Clinical trial NCT03595579
Conditions: Major Depressive Disorder
Keywords: AXS-05 Major Depressive Disorder MDD Axsome Depression Dextromethorphan Bupropion Sigma-1 NDMA ASCEND
Sponsor: Axsome Therapeutics, Inc.
Start date: 2018-05-30; Completion date: 2019-01-07
Enrollment: 97 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized, Double-Blind, Active-Controlled Study of AXS-05 for MDD.

Detailed description:
This study will evaluate the safety and efficacy of AXS-05 in a randomized, double-blind, active-controlled study in patients diagnosed with major depressive disorder (MDD) experiencing an acute episode.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: AXS-05 intervention 2: Bupropion
Intervention descriptions: intervention 1: AXS-05 taken twice daily for 6 weeks. intervention 2: Bupropion taken twice daily for 6 weeks.

Protocol documents:
Prot_000.pdf: 
Document Type: Protocol  
Protocol Title: A Randomized, Double-Blind, Active-Controlled Trial of AXS-05 Administered Orally 
to Subjects with Major Depressive Disorder 
ClinicalTrials.gov Identifier:  NCT03595579 
Document Date: June 28, 2018 
 
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.  


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AXS-05-MDD-201 
PROTOCOL 
COMPOUND 
NAME/NUMBER: 
AXS-05 
PROTOCOL NUMBER: 
AXS-05-MDD-201 
DEVELOPMENT 
PHASE: 
Phase 2 
PROTOCOL TITLE: 
A Randomized, Double-Blind, Active-Controlled Trial of AXS-05 
Administered Orally to Subjects with Major Depressive Disorder 
PROTOCOL VERSION: 
Final (v2.0) 
PROTOCOL DATE: 
28Jun2018 
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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Study Contact and Details 
 
 
 
SPONSORED BY: 
Axsome Therapeutics, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INVESTIGATORS: 
 
Multi-Center 
 
 
 


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1. SYNOPSIS 
CLINICAL STUDY SYNOPSIS: AXS-05-MDD-201 
Product Name/ 
Number 
AXS-05 (bupropion hydrochloride and dextromethorphan hydrobromide monohydrate) 
Protocol Number 
AXS-05-MDD-201 
Protocol Title 
A Randomized, Double-Blind, Active-Controlled Trial of AXS-05 Administered Orally to 
Subjects with Major Depressive Disorder 
Indication 
Treatment of Major Depressive Disorder (MDD) 
Development Phase 
2 
Objective 
To evaluate the safety and tolerability of AXS-05 and bupropion in subjects with MDD 
Study Design 
 
This study is a randomized, double-blind, active-controlled, Phase 2 trial, consisting of a screening 
period of up to 4 weeks, and a 6-week treatment period. 
Screening Period 
Prior to randomization, all subjects will enter an up to four-week screening period (Screening) to 
determine eligibility. Eligible subjects must meet the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria for MDD without psychotic features, based on the 
Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition, Clinical Trials Version (SCID-5-CT), with a current major depressive episode of at least 
4 weeks in duration.  Eligible subjects must meet all other inclusion and no exclusion criteria. 
Treatment Period 
Randomization 
Subjects who successfully complete Screening will be randomly assigned at the baseline visit 
(Baseline) to receive either AXS-05 or bupropion sustained release (SR) in a 1:1 ratio for 6 weeks. 
The randomization schedule will be computer-generated using a permuted block algorithm that 
will randomly allocate the study drug to randomization numbers. 
Treatments 
Doses will be titrated as follows: 
 
Days 1 - 3 
o 
AXS-05 group: 105 mg bupropion, 45 mg dextromethorphan QD 
o 
Bupropion group: 105 mg bupropion QD 
 
Days 4 - 42  
o 
AXS-05 group: 105 mg bupropion, 45 mg dextromethorphan BID 
o 
Bupropion group: 105 mg bupropion BID 
All QD doses will be taken in the morning, orally on an empty stomach (at least 2 hours pre- or 2 
hours post-prandial) with water. All BID doses will be taken at least 8 hours apart, orally on an 
empty stomach (at least 2 hours pre- or 2 hours post-prandial) with water. All study drug is of 
identical appearance and similar weight in order to maintain the integrity of the blind. 
Assessments and Visits 
Study visits will occur at Screening (Visit 1), Baseline (Day 0, Visit 2), and on Days 3, 7, 14, 21, 
28, 42 and 49 (Visits 3 – 9). Study procedures and assessments will be performed during study 
visits as outlined in the Schedule of Assessments. Visit 3 (Day 3) will be conducted telephonically. 
Subjects will be reminded during Visit 3 to begin BID dosing on Day 4. All subjects completing 6 
weeks of treatment or subjects prematurely discontinuing from the study will be required to 
complete a follow-up visit one week after the last dose of study drug, Visit 9, telephonically.   


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Assessments will include safety parameters, MADRS, QIDS-SR-16, CGI-S and CGI-I. 
 
 
 
 
 
 
 
Study drug compliance will also be assessed at the 80% level 
by counting the number of tablets dispensed and returned. Noncompliant subjects are subject to 
early termination from the study.  
AXS-05-MDD-201 Study Design 
 
Planned Number of 
Subjects 
A sufficient number of subjects will be screened to achieve the goal of having approximately 60 
compliant subjects complete the 6-week treatment period. 
Study Centers  
Up to approximately 5 U.S. study centers 
Diagnosis and Subject 
Selection Criteria 
-Inclusion Criteria 
-Exclusion Criteria 
Inclusion Criteria: 
1. Provides written informed consent to participate in the study, is able to understand the 
procedures and study requirements, and agrees to abide by the study restrictions and return for 
the required study assessments. 
2. Male or female outpatients, 18 to 65 years of age, inclusive. 
3. Currently meets the DSM-5 criteria for MDD without psychotic features, based on the SCID-
5-CT, with a current major depressive episode of at least 4 weeks in duration at  
Visit 1.  
4. MADRS score of ≥ 25 and CGI-S ≥ 4 at Screening (Visit 1) and Baseline (Visit 2). 
5. Normal physical examination findings and clinical laboratory test results from Screening 
(Visit 1) or abnormal results that are judged not clinically significant by the investigator. 
6. Body mass index (BMI) between 18 and 40 kg/m2, inclusive. 
7. If female of childbearing potential, having a negative urine pregnancy test result at Visit 1 and 
Visit 2, and practicing an adequate method of birth control (e.g. oral or parenteral 
contraceptives, intrauterine device, double-barrier) and does not plan to become pregnant 
during the course of the study. Long-term abstinence is acceptable as long as the subject agrees 
to use double-barrier contraception if they decide to have sexual intercourse. Female subjects 
using a hormonal contraceptive or intrauterine device must have been doing so for at least 1 
month before Screening and must follow that product’s package insert instructions including 
additional protection at times when hormonal contraceptive doses might be missed. Female 
subjects may be included without a negative urine pregnancy test if they are surgically sterile 
or at least 2 years post-menopausal. Male subjects and their female sexual partners should use 
an acceptable method of birth control (as noted above) during the study.  
Exclusion Criteria: 
Psychiatric Criteria: 
1. History of: 


