analyses will be performed on the full analysis set and additionally on the per 
protocol set as a supportive analysis. 
A supportive efficacy analysis will be carried out using an ANCOVA method where the 
change in cNTB global composite scores from baseline to Week 26 will be the outcome 
variable and treatment group and study site will be main effects. cNTB global composite 
scores at baseline, age, gender, and ApoE4 will be included as covariates. The standard 
error of the change from baseline will also be included. Missing data (at the level of the 
composite score, not at the level of the individual tests) will be imputed using a pattern 
mixture model approach. Four patterns of missing data will be considered and imputed 
independently as follows: 
 
Pattern 1: will include patients who completed treatment on study drug (any 
missing data here is considered missing at random); 
 
Pattern 2: will include patients who discontinue treatment early due to adverse 
events (AEs); 
 
Pattern 3: will include patients who discontinue treatment early due to lack of 
therapeutic efficacy (LOTE); 
 
Pattern 4: will include patients who discontinue treatment early due to reasons 
other than AE event or LOTE. 
The pattern mixture model methodology will be implemented using SAS procedures MI 
and MIANALYZE. Specifically, the following steps will be followed:  


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 30 of 66 
 
Intermittent missing data will first be imputed using the Markov Chain Monte 
Carlo (MCMC) method implemented with the SAS MI procedure, which is 
appropriate for non-monotonic missing data. 
 
Data for patients who discontinue early will be multiply imputed as follows: 
o If the patient discontinues due to an AE (Pattern 2) or LOTE (Pattern 3), 
then missing data will be assumed to follow a distribution similar to the 
baseline values observed in the placebo arm of the study; 
o If the patient discontinues due to reasons other than an AE or LOTE 
(Pattern 4), at each time point, missing data will be assumed to follow a 
distribution similar to scores for patients that are still in the study and 
randomized to the same treatment group. 
 
Results of the ANCOVA on the multiply imputed data will be summarized using 
the SAS procedure MIANALYZE. 
These analyses will be performed on the full analysis set and additionally on the per 
protocol set as a supportive analysis. 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 31 of 66 
8.2. 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
8.2.1. 
Clinical Global Impression of Change 
The CGIC is a single score with ordered values of 1 to 7 for “marked improvement” to 
“marked worsening”. A negative change from baseline indicates an improvement. 
Since the result for CGIC is one of a set of ordered scores, the number and percentage 
of patients with each score at each visit (Week 13 and Week 26) will be provided. The 
difference between groups will be evaluated by means of the van Elteren version of the 
Cochran-Mantel-Haenszel test and P values will be presented. 
8.2.2. 
Alzheimer’s Disease Cooperative Study/Activities of Daily Living Scale 
Adapted for MCI Patients  
The Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-
ADL) score is the total of scores from 18 (questions 19-24 shall not be analyzed for this 
endpoint) multiple-choice questions. Higher total scores mean better performance; a 
positive change from baseline indicates an improvement. Many of the questions begin 
with a selection of yes, no or don’t know, with no or don’t know given scores of 0 and 
yes leading to the multiple choices. Scores including many don’t know responses could 
be less reliable than scores with fewer such responses.  
The ADCS-ADL global scores and changes from baseline will be summarized (by 
treatment) at each visit. Change in ADCS-ADL scores from baseline to Week 26 (Visit 5) 
will be analyzed using a MMRM model utilizing all baseline and postbaseline data to 
assess any differences in treatment effects over time. The model will include fixed 
effects of treatment, study site, visit, and treatment by visit interaction, with baseline 
score, age, gender and ApoE4 as covariates, and a baseline by visit interaction. The 
global treatment effect estimates will be reported, with 95% confidence intervals and 
P values. Baseline will be the last non-missing observation at Visit 2. The standard error 
of the change from baseline will also be included. The adjusted mean difference 
between treatments versus placebo will be presented along with the standard error and 
a 95% confidence interval. 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
An effect size calculation will be performed, where Cohen’s d effect size will be 
calculated on the adjusted mean difference of change from baseline of treatment 
versus placebo. The effect size will be derived as the adjusted mean difference divided 
by the pooled standard deviation. 
These analyses will be performed on the full analysis set and additionally on the per 
protocol set as a supportive analysis. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 32 of 66 
A supportive efficacy analysis will be carried out using an ANCOVA method where the 
change in ADCS-ADL scores from baseline to Week 13 (Visit 4) and Week 26 (Visit 5) will 
be the outcome variable and treatment group and study site will be main effects. The 
ADCS-ADL scores at baseline, age, gender and ApoE4 will be included as covariates. 
Multiple imputation for missing values will take place using the pattern mixture model 
approach, as described in Section 8.1. The standard error of the change from baseline 
will also be included. The adjusted mean difference between treatments versus placebo 
will be presented along with the standard error and a 95% confidence interval. 
These analyses will be performed on the full analysis set and additionally on the per 
protocol set as a supportive analysis. 
8.2.3. 
Alzheimer’s Disease Assessment Scale Cognitive 14 Subscale  
The ADAS-cog consists of 11 tasks measuring the disturbances of memory, language, 
praxis, attention, and other cognitive abilities that are often referred to as the core 
symptoms of AD. The test comprises 11 items summed to a total score ranging from 0 to 
70, with lower scores indicating less severe impairment. A negative change indicates an 
improvement from baseline. The addition of delayed recall, number cancellation, and 
maze tasks – and thus turning ADAS-cog into a 12-, 13-, and 14-item scale, respectively – 
has increased the ability to detect changes in patients in the early stages of the disease. 
The ADAS-cog14 global scores and changes from baseline will be summarized (by 
treatment) at each visit. Change in ADAS-cog14 scores from baseline over Week 26 (Visit 
5) will be will be analyzed using a MMRM model utilizing all baseline and postbaseline 
data to assess any differences in treatment effects over time. The model will include 
fixed effects of treatment, study site, visit, and treatment by visit interaction, with 
baseline score, age, gender and ApoE4 as covariates, and a baseline by visit interaction. 
The global treatment effect estimates will be reported, with 95% confidence intervals 
and P values. Baseline will be the last non-missing observation at Visit 2 or before. The 
adjusted mean difference between treatments versus placebo will be presented along 
with the standard error and a 95% confidence interval. 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
An effect size calculation will be performed, where Cohen’s d effect size will be 
calculated on the adjusted mean difference of change from baseline of treatment 
versus placebo. The effect size will be derived as the adjusted mean difference divided 
by the pooled standard deviation. 
A supportive analysis will be carried out using an ANCOVA method where the change in 
ADAS-cog14 scores from baseline to Week 13 (Visit 4) and Week 26 (Visit 5) will be the 
outcome variable and treatment group and study site will be main effects. The ADAS-
cog14 scores at baseline, age, gender and ApoE4 will be included as covariates. Baseline 
will be the last non-missing observation at Visit 2 or before. Multiple imputations for 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 33 of 66 
missing values will take place using the pattern mixture model approach, as described 
in Section 8.1. The standard error of the change from baseline will also be included. 
The adjusted mean difference between treatments versus placebo will be presented 
along with the standard error and a 95% confidence interval. 
These analyses will be performed on the full analysis set and additionally on the per 
protocol set as a supportive analysis. 
8.2.4. 
Computerized Neuropsychological Test Battery Global Composite 
Score 
Change in cNTB global composite scores from baseline to Week 4 (Visit 3) and from 
baseline to Week 13 (Visit 4) will be analyzed using a MMRM model utilizing all baseline 
and postbaseline data to assess any differences in treatment effects over time. The 
model will include fixed effects of treatment, study site, visit, and treatment by visit 
interaction, with baseline score, age, gender and ApoE4 as covariates, and a baseline by 
visit interaction. The global treatment effect estimates will be reported, with 95% 
confidence intervals and P values. Baseline will be the last non-missing observation at 
Visit 2 or before. The standard error of the change from baseline will also be included. 
The adjusted mean difference between treatments versus placebo will be presented 
along with the standard error and a 95% confidence interval. 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
An effect size calculation will be performed, where Cohen’s d effect size will be 
calculated on the adjusted mean difference of change from baseline of treatment 
versus placebo. The effect size will be derived as the adjusted mean difference divided 
by the pooled standard deviation. 
These analyses will be performed on the full analysis set and additionally on the per 
protocol set as a supportive analysis.A supportive efficacy analysis will be carried out 
using an ANCOVA method where the change in cNTB global composite scores from 
baseline to Week 4 (Visit 3) and Week 13 (Visit 4) will be the outcome variable and 
treatment group and study site will be main effects. cNTB global composite scores at 
baseline, age, gender and ApoE4 will be included as covariates. The standard error of 
the change from baseline will also be included. Multiple imputation for missing values 
(at the level of the composite score, not at the level of the individual tests) will take 
place using the pattern mixture model approach, as described in Section 8.1. The 
adjusted mean difference between treatments versus placebo will be presented along 
with the standard error and a 95% confidence interval. Global composite scores will be 
calculated as described in Section 8.1. 
These analyses will be performed on the full analysis set and additionally on the per 
protocol set as a supportive analysis. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 34 of 66 
8.3. 
EXPLORATORY EFFICACY ENDPOINTS AND ANALYSES 
8.3.1. 
Computerized Neuropsychological Test Battery Episodic Memory 
Domain Composite Score 
The episodic memory domain of the cNTB is a composite score of the ISLT (immediate 
and delayed recall) and OCL tests. Calculation of the episodic memory domain 
composite score will be carried out by calculating for each given patient at each given 
assessment the z score as described in Section 8.1. A minimum of 2 out of 3 valid test 
scores are required for the calculation of the mean of the available z-scores composing 
the domain composite score. 
The cNTB episodic memory domain global scores and changes from baseline will be 
summarized (by treatment) at each visit. Change in cNTB episodic memory domain 
composite scores from baseline to Week 26 (Visit 5) will be analyzed using an MMRM 
model utilizing all baseline and postbaseline data to assess any differences in treatment 
effects over time. The model will include fixed effects of treatment, study site, visit, 
and treatment by visit interaction, with baseline score, age, gender and ApoE4 as 
covariates, and a baseline by visit interaction. The global treatment effect estimates 
will be reported, with 95% confidence intervals and P values. Baseline will be the last 
non-missing observation at Visit 2 or before. The adjusted mean difference between 
treatments versus placebo will be presented along with the standard error and a 95% 
confidence interval. 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
A supportive efficacy analysis will be carried out using an ANCOVA method where the 
change in cNTB episodic memory domain scores from baseline to Week 4 (Visit 3), Week 
13 (Visit 4) Week 26 (Visit 5) will be the outcome variable and treatment group and 
study site will be main effects. The cNTB episodic memory domain composite scores at 
baseline, age, gender and ApoE4 will be included as covariates. Multiple imputations for 
missing values (at the level of the composite score, not at the level of the individual 
tests) will take place using the pattern mixture model approach, as described in Section 
8.1. The standard error of the change from baseline will also be included. The adjusted 
mean difference between treatments versus placebo will be presented along with the 
standard error and a 95% confidence interval. 
8.3.2. 
Computerized Neuropsychological Test Battery Attention Domain 
Composite Score 
The attention domain of the cNTB is a composite score of the IDN and DET tests. 
Calculation of the attention domain composite score will be carried out by calculating 
for each given patient at each given assessment the z score as described in Section 8.1. 
Two valid test scores are required for the calculation of the mean of the available z-
scores composing the domain composite score.  


