Clinical trial NCT03226522
Conditions: Agitation in Patients With Dementia of the Alzheimer's Type Alzheimer Disease Agitation,Psychomotor
Sponsor: Axsome Therapeutics, Inc.
Start date: 2017-07-13; Completion date: 2020-04-17
Enrollment: 366 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized, double-blind, placebo-controlled study, to assess the efficacy and safety of AXS-05 in the treatment of agitation in patients with Alzheimer's disease.

Detailed description:

Arms: arm 1: AXS-05 tablets taken by mouth for 5 weeks. arm 2: Bupropion tablets taken by mouth for 5 weeks. arm 3: Placebo tablets taken by mouth for 5 weeks.
Interventions: intervention 1: AXS-05 intervention 2: Bupropion intervention 3: Placebo
Intervention descriptions: intervention 1: AXS-05 intervention 2: Bupropion intervention 3: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
Document Type: Protocol and Statistical Analysis Plan
Protocol Title: ADVANCE: Addressing Dementia Via Agitation-Centered Evaluation
A Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy and Safety of AXS-05 
for the Treatment of Agitation in Subjects with Dementia of the Alzheimer’s Type
ClinicalTrials.gov Identifier:  NCT03226522 
Document Date: March 16, 2020
Certain information within this protocol has been redacted to protect either personally identifiable 
information (PII) or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
•
Named persons or organizations associated with the study.
•
Proprietary information, such as scales or coding systems, which are considered confidential 
information.
•
Other information as needed to protect the confidentiality of Axsome Therapeutics, personal 
information, or to otherwise protect the integrity of the clinical study.


Axsome Therapeutics, Inc. 
Confidential 
AXS-05-AD-301 
PROTOCOL 
COMPOUND 
NAME/NUMBER: 
AXS-05 
PROTOCOL NUMBER: 
AXS-05-AD-301 
 
 
DEVELOPMENT 
PHASE: 
Phase 2/3 
PROTOCOL TITLE: 
ADVANCE: Addressing Dementia Via Agitation-Centered 
Evaluation 
A Randomized, Double-blind, Placebo-controlled Trial to Assess the 
Efficacy and Safety of AXS-05 for the Treatment of Agitation in 
Subjects with Dementia of the Alzheimer’s Type 
PROTOCOL VERSION: 
Amendment 3 
PROTOCOL DATE: 
March 16, 2020 
 
This study will be performed in compliance with Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of Axsome Therapeutics, Inc. 










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AXS-05-AD-301 
Version: Amendment 3_16Mar2020 
Page 6 
Planned Number of 
Subjects 
Approximately 435 subjects (145 per arm) will be randomized to achieve approximately 300 
completed subjects.  As part of protocol amendment 2, randomization to the bupropion arm was 
discontinued. 
Study Centers 
Up to approximately 60 study centers in the U.S., Canada, and Australia. 
Diagnosis and Subject 
Selection Criteria 
-Inclusion Criteria
-Exclusion Criteria
Inclusion Criteria: 
1.
Male or female outpatients, 65 to 90 years of age, inclusive.
2.
Diagnosis of probable Alzheimer’s disease (AD) based on the 2011 National Institute on
Aging-Alzheimer Association (NIA-AA) criteria.
3.
Clinically significant agitation, at the time of screening and for at least 2 weeks prior to
randomization, that interferes with daily routine activities and for which a prescription
medication is deemed indicated, in the opinion of the investigator.
4.
The diagnosis of agitation must meet the International Psychogeriatric Association (IPA)
provisional definition of agitation, as evidenced by each of the following:
A.
The patient exhibits at least one of the following behaviors that are associated with
observed or inferred evidence of emotional distress (e.g. rapid changes in mood,
irritability, outbursts), and the behavior has been persistent or frequently recurrent for
at least 2 weeks and represents a change from the patient’s usual behavior:
a)
Physical aggression (e.g. grabbing, shoving, pushing, resisting, hitting others,
kicking objects or people, scratching, biting, throwing objects, hitting self,
slamming doors, tearing things, and destroying property)
b)
Verbal aggression (e.g. yelling, speaking in an excessively loud voice, using
profanity, screaming, shouting)
c)
Excessive motor activity (examples include: pacing, rocking, gesturing, pointing
fingers, restlessness, performing repetitious mannerisms)
B.
Behaviors are severe enough to produce excess disability, which in the clinician’s
opinion is beyond that due to cognitive impairment and including at least one of the
following:
a)
Significant impairment in interpersonal relationships.
b)
Significant impairment in other aspects of social functioning.
c)
Significant impairment in ability to perform or participate in daily living activities.
C.
The agitation is not attributable solely to another psychiatric disorder, suboptimal care
conditions, medical condition, or the physiological effects of a substance.
7.
Caregiver must be:
a)
A family member who has been providing care to the patient for at least 3 months prior
to Screening.
b)
Knowledgeable of the patient, and reliable in providing care to the patient.
c)
In regular contact with the patient and spend a minimum of 16 hours per week (a
minimum of 4 hours on 4 separate days) with the patient.
d)
Capable, in the opinion of the investigator, of providing an adequate rating of the
patient’s condition.
8.
Caregiver must also:
a)
Be able and willing to communicate with site personnel and to comply with all required
study procedures including not administering any prohibited medications during the
course of the study, and to oversee the patient’s compliance with the study treatment.