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a. 
Any depressive episode with psychotic or catatonic features 
b. Any manic, hypomanic or mixed episode, including bipolar disorder (Type 1 or Type 2) 
and substance-induced (e.g. antidepressant-induced) manic, hypomanic/mixed episode 
c. 
Schizophrenia, schizoaffective, or other psychotic disorder 
d. Panic disorder, with or without agoraphobia 
e. 
Obsessive-compulsive disorder 
f. 
Bulimia or anorexia nervosa 
g. Any persistent neurocognitive disorder 
h. Any other anxiety disorder which has been the primary focus of clinical attention for the 
six months prior to Screening, while MDD was a secondary focus of attention 
2. History of treatment resistant depression defined as 2 or more failed treatments of adequate 
dose and duration in the current depressive episode. 
3. Post-traumatic stress disorder, active within 3 years of Visit 1. 
4. Borderline or antisocial personality disorder or other disorder of sufficient severity to interfere 
with participation in this study. 
5. Alcohol/substance use disorder (other than nicotine or caffeine), active within 1 year of  
Visit 1. 
6. Psychiatric hospitalization within current depressive episode.  
7. Psychiatric symptoms secondary to any other general medical condition. 
8. Clinically significant risk of suicide or harm to self or others.  Risk of suicide is determined 
by meeting any of the following criteria: 
a. 
In the judgment of the investigator, the subject may be a significant risk for suicide as 
judged by the psychiatric interview or information collected in the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Visit 1 or Visit 2 (e.g., The subject responded “yes” to 
question 4 or question 5 on the screening C-SSRS, and the most recent episode occurred 
within the current depressive episode). 
b. The subject has attempted suicide within the current depressive episode. 
c. 
MADRS Item 10 score ≥ 5 at Visit 1 or Visit 2. 
Treatment-Related Criteria: 
9. Use of drugs that are strong inhibitors of CYP2D6 (e.g. fluoxetine, paroxetine, quinidine) as 
defined in FDA’s Guidance for Industry: Drug Interaction Studies - Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations. 
10. Use of drugs that are inhibitors of CYP2B6, the primary enzyme that metabolizes bupropion 
(e.g. clopidogrel, ticlopidene, prasugrel), or that are inducers of CYP2B6 (e.g. ritonavir, 
lopinavir, efavirenz). Please refer to the Wellbutrin SR (bupropion) FDA package insert. 
11. Current use, or use within 14 days before Visit 1 of monoamine oxidase inhibitors (MAOIs), 
or linezolid, or intravenous methylene blue. 
12. Use of opioids (e.g., codeine, oxycodone, morphine) within 14 days before Visit 1. 
13. Having received any prohibited medications, supplements or herbal products
 
 
, including any antipsychotic, anticonvulsant/mood stabilizer, anxiolytic, 
benzodiazepine, ADT, or ADT augmentation agent (e.g., T3 [except as treatment for thyroid 
condition], 2nd antidepressant, etc.) within 1 week or 5 half- lives of the medication, 
whichever is longer, prior to Visit 2; however, 4 weeks is required for T3, 2 weeks is required 
for MAOIs. Lithium must be tapered and followed by a 1-week washout. The safe withdrawal 
from benzodiazepine treatment should be decided by the patient’s treating clinician and also 
monitored by the principal investigator. 
14. History of electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic 
stimulation, or any experimental central nervous system treatment during the current episode 
or in the 6 months before Visit 1 (whichever is longer). 
15. Requiring concomitant treatment with any of the prohibited medications, supplements, or 
herbal products 
, including any psychotropic drug or any drug with 


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psychotropic activity or with a potentially psychotropic component, except for the following: 
a. 
Eszopiclone, zolpidem, zolpidem extended-release, zopiclone or zaleplon for insomnia 
may be continued provided the medication has been used in a consistent manner for 4 
weeks prior to enrollment and at doses that do not exceed the maximum labeled amounts. 
16. Initiation or termination of psychotherapy for depression within 3 months of Visit 1, or plans 
to initiate, terminate, or change such therapy during the course of the study (Support meetings 
or counseling [e.g., marital counseling] are allowed provided they are no more frequent than 
weekly and do not have treatment of depression as their objective). 
17. Ongoing, initiation or termination of phototherapy within 1 month of Visit 1. 
Other Medical Criteria: 
18. History of seizure disorder; undergoing abrupt discontinuation of alcohol, benzodiazepines, 
barbiturates or 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). 
19. Female subjects who meet either of the following criteria: 
a. 
Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study. 
b. Sexually active females who are less than 2 years postmenopausal, and are either not 
surgically sterile (tubal ligation, bilateral oophorectomy or hysterectomy), or not 
practicing a reliable method of contraception that will continue throughout the duration 
of the study. Reliable contraception is defined as oral contraceptives (consisting of an 
estrogen-progestin 
combination 
or 
progestin 
alone), 
transdermally 
delivered 
contraceptives (e.g., Ortho Evra), depot injections (e.g., Depo-Provera), vaginal 
contraceptive ring (e.g. NuvaRing), contraceptive implants (e.g., Implanon, Norplant 
II/Jadelle), an intrauterine device, or double-barrier method (e.g. diaphragm plus condom 
accepted). Females using a hormonal contraceptive or intrauterine device must have been 
doing so for at least 1 month before Visit 1 and must follow that product’s package insert 
instructions including additional protection at times when hormonal contraceptive doses 
might be missed. Rhythm, withdrawal, single-barrier methods (i.e., contraceptive sponge, 
female condom or male condom or diaphragm alone) are not acceptable methods of 
contraception. Long-term abstinence is acceptable as long as patients agree to use double-
barrier contraception if they decide to have sexual intercourse. 
20. Positive serum ethanol test or urine drug screen (UDS) for any prohibited medication or drugs 
of abuse (cocaine, marijuana, PCP, opioid or other agent that in the opinion of the investigator 
is being abused) at Visit 1. Subjects should be advised not to drink alcohol for at least 8 hours 
prior to screening labs. 
21. Any current or recent medical, psychiatric, or social condition that, in the investigator’s 
opinion, is likely to interfere with the conduct of the study, confounds the interpretation of 
study results, or endangers the subject’s well-being. This includes (but is not limited to) any 
clinically 
significant 
oncologic, 
hematologic, 
endocrine/metabolic, 
cardiovascular, 
respiratory, renal, hepatic, gastrointestinal, infectious or neurologic disease or has a chronic 
disease which is unstable or progressive.  
22. Hypertension defined as resting, sitting systolic blood pressure (BP) ≥150 mm Hg or diastolic 
blood pressure ≥ 95 mm Hg. Patients with high BP (as defined above) may be accepted in the 
study if they subsequently have acceptable BP values on reassessment at least 30 minutes 
apart. 
23. Hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change 
in dosage for at least 1 month before Visit 1 (Serum TSH must be > 0.75 × the LLN and < 
1.25 × ULN). 
24. History of allergy or hypersensitivity to bupropion, dextromethorphan, opiate drugs (e.g. 
codeine, etc.), or any other ingredient in the study medication. 