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 35 of 66 
The cNTB attention domain global scores and changes from baseline will be summarized 
(by treatment) at each visit. Change in cNTB attention domain scores from baseline 
over Week 26 will be analyzed using a MMRM model utilizing all baseline and 
postbaseline data to assess any differences in treatment effects over time. The model 
will include fixed effects of treatment, study site, visit, and treatment by visit 
interaction, with baseline score, age, gender and ApoE4 as covariates, and a baseline by 
visit interaction. The global treatment effect estimates will be reported, with 95% 
confidence intervals and P values. Baseline will be the last non-missing observation at 
Visit 2 or before. The adjusted mean difference between treatments versus placebo will 
be presented along with the standard error and a 95% confidence interval. 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
A supportive efficacy analysis will be carried out using an ANCOVA method where the 
change in cNTB attention domain composite scores from baseline to Week 4 (Visit 3), 
Week 13 (Visit 4) and Week 26 (Visit 5) will be the outcome variable and treatment 
group and study site will be main effects. cNTB attention domain composite scores at 
baseline, age, gender and ApoE4 will be included as covariates. Multiple imputations for 
missing values (at the level of the composite score, not at the level of the individual 
tests) will take place using the pattern mixture model approach, as described in Section 
8.1. The standard error of the change from baseline will also be included. The adjusted 
mean difference between treatments versus placebo will be presented along with the 
standard error and a 95% confidence interval. 
8.3.3. Executive Function Domain Composite Score 
The executive function domain is a composite score of the OBK, COWAT and CFT tests. 
Calculation of the executive function domain composite score will be carried out by 
calculating for each given patient at each given assessment the z score as described in 
Section 8.1. A minimum of 2 out of 3 valid test scores are required for the calculation of 
the mean of the available z-scores composing the domain composite score. 
The cNTB executive function domain global scores and changes from baseline will be 
summarized (by treatment) at each visit. Change in cNTB executive function domain 
scores from baseline over Week 26 will be analyzed using a MMRM model utilizing all 
baseline and postbaseline data to assess any differences in treatment effects over time. 
The model will include fixed effects of treatment, study site, visit, and treatment by 
visit interaction, with baseline score, age, gender and ApoE4 as covariates, and a 
baseline by visit interaction. The global treatment effect estimates will be reported, 
with 95% confidence intervals and P values. Baseline will be the last non-missing 
observation at Visit 2 or before. The adjusted mean difference between treatments 
versus placebo will be presented along with the standard error and a 95% confidence 
interval. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 36 of 66 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
A supportive efficacy analysis will be carried out using an ANCOVA method where the 
change in cNTB executive function domain scores from baseline to Week 4 (Visit 3), 
Week 13 (Visit 4) and Week 26 (Visit 5) will be the outcome variable and treatment 
group and study site will be main effects. The cNTB executive function domain scores at 
baseline, age, gender and ApoE4 will be included as covariates. Multiple imputations for 
missing values (at the level of the composite score, not at the level of the individual 
tests) will take place using the pattern mixture model approach, as described in Section 
8.1. The standard error of the change from baseline will also be included. No 
imputation for missing values at Week 26 will take place. The adjusted mean difference 
between treatments versus placebo will be presented along with the standard error and 
a 95% confidence interval. 
8.3.4. 
Mini Mental State Examination 
The MMSE is a brief assessment instrument used to assess cognitive function in elderly 
patients. The instrument is divided into 2 sections. The first section measures 
orientation, memory, and attention; the maximum score is 21. The second section tests 
the ability of the patient to name objects, follow verbal and written commands, write a 
sentence, and copy figures: the maximum score is 9. The scoring range for the MMSE is 
0-30.   
Change in MMSE global scores from baseline to Week 26 (Visit 5) will be analyzed using 
an ANCOVA method where the change in MMSE scores from baseline to Week 26 will be 
the outcome variable and treatment group and study site will be main effects. MMSE 
scores at baseline, age, gender and ApoE4 will be included as covariates. Baseline will 
be the last non-missing observation at Screening (Visit 1). The standard error of the 
change from baseline will also be included. Multiple imputations for missing values will 
take place using the pattern mixture model approach, as described in Section 8.1. The 
adjusted mean difference between treatments versus placebo will be presented along 
with the standard error and a 95% confidence interval. 
8.3.5. 
Individual Computerized and Paper-Based Neuropsychological Test 
Battery Score 
The individual z-scores of the cNTB include ISLT (immediate and delayed recall), OCL, 
IDN, DET, OBK, and paper-based COWAT and CFT. 
Change in the individual NTB scores from baseline to Week 26 (Visit 5) will be analyzed 
using a MMRM model utilizing all baseline and postbaseline data to assess any 
differences in treatment effects over time. The model shall include fixed effects of 
treatment, study site, visit, and treatment by visit interaction, with baseline score, 
age, gender and ApoE4 as covariates, and a baseline by visit interaction. The global 
treatment effect estimates will be reported, with 95% confidence intervals and 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 37 of 66 
P values. Baseline will be the last non-missing observation at Visit 2 or before. The 
adjusted mean difference between treatments versus placebo will be presented along 
with the standard error and a 95% confidence interval. 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
As supportive analysis for the change in the individual NTB scores from baseline to Week 
4 (Visit 3), Week 13 (Visit 4) and Week 26 (Visit 5) will be analyzed using an ANCOVA 
method, where the change in individual NTB scores from baseline (Visit 2) to Week 26 
(Visit 5) will be the outcome variable and treatment group and study site will be main 
effects. The individual NTB scores at baseline, age, gender and ApoE4 will be included 
as covariates. The standard error of the change from baseline will also be included. 
Multiple imputations for missing values will take place using the pattern mixture model 
approach, as described in Section 8.1. The adjusted mean difference between 
treatments versus placebo will be presented along with the standard error and a 95% 
confidence interval. 
8.3.6. 
Neuropsychiatric Inventory 
The NPI scale consists of 12 domains that are rated for both frequency (range 1-4) and 
severity (range 1-3). A composite score for each domain is calculated (frequency × 
severity), which ranges from 1 to 12. There is a leading question for each item. If the 
symptom is not present, then the frequency, severity, and distress scores are not 
completed. In this case the score is 0 for the item. The sum of the composite scores 
yields the NPI-12 total score (range 0-144). A negative change in score indicates an 
improvement from baseline (symptom reduction). 
Change in the NPI individual items and global scores from baseline to Week 26 (Visit 5) 
will be analyzed using an ANCOVA method, where the change in the NPI scores from 
baseline to Week 26 will be the outcome variable and treatment group and study site 
will be main effects. The NPI scores at baseline, age, gender, and ApoE4 will be 
included as covariates. Baseline will be the last non-missing observation at Visit 2. The 
standard error of the change from baseline will also be included. Multiple imputations 
for missing values will take place using the pattern mixture model approach, as 
described in Section 8.1. The adjusted mean difference between treatments versus 
placebo will be presented along with the standard error and a 95% confidence interval. 
The NPI-10 total score (range 0-120) will also be calculated by removing the sleep and 
appetite and eating domains. This will be summarized and analyzed as per the NPI-12 
score. The distress score shall be listed only. 
8.3.7. 
Pittsburgh Sleep Quality Index 
The PSQI is an effective instrument used to measure the quality and patterns of sleep in 
older adults. It differentiates “poor” from “good” sleep by measuring 7 areas 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 38 of 66 
(components): subjective sleep quality, sleep latency, sleep duration, habitual sleep 
efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction 
over the last month. The patient self-rates each of these 7 areas of sleep. Scoring of 
answers is based on a 0 to 3 scale, where a score of 3 reflects the negative extreme on 
the Likert Scale. A global sum of 5 or greater indicates a “poor” sleeper.  
Change in the PSQI, for each of the 7 individual components, questions 2 and 4, and the 
global scores from baseline will be summarized (by treatment) at each visit. Change in 