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AXS-05-AD-301 
Version: Amendment 3_16Mar2020 
Page 7 
b)
Agree to accompany the patient to all site visits, be available by telephone at designated
times, and be able and willing to observe for possible adverse events and to report on
the patient’s status.
c)
Fully understand the length of the trial.
d)
Agree to undergo training in recognizing agitation symptoms and in rating of the scales
used in the study.
9.
Caregiver signed and received a copy of a caregiver’s ICF after the nature and risks of study
participation had been fully explained.
10. Patients capable of signing consent (according to the investigator), or their authorized
representatives, signing and receiving a copy of the patient’s ICF after the nature and risks
of study participation have been fully explained to them.
11. Patients who are capable of providing assent but not capable of signing the ICF, according
to the investigator, should provide assent for study participation.
a)
Patients who sign the ICF are not required to provide a separate assent.
b)
Patients who are not capable of providing assent are still allowed to participate provided 
the patient’s authorized representative agrees to participation. Investigators must
document the reasons for any patient who is unable to provide assent and maintain this
documentation with the consent/assent documents.
12. The patient has stable cardiac, pulmonary, hepatic, and renal function.
13. Patients currently receiving a drug for the treatment of AD (e.g., donepezil, rivastigmine,
galantamine, memantine) are eligible provided they have been on a stable dose of these
medications for at least 2 months prior to randomization.
14. Patients currently taking allowed medications for the treatment of agitation secondary to AD
(e.g., antipsychotics, buspirone) are eligible provided they have been on a stable dose for at
least 4 weeks prior to randomization. Patients who have recently discontinued these
medications must be off them for at least 4 weeks prior to randomization.  Antipsychotics
which are primarily metabolized by CYP2D6 are exclusionary (see permitted and prohibited
medications section).
15. Concomitant use of low dose trazodone (up to 50 mg/day), melatonin, eszopiclone, zolpidem,
zopiclone or zaleplon for nighttime management of insomnia, provided the dose and regimen
have been stable for at least 1 month prior to randomization and remain stable throughout the
study, is allowed. Contact the medical monitor regarding the use of other sleep aids.
Exclusion Criteria: 
1.
Caregiver is unwilling or unable, in the opinion of the investigator, to comply with study
instructions.
2.
Patient has dementia predominantly of non-Alzheimer’s type (e.g., vascular dementia,
frontotemporal dementia, Parkinson’s disease, substance-induced dementia).
3.
Patient is hospitalized in a mental health facility (e.g., psychiatric hospital or ward), or living 
alone.
4.
Patient has symptoms of agitation that are not secondary to AD (e.g., pain, other psychiatric
disorder or delirium due to a metabolic disorder, systemic infection or substance-induced).
5.
History or current clinical symptoms of schizophrenia, schizoaffective disorder, or bipolar
disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition (DSM-5).
6.
History of alcohol or substance use disorder (other than nicotine or caffeine) within 1 year