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25. History of intolerance to bupropion or dextromethorphan. 
26. Patients who have received dextromethorphan co-administered with quinidine (e.g. 
Nuedexta®) within the past four weeks. 
27. 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). 
28. Narrow-angle glaucoma without a patent iridectomy. 
29. Known human immunodeficiency virus (HIV) infection. 
30. Clinically significant signs of active hepatitis B and/or C infection. 
31. Screening liver enzyme test (e.g., bilirubin, aspartate aminotransferase and/or alanine 
aminotransferase) results > 2.0 x ULN. 
32. Any clinically significant abnormality on the screening laboratory tests, as assessed by the 
study investigator and/or the medical monitor. 
33. Treatment with any investigational drug within 30 days of Visit 1. 
34. Currently hospitalized or residing in an in-patient facility during the study. 
35. Unable or unlikely to comply with the study protocol or unsuitable for any other reason, 
including other conditions that might indicate that the subject is unsuitable for the study as 
judged by the investigator such as known history of poor medication compliance or significant 
instability in status of psychosocial issues. 
Test Product, Dosage, 
and Mode of 
Administration 
Treatment A: AXS-05 (105 mg bupropion, 45 mg dextromethorphan) tablet, oral 
Reference Therapies, 
Dosage, and Mode of 
Administration 
Treatment B: Bupropion SR (105 mg) matching tablet, oral 
Treatment Regimen 
Days 1 - 3 
 
AXS-05 group: 105 mg bupropion, 45 mg dextromethorphan QD 
 
Bupropion group: 105 mg bupropion QD 
Days 4 - 42 
 
AXS-05 group: 105 mg bupropion, 45 mg dextromethorphan BID 
 
Bupropion group: 105 mg bupropion BID 
All QD doses will be taken in the morning, orally on an empty stomach (at least 2 hours pre- or 2 
hours post-prandial) with water. All BID doses will be taken at least 8 hours apart, orally on an 
empty stomach (at least 2 hours pre- or 2 hours post-prandial) with water.  
Study Duration 
Up to 11 weeks: up to 4 weeks screening, followed by 6 weeks of treatment, followed by a 1-week 
follow-up visit. 
Criteria for 
Evaluation 
Safety assessments will include: 
 Adverse Event (AE) recording  
 Adverse Dropouts (ADOs) 
 Incidence of Treatment Emergent Adverse Events (TEAEs) 
 Clinical laboratory test results 
 Vital sign measurements 
 Physical examinations 
 Columbia - Suicide Severity Rating Scale (C-SSRS) 


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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 consist of all subjects who are 
randomized, subsequently take at least 1 dose of the study drug, and have at least 1 post-Baseline 
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 
All analyses, including safety analyses, will be detailed in the statistical analysis plan. 
Sample Size 
Determination 
Approximately 60 subjects (30 per arm), who are compliant and who complete the 6-week 
treatment period, are planned for this study. The sample was determined based on prior reported 
experience with trials of a similar stage, in a similar patient population, with a similar objective. A 
sufficient number of subjects will be screened to achieve the planned number of subjects. 
 
 


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Schedule of Assessments 
Visit 
Screening 
Visit 1 
Baseline 
Visit 2 
Phone Call 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 / 
ET 
Visit 9 
Follow-upa 
Study Day 
-28 to -1 
0 
3 (+1) 
7 (±2) 
14 (±2) 
21 (±2) 
28 (±2) 
42 (±2) 
49 (±2) 
Week 
-4 to -1 
 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 6 
Week 7 
Informed Consent 
Xb 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical/Psychiatric History 
X 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
 
Vital Signs, Height/Weightc 
X 
X 
 
X 
X 
X 
X 
X 
 
Laboratory Testsd 
X 
 
 
 
 
 
 
X 
 
Urine Drug Screene 
X 
X 
 
 
 
 
 
X 
 
Serum Ethanole 
X 
 
 
 
 
 
 
X 
 
Urine Pregnancy Test (all 
female subjects) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MADRS 
X 
X 
 
X 
X 
X 
X 
X 
 
QIDS-SR-16 
X 
X 
 
X 
X 
X 
X 
X 
 
CGI-S (Severity) 
X 
X 
 
X 
X 
X 
X 
X 
 
CGI-I (Improvement) 
 
 
 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Instruct to begin BID dosing 
 
 
X 
 
 
 
 
 
 
Study Drug Dispensationh 
 
X 
 
X 
X 
X 
X 
 
 
Study Drug Accountability 
 
 
X 
X 
X 
X 
X 
X 
 
Prior and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations:  SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition, Clinical Trials Version; ET = early termination; EOS = End of Study; MADRS = Montgomery-Åsberg Depression Rating 
Scale; QIDS-SR-16 = Quick Inventory of Depressive Symptomatology-Self- Rated; CGI-I = Clinical Global Impressions–
Improvement; CGI-S = Clinical Global Impressions–Severity; C-SSRS = Columbia - Suicide Severity Rating Scale; 
 
 
 
a 
Safety follow-up visit to be performed telephonically. 
b 
Informed consent must be signed prior to any study procedures being performed. 
c 
Vital signs, including blood pressure, heart rate, respiratory rate, and oral body temperature, will be measured after the subject has 
been in a seated position for at least 5 minutes.  Height will be measured at Visit 1 and weight at Visit 1 and Visit 8 (EOS or ET). 
d 
Clinical laboratory tests will include hematology, serum chemistry, urinalysis and thyroid panel. 
e 
May be performed at other study visits per investigator judgment. Subjects with positive urine drug screen or serum ethanol levels at 
Visit 1 may be allowed in study depending on circumstances described to the Medical Monitor and a negative repeat UDS is obtained 
before Visit 2.  
f 
 
  
 
 
 
 
h 
Subjects will begin to take study drug the morning of Day 1 (morning after Visit 2). 