PSQI scores from baseline to Week 26 will be analyzed using a MMRM model utilizing all 
baseline and postbaseline data to assess any differences in treatment effects over time. 
The model will include fixed effects of treatment, study site, visit, and treatment by 
visit interaction, with baseline score, age, gender and ApoE4 as covariates, and a 
baseline by visit interaction. The global treatment effect estimates will be reported, 
with 95% confidence intervals and P values. Baseline will be the last non-missing 
observation at Visit 2. The adjusted mean difference between treatments versus 
placebo will be presented along with the standard error and a 95% confidence interval. 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
As supportive analysis for the change in PSQI scores (individual components and global) 
from baseline to Week 4 (Visit 3), Week 13 (Visit 4) and Week 26 (Visit 5) will be 
analyzed using an ANCOVA method where the change in the PSQI scores from baseline to 
Week 4, Week 13, or Week 26 will be the outcome variable and treatment group and 
study site will be main effects. The PSQI scores at baseline, age, gender, and ApoE4 will 
be included as covariates. Multiple imputations for missing values will take place using 
the pattern mixture model approach, as described in Section 8.1. The standard error of 
the change from baseline will also be included. The adjusted mean difference between 
treatments versus placebo will be presented along with the standard error and a 95% 
confidence interval. 
8.3.8. 
Alzheimer’s Disease Assessment Scale Cognitive 13, 12 and 11 
Subscale  
The ADAS-cog13, ADAS-cog12 and ADAS-cog11 scores and changes from baseline will be 
summarized (by treatment) separately at each visit. Change in ADAS-cog13, ADAS-cog12 
and ADAS-cog11 scores from baseline to Week 26 (Visit 5) will be analyzed separately 
using a MMRM model utilizing all baseline and postbaseline data to assess any 
differences in treatment effects over time. The model will include fixed effects of 
treatment, study site, visit, and treatment by visit interaction, with baseline score as a 
covariate, and a baseline by visit interaction. The global treatment effect estimates will 
be reported, with 95% confidence intervals and P values. Baseline will be the last non-
missing observation at Visit 2. The adjusted mean difference between treatments versus 
placebo will be presented along with the standard error and a 95% confidence interval. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 39 of 66 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
As supportive analysis for the change in ADAS-cog 11, 12 and 13 scores from baseline to 
Week 13 (Visit 4) and Week 26 (Visit 5) will be analyzed using an ANCOVA method, 
where the change in ADAS-cog 11, 12 and 13 scores from baseline to Week 26 will be 
the outcome variable and treatment group and study site will be main effects. The 
ADAS-cog 11, 12 and 13 scores at baseline, age, gender, and ApoE4 will be included as 
covariates. Multiple imputations for missing values will take place using the pattern 
mixture model approach, as described in Section 8.1. The standard error of the change 
from baseline will also be included. The adjusted mean difference between treatments 
versus placebo will be presented along with the standard error and a 95% confidence 
interval. 
8.3.9. 
Computerized Neuropsychological Test Battery Global Composite 
Score without Paper-Based Components 
The cNTB global composite score contains both computerized and paper-based (CFT and 
COWAT) scores. As an exploratory analysis, the analyses on the cNTB global composite 
score shall be repeated with the paper-based components removed. 
Change in cNTB global composite scores from baseline to Week 4 (Visit 3), from baseline 
to Week 13 (Visit 4), and from baseline to Week 26 (Visit 5) will be analyzed using a 
MMRM model utilizing all baseline and postbaseline data to assess any differences in 
treatment effects over time. The model will include fixed effects of treatment, study 
site, visit, and treatment by visit interaction, with baseline score, age, gender and 
ApoE4 as covariates, and a baseline by visit interaction. The global treatment effect 
estimates will be reported, with 95% confidence intervals and P values. Baseline will be 
the last non-missing observation at Visit 2 or before. The standard error of the change 
from baseline will also be included. The adjusted mean difference between treatments 
versus placebo will be presented along with the standard error and a 95% confidence 
interval. 
These analyses will be performed using PROC MIXED in SAS, and adjusted means will be 
obtained by using the LSMEANS statement. 
A supportive efficacy analysis will be carried out using an ANCOVA method where the 
change in cNTB global composite scores from baseline to Week 4 (Visit 3), Week 13 
(Visit 4), and Week 26 (Visit 5) will be the outcome variable and treatment group and 
study site will be main effects. cNTB global composite scores at baseline, age, gender, 
and ApoE4 will be included as covariates. The standard error of the change from 
baseline will also be included. Multiple imputation for missing values (at the level of the 
composite score, not at the level of the individual tests) will take place using the 
pattern mixture model approach, as described in Section 8.1. The adjusted mean 
difference between treatments versus placebo will be presented along with the 
standard error and a 95% confidence interval. Global composite scores will be 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 40 of 66 
calculated as described in Section 8.1, but with the removal of the paper-based CFT and 
COWAT components. 
8.3.10. Combined Piromelatine Treatment Group 20 mg + 50 mg vs Placebo 
An additional exploratory efficacy analysis will be carried out for the primary and 
secondary efficacy endpoints (as detailed in Sections 4.1 and 4.2) comparing placebo 
with a combined treatment group of 20 mg + 50 mg. 
These analyses will be performed on the full analysis set using the MMRM model and will 
include calculation of an effect size. See Section 8.1 and 8.2 for the individual analyses. 
8.3.11. ApoE4 Carrier Status 
An additional exploratory efficacy analysis will be carried out for all primary and 
secondary efficacy endpoints (as detailed in Sections 4.1 and 4.2) separately for ApoE4 
carriers and non-carriers (as described in Section 7.5). 
These analyses will be performed on the full analysis set using the MMRM model and will 
include calculation of an effect size. See Sections 8.1 and 8.2 for the individual 
analyses. 
These analyses will be performed only for patients who have provided their consent to 
use their genetic material for the analysis of the ApoE gene. 
8.3.12. Insomnia at Baseline 
An additional exploratory efficacy analysis will be carried out for all primary and 
secondary efficacy endpoints (as detailed in Sections 4.1 and 4.2) separately for 
patients with and without insomnia as determined by the PSQI score obtained at 
baseline (as described in Section 7.5). 
These analyses will be performed on the full analysis set using the MMRM model and will 
include calculation of an effect size. See Sections 8.1 and 8.2 for the individual 
analyses. 
8.3.13. Alzheimer’s Disease Medications at Baseline 
An additional exploratory efficacy analysis will be carried out for all primary and 
secondary efficacy endpoints (as detailed in Sections 4.1 and 4.2) separately for 
patients receiving Alzheimer’s disease medications (acetylcholinesterase inhibitors 
and/or memantine) and naïve patients (as described in Section 7.5). 
These analyses will be performed on the full analysis set using the MMRM model and will 
include calculation of an effect size. See Sections 8.1 and 8.2 for the individual 
analyses. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 41 of 66 
8.3.14 
Clinical Dementia Rating 
The Clinical Dementia Rating (CDR) data will be listed only. 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 42 of 66 
9. 
SAFETY 
The safety analysis set will be used for the listing of safety data and for all safety 
analyses. Safety will be assessed on the basis of adverse event (AE) reports, clinical 
laboratory data (including sex hormones), ECG parameters, physical examinations, vital 
signs and suicidal ideation (Sheehan-STS).  
9.1. 
EXTENT OF EXPOSURE 
The duration of exposure (in days) to study medication will be summarized using 
summary statistics for continuous variables. This will be calculated using the safety 
analysis set. 
Duration of exposure will be calculated by: 
Date of last dose – date of first dose + 1 
The study medication accountability will be listed along with the duration of exposure. 
9.2. 
TREATMENT COMPLIANCE  
Treatment compliance will be calculated at each visit by the investigator. Compliance 
to study medication will be summarized using summary statistics for continuous 
variables for each visit and overall. This will be calculated using the full analysis set. 
Compliance (%) for each visit will be calculated as: 
(Number of tablets actually taken / number of days since last visit) * 100 
Compliance will also be listed. 
For Screening (Visit 1), compliance will be calculated as: 
(Number of tablets actually taken / number of days since beginning of run-in) * 
100 
9.3. 
ADVERSE EVENTS 
Adverse events will be collected throughout the study, from informed consent until the 
end of the treatment period. 
Adverse events will be summarized by the SOC and PT based on the MedDRA dictionary 
version 17.1 or later.  
 