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Version: Amendment 3_16Mar2020 
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of randomization. 
7.
Use of serotonergic medications, such as selective serotonin reuptake inhibitors (SSRIs) and
serotonin norepinephrine reuptake inhibitors (SNRIs) are prohibited to avoid the risk of
serotonin syndrome.  These products are exclusionary if used within 2 weeks, or 5 half-lives,
whichever is longer, of randomization.
8.
Current use, or use within 14 days before study drug dosing, of monoamine oxidase
inhibitors (MAOIs), linezolid, or intravenous methylene blue.
9.
History of seizure disorder, anorexia nervosa or bulimia; undergoing abrupt discontinuation
of alcohol, benzodiazapines, barbiturates and antiepileptic drugs; or any other condition that
increases the risk of seizure such as stroke, significant head injury, tumor or infection of the
central 
nervous 
system, 
arteriovenous 
malformation, 
neuroleptic 
malignant
syndrome/serotonin syndrome, or clinically significant, as deemed by the investigator,
metabolic disorders (e.g., clinically significant hypoglycemia, hyponatremia, severe hepatic
impairment, and hypoxia).
10. Any concurrent medical condition that might interfere with the conduct of the study,
confounds the interpretation of study results, or endangers the patient’s well-being. This
includes a history of malignancy within the last two years (except skin basal-cell carcinoma
or untreated prostate cancer), or any significant hematologic, endocrine/metabolic (e.g.
poorly controlled diabetes), cardiovascular (e.g. poorly controlled hypertension, unstable
ischemic cardiac disease, dilated cardiomyopathy, or unstable valvular heart disease),
unstable or progressive pulmonary, renal, hepatic, gastrointestinal or neurologic, or other
chronic disease. Certain other non-metastatic cancer may be allowed. Each case to be
evaluated individually with medical monitor.
11. Hypertension defined as resting, sitting systolic blood pressure (BP) ≥150 mm Hg or
diastolic BP ≥ 95 mm Hg.  Patients with systolic BP >134 mm Hg or diastolic BP > 85 mm
Hg should be receiving adequate treatment for hypertension. Blood pressure values may be
confirmed by serial assessments (at least 30 minutes apart), if needed.
12. Gastric bypass or any condition that would be expected to affect drug absorption (lap band
procedures are acceptable if there is no problem with absorption).
13. Narrow-angle glaucoma without a patent iridectomy.
14. Known human immunodeficiency virus (HIV) infection.
15. Known history of hepatitis B or C infection.
16. Screening liver enzyme test (e.g., bilirubin, aspartate aminotransferase and/or alanine
aminotransferase) results > 2.0 x ULN.
17. Any clinically significant abnormality on the screening laboratory tests, as assessed by the
study investigator and/or the medical monitor.
18. History of allergy or hypersensitivity to bupropion, dextromethorphan, opiate drugs (e.g.
codeine, etc.), or any other ingredient in the study medication.
19. History of allergy to benzodiazepines (e.g., lorazepam).
20. History of intolerance to bupropion or dextromethorphan.
21. Patients who have received dextromethorphan co-administered with quinidine (e.g.
Nuedexta®) and did not respond to treatment.
22. Patients who have been taking disallowed concomitant medications within 2 weeks or 5
half-lives, whichever is longer, prior to Baseline.
23. Patients currently being treated, or who have been treated with any investigational product
(drug or device) within 30 days or 5 half-lives, whichever is longer, of Baseline.
24. Patients determined to have a high imminent risk of falls during the study based on a clinical




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Version: Amendment 3_16Mar2020 
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Safety Measures 
Adverse Event (AE) recording
Adverse Dropouts (ADOs)
Incidence of Treatment Emergent Adverse Events (TEAEs)
Clinical laboratory test results
Vital sign measurements
ECG findings
Physical examination findings
Columbia – Suicide Severity Rating Scale (C-SSRS)


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Version: Amendment 3_16Mar2020 
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Statistical Methods 
Analysis Populations:  
The following analysis populations are planned for this study: 
Modified Intent-to-Treat (mITT) Population—the mITT will be the primary efficacy analysis
population and will consist of all subjects who are randomized, subsequently take at least 1
dose of the study drug, and have at least 1 post-Baseline efficacy assessment
Intent-to-Treat Population—the ITT will include all subjects who are randomized
Safety Population—the Safety Population will be the primary safety analysis population and
will include all subjects who receive at least 1 dose of the study drug
Primary Efficacy Analysis: 
The primary endpoint will be the change from Baseline (Day 1) to Week 5 in the CMAI total 
score. The primary comparison will be AXS-05 versus placebo. 
The changes from Baseline in the CMAI total score will be analyzed using a Mixed Model with 
Repeated Measures (MMRM). This model will include treatment, week, and treatment-by-week 
interaction as factors, Baseline value as a covariate, and subject as a random effect. Treatment 
effects and the differences between treatments will be estimated using the least-square mean 
estimates and will be reported together with the 2-sided 95% confidence interval of the treatment 
difference. The null hypothesis of no treatment difference will be tested at a two-sided 
significance level of 0.05. 
Safety Analysis: 
Adverse events will be coded by system organ class (SOC) and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA) reporting system. TEAEs are those 
that occur following the start of treatment with study drug through follow up (7 days after the 
last dose), and SAEs that occur from the start of treatment with study drug through 30 days after 
the last dose. The number and percentage of subjects with TEAEs will be displayed for each 
treatment group by SOC and preferred term. Additionally, TEAEs will be tabulated for each 
treatment group by severity and by relationship to the study drug. A listing of SAEs will be 
provided if applicable. 
Descriptive summaries will be calculated, and data listings provided for hematologic, 
biochemical, and urinalysis laboratory parameters, and vital signs measurements, as appropriate. 
Sample Size 
Determination 
Approximately 300 completed subjects (100 per treatment group) will provide 90% to detect a 
treatment difference for the primary efficacy variable (change from baseline in CMAI total score 
at Week 5) at a two-sided significance level of 0.05.  In the sample size calculation, it was 
assumed the effect size was 0.46.  Approximately 435 subjects (145 subjects each in the AXS-
05, bupropion SR, and placebo arms) will be randomized to achieve approximately 300 
completed subjects, assuming an approximately 30% drop-out rate.  As part of protocol 
amendment 2, randomization to the bupropion arm was discontinued. 