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2. TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS .........................................................................................11 
2.1 
List of Figures ...................................................................................................15 
3. 
LIST OF ABBREVIATIONS ..................................................................................15 
4. 
INTRODUCTION ....................................................................................................17 
4.1 
Background .......................................................................................................17 
4.2 
Rationale for the Evaluation of AXS-05 for Major Depressive Disorder .........17 
5. 
OBJECTIVES ...........................................................................................................18 
6. 
STUDY DESIGN ......................................................................................................18 
6.1 
Overall Study Design and Plan .........................................................................18 
6.2 
Discussion of Study Design ..............................................................................20 
6.3 
Study Sites .........................................................................................................20 
6.4 
Point of Contact ................................................................................................20 
7. 
SUBJECT POPULATION .......................................................................................20 
7.1 
Selection of Study Population and Diagnosis ...................................................20 
7.2 
Study Entry Criteria ..........................................................................................20 
7.2.1 Inclusion Criteria ...................................................................................20 
7.2.2 Exclusion Criteria ..................................................................................21 
7.3 
Premature Subject Withdrawal .........................................................................24 
7.4 
Subject Replacement Criteria ............................................................................24 
8. 
TREATMENTS ........................................................................................................25 
8.1 
Identification of Investigational Product ...........................................................25 
8.2 
Labeling and Packaging ....................................................................................25 
8.2.1 Labeling .................................................................................................25 
8.2.2 Packaging ..............................................................................................25 
8.3 
Study Drug Administration ...............................................................................25 
8.4 
Dispensing and Storage .....................................................................................25 
8.5 
Method of Assigning Subjects to Treatment Groups ........................................26 
8.6 
Blinding and Unblinding Treatment Assignment .............................................26 
8.7 
Selection of Doses in the Study ........................................................................27 
8.8 
Selection of Timing of Dose .............................................................................27 
8.9 
Dose Adjustment Criteria ..................................................................................27 
8.10 Drug Accountability ..........................................................................................27 
8.11 Treatment Compliance ......................................................................................27 
8.12 Prior and Concomitant Therapies......................................................................28 


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8.12.1 Prohibited Therapies ..............................................................................28 
8.13 Treatment after the End of Study ......................................................................28 
9. 
STUDY PROCEDURES ..........................................................................................29 
9.1 
Study Periods, Visits, and Procedures...............................................................29 
9.1.1 Visit 1, Screening (Days −28 to −1) ......................................................29 
9.1.2 Visit 2, Baseline (Day 0) .......................................................................30 
9.1.3 Visit 3 (Day 3) .......................................................................................30 
9.1.4 Visit 4, 5, 6, and 7 (Days 7, 14, 21, and 28) ..........................................31 
9.1.5 Visit 8 (Day 42) / Early Termination ....................................................31 
9.1.6 Visit 9 (Day 49) / 1-Week Follow-up Phone Call .................................32 
9.2 
Study Duration ..................................................................................................32 
9.3 
Assessments ......................................................................................................32 
9.3.1.1 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
(SCID-5-CT) ..............................................................................................32 
9.3.1.2 
Montgomery-Åsberg Depression Rating Scale (MADRS) .......33 
9.3.1.3 
Quick Inventory of Depressive Symptomology – Self-Rated (QIDS-
SR-16) 
33 
9.3.1.4 
Clinical Global Impression – Severity (CGI-S) ........................33 
9.3.1.5 
Clinical Global Impression – Improvement (CGI-I) .................33 
9.3.1.6 
 
9.3.2 Clinical Pharmacology ..........................................................................33 
9.3.2.1 
 
9.3.3 Safety .....................................................................................................34 
9.3.3.1 
Adverse Events..........................................................................34 
9.3.3.2 
Clinical Laboratory Safety Assessments ...................................34 
9.3.3.3 
Clinical Examinations ...............................................................35 
10. ADVERSE EVENTS ................................................................................................36 
10.1 Definitions .........................................................................................................36 
10.1.1 Adverse Events ......................................................................................36 
10.1.2 Adverse Drug Reaction .........................................................................36 
10.1.3 Unexpected Adverse Event/Adverse Drug Reaction ............................37 
10.1.4 Serious Adverse Events/Drug Reaction ................................................37 
10.1.5 Treatment-Emergent Adverse Events ...................................................38 
10.2 Management of Adverse Events .......................................................................38 
10.2.1 Collection of Adverse Events ................................................................38 
10.2.2 Evaluation of Adverse Events ...............................................................38 
10.2.2.1 Severity of Adverse Events .......................................................38 
10.2.2.2 Seriousness ................................................................................39 


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10.2.2.3 Action(s) Taken .........................................................................39 
10.2.2.4 Outcome at the Time of Last Observation ................................39 
10.2.2.5 Adverse Event Relationship to the Study Drug ........................39 
10.2.3 Documentation ......................................................................................40 
10.2.4 Treatment of Adverse Events ................................................................41 
10.2.5 Follow-up of Adverse Events ................................................................41 
10.2.6 Notification ............................................................................................41 
10.2.6.1 Serious Adverse Events.............................................................41 
10.2.6.2 Adverse Drug Reactions ...........................................................43 
10.2.6.3 Nonserious Adverse Events ......................................................43 
10.3 Special Considerations ......................................................................................43 
10.3.1 Adverse Events of Special Interest ........................................................43 
10.3.2 Pregnancy ..............................................................................................43 
10.3.3 Overdose ................................................................................................43 
11. DATA SAFETY MONITORING BOARD ............................................................43 
12. STATISTICS .............................................................................................................43 
12.1.1 Safety Endpoints ....................................................................................44 
12.2 Sample Size Determination ...............................................................................44 
12.3 Analysis Populations .........................................................................................44 
12.4 Statistical Analyses ...........................................................................................44 
12.4.1 Study Subjects and Demographics ........................................................44 
12.4.1.1 Disposition and Withdrawals ....................................................44 
12.4.1.2 Protocol Deviations ...................................................................45 
12.4.1.3 Demographics and Other Baseline Characteristics ...................45 
12.4.1.4 Medical History and Clinical Laboratory .................................45 
12.4.2 Exposure and Compliance .....................................................................45 
12.4.3 Safety and Tolerability Analyses ..........................................................45 
12.4.3.1 Adverse Events..........................................................................45 
12.4.3.2 Clinical Laboratory Evaluations ...............................................45 
12.4.3.3 Vital Signs .................................................................................46 
12.4.3.4 Physical Examination Findings .................................................46 
12.4.3.5 Other Safety Parameters – C-SSRS ..........................................46 
12.4.3.6 
 