Treatment emergent adverse events (TEAEs) are defined as any adverse events (AEs) 
that occur after the start of administration of the first dose of study drug and through 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 43 of 66 
14 days after the last dose of study drug, or any event that is present at baseline and 
continues after the first dose of study drug but worsens in intensity.  
 
See Section 14.1 of the protocol for definition of serious adverse events (SAEs).   
Treatment emergent AEs will be characterized based on the onset date relative to each 
patient’s participation in the study.   
Adverse events with incomplete start dates will be considered a TEAE if: 
 
Day and month are missing and the year is equal to or after the year of the 
first dose date;  
 
Day is missing and the year is after the year of the first dose;  
 
Day is missing and the year is equal to the year of the first dose date and the 
month is equal to or after the month of the first dose date; 
 
Year is missing; or 
 
Complete date is missing. 
If the relationship to study treatment is missing then related will be used for the 
summaries. Similarly, events with missing intensity or severity will be counted as severe 
(Grade 3).   
The summary tables will include the number of subjects and the number of events. 
Percentages will be based on the number of subjects. For summaries by SOC and PT, a 
patient will be counted once at the SOC level and once at each PT within the SOC level. 
For summaries by SOC, PT, and maximum severity, a patient will be counted once at 
the highest severity level for which the event occurred at the SOC level and the highest 
severity level for each unique PT within that SOC level. Therefore, patients may only 
contribute once to each PT and once to each SOC level.    
The summaries presenting frequency of AEs by SOC and PT will be ordered by overall 
descending frequency of SOC and then, within a SOC, by overall descending frequency 
of PT. 
The following AE tables will be provided: 
 
An overall summary of the number and percentage of patients reporting AEs, 
TEAEs, treatment-related TEAEs, severe TEAEs, serious TEAEs, treatment-related 
serious TEAEs, and TEAEs leading to withdrawal of study medication; 
 
TEAEs, overall and by SOC and PT; 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 44 of 66 
 
Serious TEAEs, overall and by SOC and PT; 
 
TEAEs related to study medication, overall and by SOC and PT; 
 
TEAEs, overall and by SOC, PT and maximum severity; 
 
TEAEs leading to withdrawal of study medication, overall and by SOC and PT; 
 
TEAEs, overall and by PT; 
 
All AEs, overall and by SOC and PT; 
 
All AEs, overall and by SOC, PT and maximum severity.   
With the exception of the all AEs table, only the TEAEs will be included in the summary 
tables; however, all AEs will be included in the listings. Any AE occurring during the 
single-blind run-in, before the first dose of study medication in the double-blind 
treatment phase, will be included in the summaries of all AEs only. Any AE occurring 
before the single-blind run-in will be included in the data listings but will not be 
included in the summary tables of AEs. Any AE occurring within the defined 14 day 
follow-up period after discontinuation of study medication will be included in the AE 
summaries. 
 
With the exception of the all AEs tables, the summaries of TEAEs will present frequency 
of AEs by SOC and PT, will be ordered by overall descending frequency of SOC and then, 
within a SOC, by overall descending frequency of PT.  
 
 
An additional listing will be provided for SAEs leading to withdrawal from the study. 
TEAEs will be flagged in the listings. 
 