Axsome Therapeutics, Inc. 
 
Confidential and Proprietary 
 
AXS-05-AD-301 
Version: Amendment 3_16Mar2020 
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Schedule of Assessments 
Visit 
Screening 
Visit 1 
Baseline 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / 
ETa 
Follow-
upb 
Visit 7 
Study Day 
-28 to -1 
1 
8 (±3) 
15 (±3) 
22 (±3) 
36 (±3) 
43 (±3) 
End of Week 
Weeks 
-4 to -1 
 
Week 
1 
Week 2 
Week 3 
Week 5 
Week 6 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
X 
 
Vital signsd  
X 
Xe 
X 
X 
X 
X 
 
Electrocardiogram 
X 
 
 
 
 
X 
 
Review previous and concomitant medications 
X 
X 
X 
X 
X 
X 
X  
Height and weight 
X 
 
 
 
 
X 
 
Clinical laboratory testsf 
X 
 
 
 
 
X 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
Cohen-Mansfield Agitation Inventory (CMAI) 
 
X 
X 
X 
X 
X 
 
Modified Alzheimer’s Disease Cooperative Study-Clinical 
Global Impression of Change for Agitation (mADCS-CGIC) 
 
X 
 
 
 
X 
 
Administer first dose of study medication in clinic 
 
Xh 
 
 
 
 
 
Administer last dose of study medication in clinic 
 
 
 
 
 
X 
 
Review of adverse events 
 
Xi 
X 
X 
X 
X 
X 
Blood sample for drug concentration 
 
 
 
X 
 
Xj 
 
Blood sample for CYP2D6 genotyping  
 
X 
 
 
 
 
 
Caregiver to Complete Daily Caregiver Diaryg 
 
X 
X 
X 
X 
X 
 
Review and return study medication and Caregiver Diary 
 
 
X 
X 
X 
X 
 
Dispense study medication  
 
X 
X 
X 
 
 
 
a 
Early Termination (ET) visit for subjects who withdraw prior to study completion, the Follow-up Visit will occur 1 week after ET. 
b 
Follow up visit may be conducted by phone.  If the patient reports AEs that require follow-up an in-clinic visit should be performed.  
c 
A complete physical examination (excluding breast and genitourinary examination) will be performed at Screening and a brief physical examination will 
be performed at Week 5 or at Early Termination. 
d 
Vital signs, including seated and orthostatic blood pressure and pulse, respiratory rate, and oral temperature, will be measured.  
e 
On Day 1, vital signs should be collected pre-dose and at least 1 hour following the dose. 
f 
Clinical laboratory tests will include hematology, serum chemistry, and urinalysis.  
g 
A Caregiver Diary will be used to record the number of tablets of study medication and rescue medication (lorazepam) administered and the time of 
administration, adverse events, and subject behaviors. Study personnel will train caregivers how to complete the diary, retraining to occur as needed. 
h 
Subjects should be monitored in the clinic after the first dose.  At a minimum, vital signs should be recorded 1 hour following the dose.  If any changes in 
the subjects health status, subjects should stay in clinic for at least 3 hours following the dose and have additional safety assessments performed, such as 
ECG evaluation and/ or serum electrolytes, as appropriate. 
i 
During Week 1, sites are encouraged to contact subjects by phone to review and follow up on AEs. 
j 
At visit 6, a pre- and post-dose (within 3 hours after dosing) sample should be collected.