13. STUDY CONDUCT..................................................................................................46 
13.1 Sponsor and Investigator Responsibilities ........................................................46 
13.1.1 Sponsor Responsibilities .......................................................................46 
13.1.2 Investigator Responsibilities .................................................................46 


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13.2 Site Initiation .....................................................................................................47 
13.3 Study Documents ..............................................................................................47 
13.3.1 Investigator’s Regulatory Documents ...................................................47 
13.3.2 Case Report Forms ................................................................................48 
13.3.3 Source Documents .................................................................................48 
13.4 Data Quality Control .........................................................................................48 
13.4.1 Monitoring Procedures ..........................................................................48 
13.4.2 Data Management ..................................................................................49 
13.4.3 Quality Assurance/Audit .......................................................................49 
13.5 Study Termination .............................................................................................49 
13.5.1 Regular Study Termination ...................................................................49 
13.5.2 Premature Study Termination ...............................................................50 
13.6 Study Site Closure .............................................................................................50 
13.6.1 Record Retention ...................................................................................50 
13.7 Changes to the Protocol ....................................................................................51 
13.8 Use of Information and Publication ..................................................................51 
14. FINAL CLINICAL STUDY REPORT ...................................................................51 
15. ETHICAL AND LEGAL CONSIDERATIONS ....................................................52 
15.1 Declaration of Helsinki and Good Clinical Practice .........................................52 
15.2 Subject Information and Informed Consent ......................................................52 
15.3 Approval by Institutional Review Board and Independent Ethics Committee .53 
15.4 Finance and Insurance .......................................................................................53 
16. REFERENCES .........................................................................................................54 
17. ATTACHMENTS .....................................................................................................56 
17.1 Investigator’s Agreement ..................................................................................56 
17.2 Schedule of Assessments ..................................................................................57 
APPENDICES ..................................................................................................................58 
 
 
B. 
Regulations and Good Clinical Practice Guidelines .........................................62 
C.      Structured Clinical Interview for DSM-5, Clinical Trials (SCID-5-CT) ..........63 
D. 
Montgomery and Åsberg Depression Rating Scale (MADRS) ........................93 
E. 
Quick Inventory of Depressive Symptomology – Self-Rated (QIDS-SR-16) ..97 
F. 
Clinical Global Impression of Severity of Illness (CGI-S) ...............................99 
G. 
Clinical Global Impression of Improvement of Illness (CGI-I)......................100 
H. 
Columbia – Suicide Severity Rating Scale (C-SSRS) – Lifetime...................101 
I. 
Columbia – Suicide Severity Rating Scale (C-SSRS) – Since Last Visit .......104 
 
 


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LIST OF FIGURES 
2.1 List of Figures 
Figure 6.1 
Study Design .........................................................................................18 
 
3. LIST OF ABBREVIATIONS 
 
ADOs 
Adverse Dropouts 
ADR 
ADT 
Adverse Drug Reaction 
Antidepressant Therapy 
AE 
ALT 
Adverse Event 
Alanine Aminotransferase 
AUC 
Area Under the Curve 
AXS 
BID 
BMI 
Axsome Therapeutics 
Twice Daily (bis in die) 
Body Mass Index 
BP 
BUP 
Blood Pressure 
Bupropion 
CFR 
CGI-I 
Code of Federal Regulations 
Clinical Global Impression of Improvement of Illness 
CGI-S 
Clinical Global Impression of Severity of Illness 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRF 
CRP 
Case Report Form 
C-Reactive Protein 
CSR 
C-SSRS 
Clinical Study Report 
Columbia – Suicide Severity Rating Scale 
DM 
Dextromethorphan 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
EOS 
End of Study 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
HIV 
Good Clinical Practice 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat Population 
LLC 
LLN 
Limited Liability Company 
Lower Limit of Normal 
MADRS 
Montgomery-Åsberg Depression Rating Scale 


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MAOI 
Monoamine Oxidase Inhibitors 
MDD 
MDE 
MedDRA 
mg 
Major Depressive Disorder 
Major Depressive Episode 
Medical Dictionary for Regulatory Activities 
Milligram 
mITT 
Modified Intent-to-Treat Population 
NJ 
New Jersey 
NMDA 
N-methyl-D-aspartate 
NY 
New York 
OTC 
Over-the-Counter 
PI 
PK 
QD 
QIDS-SR-16 
Principal Investigator 
Pharmacokinetic 
Once Daily (quoque die) 
Quick Inventory of Depressive Symptomatology-Self- Rated 
SAE 
Serious Adverse Event 
SAP 
SCID-5-CT 
Statistical Analysis Plan 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
SD 
Standard Deviation 
SNRIs 
Serotonin-Norepinephrine Reuptake Inhibitors 
SOC 
System Organ Class 
SR 
Sustained Release 
SSRIs 
Selective Serotonin Reuptake Inhibitors 
TEAE 
Treatment-Emergent Adverse Events 
TMF 
TSH 
Trial Master File 
Thyroid-Stimulating Hormone 
U.S. 
UADR 
United States 
Unexpected Adverse Drug Reaction 
UAE 
UDS 
Unexpected Adverse Event 
Urine Drug Screen 
ULN 
Upper Limit of Normal 
USA 
 
United States of America 
 
 
 
 