 
9.4. 
LABORATORY EVALUATIONS 
All blood and urine samples will be analyzed using a local laboratory. The sampling will 
be performed at the site at Screening (Visit 1), Visit 4 (Week 13), and Visit 5 (Week 26) 
and as soon as possible following the premature discontinuation visit (if applicable).  
The following parameters will be measured: 
- 
Hematology: hemoglobin, hematocrit, red blood cells, mean corpuscular 
hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular 
hemoglobin concentration, large unstained cells, white blood cells, lymphocytes, 
monocytes, neutrophils, eosinophils, basophils and platelets. 
- 
Chemistry: creatinine, uric acid, urea, aspartate aminotransferase (ASAT), 
alanine aminotransferase (ALAT), albumin, gamma-glutamyltransferase (GGT), 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 45 of 66 
total protein, sodium, potassium, chloride, calcium, phosphorus, glucose, 
alkaline phosphatase, total bilirubin, total testosterone, free testosterone, Sex 
Hormone Binding Globulin (SHBG) and prolactin. 
- 
Urinalysis: bilirubin, blood, clarity, color, glucose, ketones, leukocyte esterase, 
nitrite, pH, protein, specific gravity and urobilinogen. 
All summaries of hematology, chemistry and urinalysis will be based on results in 
standard international (SI) system of units, conversion will be performed according to 
the data management plan (DMP) prior to the transfer to INC Research. The high and 
low classifications will be derived relative to the result and normal range in SI units.  
Summary tables for hematology, chemistry and urinalysis laboratory variables will 
include the following: descriptive statistics for SI values and change from baseline for 
all continuous variables by assessment for each module and dose level. In general, any 
quantitative assessments for urinalysis will be summarized using the number and 
percentage of subjects with the given result. Percentages will be calculated out of the 
number of subjects with non-missing data. Shift tables showing the number of patients 
having values below, within and above the normal range at each assessment at 
Screening and each post baseline visit will be presented. 
All laboratory results in original and SI units will be included in data listings. Tests will 
be listed in alphabetical order. Urine drug screen will be listed. 
Optional blood sampling for ApoE4 genotyping (e4/e4, e4/e3, e4/e2, e3/e3, e3/e2, 
e2/e2) will be listed. This data will be collected and reported after DBL. 
9.5. 
VITAL SIGNS  
Vital sign measurements will include measurements of heart rate (beats/min) and 
systolic and diastolic blood pressure (mmHg). Height (cm) and weight (kg) will also be 
recorded at Screening (Visit 1) and at Visit 5 (Week 26) for weight only. BMI (kg/m2) will 
be calculated at Screening also and summarized with the demography data (see Section 
7.3). 
 
Vital signs will be taken before administration of study drug.  
 
Summary tables by visit and time point and change from baseline to visit and time point 
for each vital sign parameter will be provided. 
All vital signs measurement data will be listed.  
9.6. 
ECG  
Resting 12-lead ECGs will be recorded at Screening (Visit 1), Visit 4 (Week 13), Visit 5 
(Week 26), and early termination visit. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 46 of 66 
Summary tables by visit and time point and change from baseline to visit and time point 
for each ECG parameter (heart rate (bpm), PR interval (msec)), QRS interval (msec), QT 
interval (msec), RR interval (msec) and QTcF interval (msec) will be provided.    
The overall results of the ECGs recorded as “normal”, “abnormal, not clinically 
significant (NCS)” or “abnormal, clinically significant (CS)” will be summarized by 
treatment group at each time point.  
12-lead ECG data will be listed. 
9.7. 
PHYSICAL EXAMINATION 
Physical examination will be performed at Screening (Visit 1), Visit 4 (Week 13), Visit 5 
(Week 26), and early termination visit. 
 
At all visits, the assessment of clinically significance abnormal finding will be reported 
as either medical history or an AE as applicable.  
 
The overall physical examination results recorded as “normal” or “abnormal” will be 
summarized by treatment group at each visit. 
 
Physical examination data will also be listed. 
9.8. 
OTHER SAFETY 
Suicidal ideation will be rated at Screening (Visit 1), Visit 4 (Week 13), and Visit 5 
(Week 26) using the Sheehan-STS. 
A summary table by visit and change from baseline to visit will be provided for the total 
score. A summary table of the individual Sheehan-STS scores will also be provided by 
visit showing the number and percentage of subjects with each response for each 
individual question. 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 47 of 66 
10. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Sample size and statistical power: In order to meet piromelatine drug development 
program timelines it has been decided to reduce the sample size for the ReCOGNITION 
study from 500 to 400 evaluable subjects. This reduction results from changing the 
originally highly powered study at 88% to 80%, while keeping the effect size (0.35) based 
on which the sample size was calculated. This is still an acceptable power in clinical 
trials which Neurim believes is appropriate to confirm the potential efficacy of 
piromelatine. 
Primary endpoint: Version 7 of the protocol included the addition of COWAT and CFT to 
executive function domain of the cNTB. These two tests should have been included also 
in the global composite score. The rules for a valid global composite score will include 
now over 8 tests (ISLT immediate and delayed, OCL, IDN, DET, OBK, COWAT and CFT) 
instead of 6, of which the executive function domain will include 3 tests (OBK, COWAT 
and CFT). 
Primary and secondary statistical analysis: For all endpoints the order was reversed; 
MMRM will be used as the primary endpoint, while ANCOVA will be used as the 
secondary analysis. 
Secondary and exploratory analysis: cNTB attention, cNTB episodic and executive 
function domains have been moved from secondary to exploratory efficacy endpoints. 
Co-variates: Age, gender, and ApoE4 will be used as co-variates for the MMRM and 
ANCOVA. 
Imputations: The pattern mixture model approach will be used for the ANCOVA in cases 
of missing values as described in Section 8.1. 
Analysis of the CGIC endpoint: The protocol states that the ANCOVA method will be 
used to analyze the change from baseline between the treatment groups. As there is no 
baseline result recorded in the CRF, this method is not appropriate for this endpoint. 
The difference between the treatment groups will instead be evaluated by means of the 
van Elteren version of the Cochran-Mantel-Haenszel test. 
MMSE: Section 17.3.4 of the protocol states that MMSE will be analyzed using an 
ANCOVA. This analysis will be performed on the global scores. 
NPI: Section 17.3.4 of the protocol states that NPI will be analyzed using an ANCOVA. 
This analysis will be performed on individual items and the global score of 10 and 12 
items. 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 48 of 66 
Additional analyses: For the purpose of increasing the statistical power the 20 mg and 
50 mg arms will be combined to create an active arm with larger sample size for an 
analysis as compared to placebo. This active versus placebo analysis will be applied to 
all endpoints for the FAS using the MMRM.  
As the paper-based CFT/COWAT and computerized OBK of the cNTB executive function 
domain are collected differently, an exploratory analysis shall be performed, where the 
analyses on the cNTB global composite score shall be repeated with the paper-based 
components removed as detailed in Section 8.3.9.  
Additional subgroup exploratory analyses will be performed, as detailed in Sections 
8.3.11 – 8.3.13, to explore the subgroup effects for ApoE4 carriers, insomnia at baseline 
and AD concomitant medications. 
Prior medications: Section 17.3.1 of the protocol states that prior medications will be 
summarized by treatment group, but prior medications will be listed only. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 49 of 66 
11. 
REFERENCE LIST 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 50 of 66 
12. 
PROGRAMMING CONSIDERATIONS 
All TLFs and statistical analyses will be generated using SAS® 9.3 or higher (SAS® 
Institute Inc., Cary, NC, USA). Computer-generated TLF output will adhere to the 
following specifications.   
12.1. 
GENERAL CONSIDERATIONS 
 
One SAS program can create several outputs. Or a separate SAS program will be 
created for each output. 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in Word rtf and Excel CSV format. 
 