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4. INTRODUCTION 
4.1 
Background  
Major Depressive Disorder (MDD) is a debilitating psychiatric disorder characterized by 
depressed mood or a loss of interest or pleasure in daily activities consistently for at least a  
two-week period, and which impairs social, occupational, educational, or other important 
functioning. MDD is highly prevalent and difficult to treat. In 2016, 6.7 percent of adults aged 18 
or older (16.2 million adults) had at least one Major Depressive Episode (MDE) in the past year, 
and 4.3 percent of adults (10.3 million adults) had an MDE with severe impairment in the past 
year. Adults in 2016 who had an MDE with severe impairment represented nearly two-thirds (64.0 
percent) of adults who had a past year MDE. [1]. Results of the Sequenced Treatment Alternatives 
to Relieve Depression (STAR*D) trial indicate that nearly two-thirds of treated patients with MDD 
do not experience adequate treatment response with first-line therapy, and that the majority of 
these initial failures also fail second-line treatment [2], suggesting that there are significant 
limitations to current treatments. There is therefore an urgent need for new, mechanistically novel 
treatments for MDD. 
4.2 
Rationale for the Evaluation of AXS-05 for Major Depressive Disorder 
AXS-05 is being evaluated in the current study in subjects with MDD. AXS-05 is a fixed-dose 
combination of bupropion and dextromethorphan (DM). The bupropion in the combination is used 
both for its neuropharmacological properties as well as for its ability to inhibit the metabolism of 
DM through CYP2D6. The rationale for the study of AXS-05 in depressive disorders is based on 
the neuropharmacology of DM and bupropion which are relevant to depression, clinical 
observations with these individual agents in depressed subjects, and the positive pharmacokinetic 
interaction of DM and bupropion. 
Bupropion and DM each target different receptor systems that are associated with antidepressant 
activity. Bupropion is an inhibitor of the neuronal uptake of norepinephrine and dopamine [3]. DM 
is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 receptor agonist 
and inhibitor of the serotonin transporter (SERT) and norepinephrine transporter (NET) [4]. 
Combining the distinct and independent mechanisms of action of these two compounds may be 
additive or synergistic.  
The clinical utility of DM has however been limited by its rapid metabolism through CYP2D6 in 
the majority of humans yielding low plasma levels even at high and repeated doses [5]. AXS-05 
addresses this limitation by combining DM and bupropion. As bupropion and its metabolites are 
inhibitors of CYP2D6, co-administration of bupropion and DM leads to substantially increased 
DM plasma concentrations. In three Phase 1 pharmacokinetic trials of AXS-05, administration of 
bupropion in combination with DM resulted in a significant increase in DM exposure (Cmax and 
AUC) at all doses tested (Axsome data on file). Administration of bupropion in combination with 
DM resulted in Cmax and AUC0-12 of DM on Day 8 that were 20 to 27 times and 30 to 36 times, 
respectively, the values observed on Day 1 of dosing. DM exposure increased in a dose-dependent 
manner with increasing doses of both DM and bupropion. Administration of DM did not appear 
to affect the pharmacokinetics of bupropion. There was no significant difference in the rates or 
types of adverse events in the combination groups as compared to a group receiving bupropion 
alone. The positive pharmacokinetic interaction between bupropion and DM therefore enables 
DM’s clinical utility in treating depression by increasing DM’s plasma levels into a potentially 
therapeutic range. 


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5. OBJECTIVES 
To evaluate the safety and tolerability of AXS-05 and bupropion in subjects with MDD. 
6. STUDY DESIGN 
6.1 
Overall Study Design and Plan 
This study is a randomized, double-blind, active-controlled, Phase 2 trial, consisting of a screening 
period and a 6-week treatment period. The trial is being conducted in subjects experiencing a 
current depressive episode. Informed consent will be obtained before any subsequent screening 
related procedures are performed. Assessments will include safety parameters, MADRS, QIDS-
SR-16, CGI-S and CGI-I. Subjects will be provided a Visual Analog Mood Scale (VAMS) and 
asked to complete it daily. 
The study will be divided into 3 segments: an up to four-week screening period (Screening); a 6-
week treatment period; and a 1-week follow-up period. A sufficient number of subjects will be 
screened and randomized to achieve the goal of having approximately 60 compliant subjects who 
complete the double-blind treatment period. 
The study design is depicted in Figure 6.1. 
Figure 6.1 
Study Design 
 
 


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Screening Period  
Prior to any screening related procedures, informed consent will be obtained. After providing 
informed consent, all subjects will enter an up-to four week screening period to determine 
eligibility. Eligible subjects must meet the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) criteria for MDD without psychotic features, based on the Structured 
Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 
Clinical Trials Version (SCID-5-CT), with a current major depressive episode of at least 4 weeks 
in duration.  Eligible subjects must meet all other inclusion and no exclusion criteria. 
Treatment Period 
Subjects who successfully complete Screening will be randomly assigned at Visit 2 (Baseline) to 
receive either AXS-05 or bupropion sustained release (SR) in a 1:1 ratio for 6 weeks. The 
treatments will be up-titrated in the following manner: 
Days 1 - 3 
 AXS-05 group: 105 mg bupropion, 45 mg dextromethorphan QD 
 Bupropion group: 105 mg bupropion QD 
Days 4 - 42 
 AXS-05 group: 105 mg bupropion, 45 mg dextromethorphan BID 
 Bupropion group: 105 mg bupropion BID 
All QD doses will be taken in the morning, orally on an empty stomach (at least 2 hours pre- or 2 
hours post-prandial) with water. All BID doses will be taken at least 8 hours apart, orally on an 
empty stomach (at least 2 hours pre- or 2 hours post-prandial) with water.  
All study drug including AXS-05 tablets and bupropion SR tablets are of identical appearance and 
similar weight in order to maintain the integrity of the blind. 
Assessments and Visits 
Study visits will occur at Visit 1, Baseline (Day 0, Visit 2), and on Days 3, 7, 14, 21, 28, 42 and 
49 (Visits 3 – 9). Study procedures and assessments will be performed during study visits as 
outlined in the Schedule of Assessments (See Section 17.2). Visit 3 (Day 3) will be conducted 
telephonically. Subjects will be reminded during Visit 3 to begin BID dosing on Day 4. All subjects 
completing 6 weeks of treatment or subjects prematurely discontinuing from the study will be 
required to complete a follow-up visit one week after the last dose of study drug (Visit 9), 
telephonically. 
Assessments will include safety parameters, MADRS, QIDS-SR-16, CGI-S and CGI-I. 
 
 
 
 
  
 
Study drug compliance will also be assessed at the 80% level by 
counting the number of tablets dispensed and returned. Non-compliant subjects are subject to early 
termination from the study and should return for an Early Termination visit.  


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Safety will be assessed by evaluating treatment-emergent AEs (TEAEs); clinical laboratory test 
results; vital sign measurements; and physical examination findings. 
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of the signing of the informed consent form [ICF] through follow up) will be documented. 
6.2 
Discussion of Study Design 
The safety assessments used in this study are recognized and validated standards of measurement.  
Bupropion SR is used as an active control in this trial as it is one of the two components in AXS-
05. The 3-day up-titration period for AXS-05 and bupropion SR used in this trial is meant to 
minimize AEs resulting in early drop-outs. This up-titration from QD to BID dosing is consistent 
with the label for Wellbutrin SR which recommends at least 3 days before up-titrating to BID 
dosing. No down-titration has been included consistent with the product label for Wellbutrin SR.  
6.3 
Study Sites 
The study will take place at up to 5 study sites in the United States.  
6.4 
Point of Contact 
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of the subject, and whom to contact in case of study-related 
injury. This information will be provided in the information provided to the subject and in the ICF. 
7. SUBJECT POPULATION 
7.1 
Selection of Study Population and Diagnosis 
Eligible subjects for this study must have a diagnosis of Major Depressive Disorder (MDD). A 
sufficient number of subjects will be screened to achieve the goal of having approximately 60 
compliant subjects who complete the double-blind treatment period at up to 5 study centers in the 
U.S. 
The diagnosis of MDD will be confirmed using the Structured Clinical Interview for Diagnostic 
and Statistical Manual of Mental Disorders, Fifth Edition, Clinical Trials Version SCID-5-CT. 
Eligible subjects must have a current depressive episode of at least 4 weeks. 
Eligible subjects are to have otherwise acceptable and stable general health as required by the 
inclusion and exclusion criteria, documented by medical history, physical examination, and 
clinical laboratory examinations. 
7.2 
Study Entry Criteria 
7.2.1 Inclusion Criteria 
A subject will be eligible for study participation if the subject meets all of the following criteria: 
1. Provides written informed consent to participate in the study, is able to understand the 
procedures and study requirements, and agrees to abide by the study restrictions and return for 
the required study assessments. 
2. Male or female outpatients, 18 to 65 years of age, inclusive. 
3. Currently meets the DSM-5 criteria for MDD without psychotic features, based on the SCID-


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5-CT, with a current major depressive episode of at leave 4 weeks in duration at  
Visit 1.  
4. MADRS score of ≥ 25 and CGI-S ≥ 4 at Screening (Visit 1) and Baseline (Visit 2). 
5. Normal physical examination findings and clinical laboratory test results from Screening (Visit 
1) or abnormal results that are judged not clinically significant by the investigator. 
6. Body mass index (BMI) between 18 and 40 kg/m2, inclusive. 
7. If female of childbearing potential, having a negative urine pregnancy test result at Visit 1 and 
Visit 2, and practicing an adequate method of birth control (e.g. oral or parenteral 
contraceptives, intrauterine device, double-barrier) and does not plan to become pregnant 
during the course of the study. Long-term abstinence is acceptable as long as the subject agrees 
to use double-barrier contraception if they decide to have sexual intercourse. Female subjects 
using a hormonal contraceptive or intrauterine device must have been doing so for at least 1 
month before Screening and must follow that product’s package insert instructions including 
additional protection at times when hormonal contraceptive doses might be missed. Female 
subjects may be included without a negative urine pregnancy test if they are surgically sterile 
or at least 2 years post-menopausal. Male subjects and their female sexual partners should use 
an acceptable method of birth control (as noted above) during the study.  
7.2.2 Exclusion Criteria 
A subject will be excluded from the study if the subject meets any of the following criteria: 
Psychiatric Criteria: 
1. History of: 
a) Any depressive episode with psychotic or catatonic features 
b) Any manic, hypomanic or mixed episode, including bipolar disorder (Type 1 or Type 2) 
and substance-induced (e.g. antidepressant-induced) manic, hypomanic/mixed episode 
c) Schizophrenia, schizoaffective, or other psychotic disorder 
d) Panic disorder, with or without agoraphobia 
e) Obsessive-compulsive disorder 
f) Bulimia or anorexia nervosa 
g) Any persistent neurocognitive disorder 
h) Any other anxiety disorder which has been the primary focus of clinical attention for the 
six months prior to Screening, while MDD was a secondary focus of attention 
2. History of treatment resistant depression defined as 2 or more failed prior treatments of 
adequate dose and duration in the current depressive episode. 
3. Post-traumatic stress disorder, active within 3 years of Visit 1. 
4. Borderline or antisocial personality disorder or other disorder of sufficient severity to interfere 
with participation in this study. 
5. Alcohol/substance use disorder (other than nicotine or caffeine), active within 1 year of  
Visit 1. 
6. Psychiatric hospitalization within current depressive episode.  
7. Psychiatric symptoms secondary to any other general medical condition. 
8. Clinically significant risk of suicide or harm to self or others.  Risk of suicide is determined by 
meeting any of the following criteria: 


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a) In the judgment of the investigator, the subject may be a significant risk for suicide as 
judged by the psychiatric interview or information collected in the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Visit 1 or Visit 2 (e.g., The subject responded “yes” to 
question 4 or question 5 on the screening C-SSRS, and the most recent episode occurred 
within the current depressive episode). 
b) The subject has attempted suicide within the current depressive episode. 
c) MADRS Item 10 score ≥ 5 at Visit 1 or Visit 2. 
Treatment-Related Criteria: 
9. Use of drugs that are strong inhibitors of CYP2D6 (e.g. fluoxetine, paroxetine, quinidine) as 
defined in FDA’s Guidance for Industry: Drug Interaction Studies - Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations. 
10. Use of drugs that are inhibitors of CYP2B6, the primary enzyme that metabolizes bupropion 
(e.g. clopidogrel, ticlopidene, prasugrel), or that are inducers of CYP2B6 (e.g. ritonavir, 
lopinavir, efavirenz). Please refer to the Wellbutrin SR (bupropion) FDA package insert. 
11. Current use, or use within 14 days before Visit 1 of monoamine oxidase inhibitors (MAOIs), 
or linezolid, or intravenous methylene blue. 
12. Use of opioids (e.g., codeine, oxycodone, morphine) within 14 days before Visit 1. 
13. Having received any prohibited medications, supplements or herbal products 
 