Numbering of TFLs will follow International Council on Harmonization (ICH) E3 
guidance 
 
12.2. 
TABLE, LISTING, AND FIGURE FORMAT 
12.2.1. General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 8  
 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
 
TLFs will be in black and white (no color), unless otherwise specified 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
12.2.2. Headers 
 
All output should have the following header at the top left of each page: 
Neurim ReCOGNITION Protocol NEUP11-AD2 (INC Research study number 1006401)    
 
          


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 51 of 66 
Draft/Final Run <date> 
 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
 
The date output was generated should appear along with the program name as a 
footer on each page. 
12.2.3. Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be 
used to identify TLFs with related contents. The title is centered. The analysis set 
should be identified on the line immediately following the title. The title and table 
designation are single spaced. A solid line spanning the margins will separate the 
display titles from the column headers. There will be 1 blank line between the last 
title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Safety Analysis Set 
 
12.2.4. Column Headers 
 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment. 
 
For numeric variables, include “unit” in column or row heading when appropriate. 
 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
 
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active 
comparator trials, followed by a total column (if applicable). 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 52 of 66 
12.2.5. Body of the Data Display 
12.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
 
12.2.5.2. Table Conventions 
 
Units will be included where available 
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
n 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 53 of 66 
 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned 
as >0.999 then present as >0.999 
 
Effect size Cohen’s d value should be rounded to 2 decimal places. 
 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0.  A common convention is to display as '<0.1', 
or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis set for the treatment group who 
have an observation will be the denominator. Percentages after zero counts should 
not be displayed and percentages equating to 100% should be presented as 100%, 
without any decimal places.  
 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence in the active treatment group 
in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by preferred term), drugs (by ATC1 code), and 
adverse events (by preferred term) should be displayed in decreasing order. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated 
should be reported as “-”. 
 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
 
12.2.5.3. Listing Conventions 
 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 54 of 66 
 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
 
Units will be included where available 
 
12.2.5.4. Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
12.2.6. Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
 
Subject specific footnotes should be avoided, where possible. 
 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 55 of 66 
13. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analysis. INC Research SOP 03.010 
and 03.013 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
proper clinical trial output by checking for their logic, efficiency and commenting and 
by review of the produced output. 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 56 of 66 
14. 
INDEX OF TABLES 
Table Number 
Name 
Analysis Set 
Table 14.1.1 
Patient Disposition  
Screened Set 
Table 14.1.2.1 
Protocol Deviations / Violations  
Safety Analysis Set 
Table 14.1.2.2 
Reason for Exclusion from the Analysis Set  
Safety Analysis Set 
Table 14.1.3.1 
Demographic Characteristics  
Full Analysis Set 
Table 14.1.3.2.1 
Baseline Characteristics – Alzheimer’s Disease  
Full Analysis Set 
Table 14.1.3.2.2 
Baseline Characteristics – ApoE4 Genotyping  
Full Analysis Set 
Table 14.1.3.3 
Medical/Surgical History  
Full Analysis Set 
Table 14.1.4 
Concomitant Medications 
Full Analysis Set 
Table 14.1.5 
Treatment Compliance  
Full Analysis Set 
Table 14.2.1.1 
cNTB Global Composite Scores by Visit  
Full Analysis Set 
Table 14.2.1.2 
MMRM Analysis of cNTB Global Composite Scores from 
Baseline to Week 26 
Full Analysis Set 
Table 14.2.1.3 
cNTB Global Composite Scores by Visit  
Per Protocol Set 
Table 14.2.1.4 
MMRM Analysis of cNTB Global Composite Scores from 
Baseline to Week 26 
Per Protocol Set 
Table 14.2.1.5 
cNTB Global Composite Scores: Analysis of Change 
from Baseline to Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.1.6 
cNTB Global Composite Scores: Analysis of Change 
from Baseline to Week 26 versus Placebo  
Per Protocol Set 
Table 14.2.2.1.1 
CGIC Results by Visit  
Full Analysis Set 
Table 14.2.2.1.2 
CGIC Results by Visit  
Per Protocol Set 
Table 14.2.2.2.1 
ADAS-ADL Scale adapted for MCI Patients Results by 
Visit  
Full Analysis Set 
Table 14.2.2.2.2 
MMRM Analysis of ADAS-ADL Scale adapted for MCI 
Patients Results 
Full Analysis Set 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 57 of 66 
Table 14.2.2.2.3 
ADAS-ADL Scale adapted for MCI Patients Results by 
Visit  
Per Protocol Set 
Table 14.2.2.2.4 
MMRM Analysis of ADAS-ADL Scale adapted for MCI 
Patients Results  
Per Protocol Set 
Table 14.2.2.2.5 
ADAS-ADL Scale adapted for MCI Patients Results: 
Analysis of Change from Baseline to Week 13 and 
Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.2.2.6 
ADAS-ADL Scale adapted for MCI Patients Results: 
Analysis of Change from Baseline to Week 13 and 
Week 26 versus Placebo  
Per Protocol Set 
Table 14.2.2.3.1 
ADAS-cog14 Results by Visit  
Full Analysis Set 
Table 14.2.2.3.2 
MMRM Analysis of ADAS-cog14 Results  
Full Analysis Set 
Table 14.2.2.3.3 
ADAS-cog14 Results  by Visit 
Per Protocol Set 
Table 14.2.2.3.4 
MMRM Analysis of ADAS-cog14 Results  
Per Protocol Set 
Table 14.2.2.3.5 
ADAS-cog14 Results: Analysis of Change from 
Baseline to Week 13 and Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.2.3.6 
ADAS-cog14 Results: Analysis of Change from 
Baseline to Week 13 and Week 26 versus Placebo  
Per Protocol Set 
Table 14.2.2.4.1 
MMRM Analysis of cNTB Global Composite Scores from 
Baseline to Week 4 and Week 13 
Full Analysis Set 
Table 14.2.2.4.2 
MMRM Analysis of cNTB Global Composite Scores from 
Baseline to Week 4 and Week 13 
Per Protocol Set 
Table 14.2.2.4.3 
cNTB Global Composite Scores: Analysis of Change 
from Baseline to Week 4 and Week 13 versus Placebo  
Full Analysis Set 
Table 14.2.2.4.4 
cNTB Global Composite Scores: Analysis of Change 
from Baseline to Week 4 and Week 13 versus Placebo  
Per Protocol Set 
Table 14.2.3.1.1 
cNTB Episodic Memory Domain Global Composite 
Scores by Visit  
Full Analysis Set 
Table 14.2.3.1.2 
MMRM Analysis of cNTB Episodic Memory Domain 
Global Composite Scores  
Full Analysis Set 
Table 14.2.3.1.3 
cNTB Episodic Memory Domain Global Composite 
Scores: Analysis of Change from Baseline to Week 4, 
Full Analysis Set 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 58 of 66 
Week 13 and Week 26 versus Placebo  
Table 14.2.3.2.1 
cNTB Attention Domain Global Composite Scores by 
Visit  
Full Analysis Set 
Table 14.2.3.2.2 
MMRM Analysis of cNTB Attention Domain Global 
Composite Scores  
Full Analysis Set 
Table 14.2.3.2.3 
cNTB Attention Domain Global Composite Scores: 
Analysis of Change from Baseline to Week 4, Week 13 
and Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.3.3.1 
cNTB Executive Function Global Domain Composite 
Scores by Visit  
Full Analysis Set 
Table 14.2.3.3.2 
MMRM Analysis of cNTB Executive Function Domain 
Global Composite Scores  
Full Analysis Set 
Table 14.2.3.3.3 
cNTB Executive Function Domain Global Composite 
Scores: Analysis of Change from Baseline to Week 4, 
Week 13 and Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.3.4.1 
MMSE Global Results by Visit  
Full Analysis Set 
Table 14.2.3.4.2 
MMSE Global Results: Analysis of Change from 
Screening to Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.3.5.1 
Individual Computerized and Paper-Based NTB Scores 
by Visit  
Full Analysis Set 
Table 14.2.3.5.2 
MMRM Analysis of Individual Computerized and 
Paper-Based NTB Scores  
Full Analysis Set 
Table 14.2.3.5.3 
Individual Computerized and Paper-Based NTB 
Scores: Analysis of Change from Baseline to Week 4, 
Week 13 and Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.3.6.1 
NPI Individual Items and Total Scores by Visit 
Full Analysis Set 
Table 14.2.3.6.2 
NPI Individual Items and Total  Scores: Analysis of 
Change from Baseline to Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.3.7.1 
PSQI Individual Items and Global Scores by Visit  
Full Analysis Set 
Table 14.2.3.7.2 
MMRM Analysis of PSQI Individual Items and Global 
Scores  
Full Analysis Set 
Table 14.2.3.7.3 
PSQI Individual Items and Global Scores: Analysis of 
Change from Baseline to Week 4, Week 13 and Week 
Full Analysis Set 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 59 of 66 
26 versus Placebo  
Table 14.2.3.8.1 
ADAS-cog13, ADAS-cog12 and ADAS-cog11 Results by 
Visit  
Full Analysis Set 
Table 14.2.3.8.2 
MMRM Analysis of ADAS-cog13, ADAS-cog12 and ADAS-
cog11  
Full Analysis Set 
Table 14.2.3.8.3 
ADAS-cog13, ADAS-cog12 and ADAS-cog11 Results: 
Analysis of Change from Baseline to Week 13 and 
Week 26 versus Placebo  
Full Analysis Set 
Table 14.2.3.9.1 
cNTB Global Composite Scores without Paper-Based 
Components by Visit  
Full Analysis Set 
Table 14.2.3.9.2 
MMRM Analysis of cNTB Global Composite Scores 
without Paper-Based Components from Baseline to 
Week 4, Week 13 and Week 26 
Full Analysis Set 
Table 14.2.3.9.3 
cNTB Global Composite Scores without Paper-Based 
Components: Analysis of Change from Baseline to 
Week 4, Week 13 and Week 26 versus Placebo  
Full Analysis Set 
14.2.3.10.1.1 
cNTB Global Composite Scores by Visit: Combined 
Piromelatine Treatment 
Full Analysis Set 
14.2.3.10.1.2 
MMRM Analysis of cNTB Global Composite Scores from 
Baseline to Week 4, Week 13 and Week 26: 
Combined Piromelatine Treatment 
Full Analysis Set 
14.2.3.10.2.1 
CGIC Results by Visit: Combined Piromelatine 
Treatment 
Full Analysis Set 
14.2.3.10.3.1 
ADCS-ADL Scale Adapted for MCI Patients Results by 
Visit: Combined Piromelatine Treatment 
Full Analysis Set 
14.2.3.10.3.2 
MMRM Analysis of ADCS-ADL Scale Adapted for MCI 
Patients Results: Combined Piromelatine Treatment 
Full Analysis Set 
14.2.3.10.4.1 
ADAS-cog14 Results by Visit: Combined Piromelatine 
Treatment 
Full Analysis Set 
14.2.3.10.4.2 
MMRM Analysis of ADAS-cog14 Results: Combined 
Piromelatine Treatment 
Full Analysis Set 
14.2.3.11.1.1 
cNTB Global Composite Scores by Visit: ApoE4 Carrier 
Status 
Full Analysis Set 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 60 of 66 
14.2.3.11.1.2 
MMRM Analysis of cNTB Global Composite Scores from 
Baseline to Week 4, Week 13 and Week 26: ApoE4 
Carrier Status 
Full Analysis Set 
14.2.3.11.2.1 
CGIC Results by Visit: ApoE4 Carrier Status 
Full Analysis Set 
14.2.3.11.3.1 
ADCS-ADL Scale Adapted for MCI Patients Results by 
Visit: ApoE4 Carrier Status 
Full Analysis Set 
14.2.3.11.3.2 
MMRM Analysis of ADCS-ADL Scale Adapted for MCI 
Patients Results: ApoE4 Carrier Status 
Full Analysis Set 
14.2.3.11.4.1 
ADAS-cog14 Results by Visit: ApoE4 Carrier Status 
Full Analysis Set 
14.2.3.11.4.2 
MMRM Analysis of ADAS-cog14 Results: ApoE4 Carrier 
Status 
Full Analysis Set 
14.2.3.12.1.1 
cNTB Global Composite Scores by Visit: Baseline 
Insomnia 
Full Analysis Set 
14.2.3.12.1.2 
MMRM Analysis of cNTB Global Composite Scores from 
Baseline to Week 4, Week 13 and Week 26: Baseline 
Insomnia 
Full Analysis Set 
14.2.3.12.2.1 
CGIC Results by Visit: Baseline Insomnia 
Full Analysis Set 
14.2.3.12.3.1 
ADCS-ADL Scale Adapted for MCI Patients Results by 
Visit: Baseline Insomnia 
Full Analysis Set 
14.2.3.12.3.2 
MMRM Analysis of ADCS-ADL Scale Adapted for MCI 
Patients Results: Baseline Insomnia 
Full Analysis Set 
14.2.3.12.4.1 
ADAS-cog14 Results by Visit: Baseline Insomnia 
Full Analysis Set 
14.2.3.12.4.2 
MMRM Analysis of ADAS-cog14 Results: Baseline 
Insomnia 
Full Analysis Set 
14.2.3.13.1.1 
cNTB Global Composite Scores by Visit: Alzheimer’s 
Disease Medications at Baseline 
Full Analysis Set 
14.2.3.13.1.2 
MMRM Analysis of cNTB Global Composite Scores from 
Baseline to Week 4, Week 13 and Week 26: 
Alzheimer’s Disease Medications at Baseline 
Full Analysis Set 
14.2.3.13.2.1 
CGIC Results by Visit: Alzheimer’s Disease 
Medications at Baseline 
Full Analysis Set 
14.2.3.13.3.1 
ADCS-ADL Scale Adapted for MCI Patients Results by 
Full Analysis Set 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 61 of 66 
Visit: Alzheimer’s Disease Medications at Baseline 
14.2.3.13.3.2 
MMRM Analysis of ADCS-ADL Scale Adapted for MCI 
Patients Results: Alzheimer’s Disease Medications at 
Baseline 
Full Analysis Set 
14.2.3.13.4.1 
ADAS-cog14 Results by Visit: Alzheimer’s Disease 
Medications at Baseline 
Full Analysis Set 
14.2.3.13.4.2 
MMRM Analysis of ADAS-cog14 Results: Alzheimer’s 
Disease Medications at Baseline 
Full Analysis Set 
Table 14.3.1.1 
Overall Summary of All Adverse Events (AEs)  
Safety Analysis Set 
Table 14.3.1.2 
Treatment Emergent Adverse Events (TEAEs) by 
System Organ Class and Preferred Term  
Safety Analysis Set 
Table 14.3.1.3 
Serious Treatment Emergent Serious Adverse Events 
(TEAEs) by System Organ Class and Preferred Term  
Safety Analysis Set 
Table 14.3.1.4 
Treatment Emergent Adverse Events (TEAEs) Related 
to Study Medication by System Organ Class and 
Preferred Term  
Safety Analysis Set 
Table 14.3.1.5 
Treatment Emergent Adverse Events (TEAEs) by 
System Organ Class, Preferred Term and Maximum 
Severity  
Safety Analysis Set 
Table 14.3.1.6 
Treatment Emergent Adverse Events (TEAEs) Leading 
to Withdrawal of Study Medication by System Organ 
Class and Preferred Term  
Safety Analysis Set 
Table 14.3.1.7 
Treatment Emergent Adverse Events (TEAEs) by 
Preferred Term  
Safety Analysis Set 
Table 14.3.1.8 
All Adverse Events (AEs) by System Organ Class and 
Preferred Term  
Safety Analysis Set 
Table 14.3.1.9 
All Adverse Events (AEs) by System Organ Class, 
Preferred Term and Maximum Severity  
Safety Analysis Set 
Table 14.3.2.1 
Listing of all Serious Adverse Events  Leading to 
Withdrawal from the Study  
Safety Analysis Set 
Table 
14.3.4.1.1.1 
Laboratory Results by Visit: Hematology  
Safety Analysis Set 
Table 
Shift from Baseline in Laboratory Results by Visit: 
Safety Analysis Set 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 62 of 66 
14.3.4.1.1.2 
Hematology  
Table 
14.3.4.1.2.1 
Laboratory Results by Visit: Chemistry  
Safety Analysis Set 
Table 
14.3.4.1.2.2 
Shift from Baseline in Laboratory Results by Visit: 
Chemistry  
Safety Analysis Set 
Table 
14.3.4.1.3.1 
Laboratory Results by Visit: Urinalysis  
Safety Analysis Set 
Table 
14.3.4.1.3.2 
Shift from Baseline in Laboratory Results by Visit: 
Urinalysis  
Safety Analysis Set 
Table 14.3.4.2 
Vital Signs by Visit  
Safety Analysis Set 
Table 14.3.4.3.1 
ECG Interval Results by Visit  
Safety Analysis Set 
Table 14.3.4.3.2 
Overall Results of 12-lead ECG by Visit  
Safety Analysis Set 
Table 14.3.4.4 
Overall Results of Physical Examination by Visit  
Safety Analysis Set 
Table 14.3.4.5.1 
Total Sheehan-STS Results by Visit  
Safety Analysis Set 
Table 14.3.4.5.2 
Individual Sheehan-STS Results by Visit 
Safety Analysis Set 
Table 14.3.4.6 
Extent of Exposure  
Safety Analysis Set 
 
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 63 of 66 
15. 
INDEX OF LISTINGS 
Listing 
Number 
Name 
Analysis Set 
Listing 16.2.1 
Patient Disposition 
Screened Set 
Listing 16.2.2 
Protocol Deviations 
Safety Analysis Set 
Listing 16.2.3.1 
Informed Consent and  Patient Eligibility 
Screened Set 
Listing 16.2.3.2 
Exclusions from Analysis Sets 
 
Listing 16.2.3.3 
Randomization 
Screened Set 
Listing 16.2.3.4 
Modified Caregiver Telephone Call 
Safety Analysis Set 
Listing 16.2.3.5 
Central Review 
Safety Analysis Set 
Listing 16.2.4.1 
Demographic Characteristics and Education Status 
Safety Analysis Set 
Listing 16.2.4.2 
Medical/Surgical History 
Safety Analysis Set 
Listing 16.2.4.3 
Baseline Characteristics - Alzheimer’s Disease 
Safety Analysis Set 
Listing 16.2.4.4 
Prior and Concomitant Medications 
Safety Analysis Set 
Listing 16.2.4.5 
CT/MRI Scan 
Safety Analysis Set 
Listing 16.2.4.6 
PET/CSF Scan 
Safety Analysis Set 
Listing 16.2.5.1 
Study Medication Accountability 
Safety Analysis Set 
Listing 16.2.5.2 
Patient Compliance 
Safety Analysis Set 
Listing 16.2.5.3 
Caregiver Telephone Call 
Safety Analysis Set 
Listing 
16.2.6.1.1 
Individual Computerized and Paper-Based 
Neuropsychological  Test Battery Scores 
Safety Analysis Set 
Listing 
16.2.6.1.2 
Neuropsychological Test Composite Scores 
Safety Analysis Set 
Listing 16.2.6.2 
Clinical Global Impression of Change 
Safety Analysis Set 
Listing 16.2.6.3 
Alzheimer’s Disease Cooperative Study/Activities of Daily 
living Scale Adapted for MCI Patients 
Safety Analysis Set 
Listing 
16.2.6.4.1 
Alzheimer’s Disease Assessment Scale Cognitive Subscale-
14 Results Part 1 
Safety Analysis Set 
Listing 
16.2.6.4.2 
Alzheimer’s Disease Assessment Scale Cognitive Subscale-
14 Results Part 2 
Safety Analysis Set 
Listing 
16.2.6.4.3 
Alzheimer’s Disease Assessment Scale Cognitive Subscale-
14 Results Part 3 
Safety Analysis Set 
Listing 
16.2.6.4.4 
Alzheimer’s Disease Assessment Scale Cognitive Subscale-
14 Results Part 4 
Safety Analysis Set 
Listing 
16.2.6.4.5 
Alzheimer’s Disease Assessment Scale Cognitive Subscales 
Scores 
Safety Analysis Set 
Listing 
16.2.6.5.1 
Executive Function Domain - Controlled Oral Word 
Association Test 
Safety Analysis Set 
Listing 
16.2.6.5.2 
Executive Function Domain – Category Fluency Test 
Safety Analysis Set 
Listing 16.2.6.6 
Mini Mental State Examination 
Safety Analysis Set 
Listing 16.2.6.7 
Neuropsychiatric Inventory 
Safety Analysis Set 
Listing 
16.2.6.8.1 
Pittsburgh Sleep Quality Index Part 1 
Safety Analysis Set 
Listing 
16.2.6.8.2 
Pittsburgh Sleep Quality Index Part 2 
Safety Analysis Set 
Listing 16.2.6.9 
Clinical Dementia Rating 
Safety Analysis Set 
Listing 16.2.7.1 
All Adverse Events 
Safety Analysis Set 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 64 of 66 
Listing 
16.2.8.1.1 
Laboratory Results: Hematology 
Safety Analysis Set 
Listing 
16.2.8.1.2 
Laboratory Results: Chemistry 
Safety Analysis Set 
Listing 
16.2.8.1.3 
Laboratory Results: Hormones (Testosterone, SHBG, 
Prolactin) 
Safety Analysis Set 
Listing 
16.2.8.1.4 
Laboratory Results: Urinalysis 
Safety Analysis Set 
Listing 
16.2.8.1.5 
Laboratory Results: Urine Drug Screen 
Safety Analysis Set 
Listing 
16.2.8.1.6 
Optional Blood Sample for ApoE4 Genotyping 
Safety Analysis Set 
Listing 
16.2.8.2.1 
Vital Signs 
Safety Analysis Set 
Listing 
16.2.8.2.2 
12-Lead ECG 
Safety Analysis Set 
Listing 
16.2.8.2.3 
Physical Examination 
Safety Analysis Set 
Listing 
16.2.8.2.4.1 
Sheehan-STS - Part 1 
Safety Analysis Set 
Listing 
16.2.8.2.4.2 
Sheehan-STS - Part 2 
Safety Analysis Set 
Listing 
16.2.8.2.4.3 
Sheehan-STS - Part 3 
Safety Analysis Set 
 
  
 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 65 of 66 
16. 
APPENDICES 
 
NEUP11-AD2_Table and Figure Shells_Final Version 1.0 
 
NEUP11-AD2_Listing Shells_Final Version 1.0 


Statistical Analysis Plan 
Neurim ReCOGNITION Protocol NEUP11-AD2 
Version 1.0 
INC Research 1006401 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.02     
  INC Research © LLC 
Page 66 of 66 
17. 
MOCK-UPS 
Attachments: 
 
NEUP11-AD2_Listing Shells_Final Version 1.0 
 
NEUP11-AD2_Table and Figure Shells_Final Version 1.0