 
, including any antipsychotic, anticonvulsant/mood stabilizer, anxiolytic, 
benzodiazepine, ADT, or ADT augmentation agent (e.g., T3 [except as treatment for thyroid 
condition], 2nd antidepressant, etc.) within 1 week or 5 half- lives of the medication, whichever 
is longer, prior to Visit 2; however, 4 weeks is required for T3, 2 weeks is required for MAOIs. 
Lithium must be tapered and followed by a 1-week washout. The safe withdrawal from 
benzodiazepine treatment should be decided by the patient’s treating clinician and also 
monitored by the principal investigator. 
14. History of electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic 
stimulation, or any experimental central nervous system treatment during the current episode 
or in the 6 months before Visit 1 (whichever is longer). 
15. Requiring concomitant treatment with any of the prohibited medications, supplements, or 
herbal products 
 including any psychotropic drug or any drug with 
psychotropic activity or with a potentially psychotropic component, except for the following: 
a) Eszopiclone, zolpidem, zolpidem extended-release, zopiclone or zaleplon for insomnia 
may be continued provided the medication has been used in a consistent manner for 4 
weeks prior to enrollment and at doses that do not exceed the maximum labeled amounts. 
16. Initiation or termination of psychotherapy for depression within 3 months of Visit 1, or plans 
to initiate, terminate, or change  such therapy during the course of the study (Support 
meetings or counseling [e.g., marital counseling] are allowed provided they are no more 
frequent than weekly and do not have treatment of depression as their objective). 
17. Ongoing, initiation or termination of phototherapy within 1 month of Visit 1. 
Other Medical Criteria: 
18. History of seizure disorder; undergoing abrupt discontinuation of alcohol, benzodiazepines, 
barbiturates or antiepileptic drugs; or any other condition that increases the risk of seizure such 


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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). 
19. Female subjects who meet either of the following criteria: 
a. Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the 
study. 
b. Sexually active females who are less than 2 years postmenopausal, and are either 
not surgically sterile (tubal ligation, bilateral oophorectomy or hysterectomy), or 
not practicing a reliable method of contraception that will continue throughout the 
duration of the study. Reliable contraception is defined as oral contraceptives 
(consisting of an estrogen-progestin combination or progestin alone), transdermally 
delivered contraceptives (e.g., Ortho Evra), depot injections (e.g., Depo-Provera), 
vaginal contraceptive ring (e.g. NuvaRing), contraceptive implants (e.g., Implanon, 
Norplant II/Jadelle), an intrauterine device, or double-barrier method (e.g. 
diaphragm plus condom accepted). Females using a hormonal contraceptive or 
intrauterine device must have been doing so for at least 1 month before Visit 1 and 
must follow that product’s package insert instructions including additional 
protection at times when hormonal contraceptive doses might be missed. Rhythm, 
withdrawal, single-barrier methods (i.e., contraceptive sponge, female condom or 
male condom or diaphragm alone) are not acceptable methods of contraception. 
Long-term abstinence is acceptable as long as patients agree to use double-barrier 
contraception if they decide to have sexual intercourse. 
20. Positive serum ethanol test or urine drug screen (UDS) for any prohibited medication or drugs 
of abuse (cocaine, marijuana, PCP, opioid or other agent that in the opinion of the investigator 
is being abused) at Visit 1. Subjects should be advised not to drink alcohol for at least 8 hours 
prior to screening labs. 
21. Any current or recent medical, psychiatric, or social condition that, in the investigator’s 
opinion, is likely to interfere with the conduct of the study, confounds the interpretation of 
study results, or endangers the subject’s well-being. This includes (but is not limited to) any 
clinically 
significant 
oncologic, 
hematologic, 
endocrine/metabolic, 
cardiovascular, 
respiratory, renal, hepatic, gastrointestinal, infectious or neurologic disease or has a chronic 
disease which is unstable or progressive.  
22. Hypertension defined as resting, sitting systolic blood pressure (BP) ≥150 mm Hg or diastolic 
blood pressure ≥ 95 mm Hg. Patients with high BP (as defined above) may be accepted in the 
study if they subsequently have acceptable BP values on reassessment at least 30 minutes apart. 
23. Hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change 
in dosage for at least 1 month before Visit 1 (Serum TSH must be > 0.75 × the LLN and < 1.25 
× ULN). 
24. History of allergy or hypersensitivity to bupropion, dextromethorphan, opiate drugs (e.g. 
codeine, etc.), or any other ingredient in the study drug. 
25. History of intolerance to bupropion or dextromethorphan. 
26. Patients who have received dextromethorphan co-administered with quinidine (e.g. 
Nuedexta®) within the past four weeks. 
27. Gastric bypass or any condition that would be expected to affect drug absorption (lap band 


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procedures are acceptable if there is no problem with absorption). 
28. Narrow-angle glaucoma without a patent iridectomy.
29. Known human immunodeficiency virus (HIV) infection.
30. Clinically significant signs of active hepatitis B and/or C infection.
31. Screening liver enzyme test (e.g., bilirubin, aspartate aminotransferase and/or alanine
aminotransferase) results > 2.0 x ULN.
32. Any clinically significant abnormality on the screening laboratory tests, as assessed by the
study investigator and/or the medical monitor.
33. Treatment with any investigational drug within 30 days of Visit 1.
34. Currently hospitalized or residing in an in-patient facility during the study.
35. Unable or unlikely to comply with the study protocol or unsuitable for any other reason,
including other conditions that might indicate that the subject is unsuitable for the study as
judged by the investigator such as known history of poor medication compliance or significant
instability in status of psychosocial issues.
7.3 
Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The Investigator should make every reasonable 
attempt to keep subjects in the study; however, subjects must be withdrawn from the study 
immediately if they withdraw consent to participate.  
Investigators must attempt to contact subjects who fail to attend scheduled visits by telephone or 
other means to exclude the possibility of an AE being the cause of withdrawal. Should this be the 
cause, the AE must be documented, reported, and followed as described in Section 10.2. 
Axsome reserves the right to request the withdrawal of a subject because of protocol violations or 
other reasons. 
The Investigator also has the right to withdraw subjects from the study or discontinue study drug 
treatment at any time for any reason. Examples of reasons for discontinuation may include: 
intolerable or unacceptable AEs, intercurrent illness, noncompliance with study procedures, 
administrative reasons, or in the Investigator’s opinion, to protect the subject’s best interest.   
If a subject is withdrawn or discontinues treatment before completing the study, the reason and the 
date of discontinuation will be recorded on the appropriate case report form (CRF). Whenever 
possible and reasonable, the evaluations that were to be conducted at the completion of the study 
should be performed at the time a subject withdraws from the study.   
Subjects who discontinue treatment should be encouraged to continue completing study visits and 
procedures so long as the subject does not withdraw consent.   
7.4 
Subject Replacement Criteria 
Subjects who are withdrawn for noncompliance or other reasons may be replaced to achieve the 
goal of approximately 60 compliant subjects who complete the double-blind treatment period. 


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8. TREATMENTS 
8.1 
Identification of Investigational Product 
The following study drugs will be provided: 
Treatment A: AXS-05 (105 mg bupropion, 45 mg dextromethorphan) tablet, oral 
Treatment B: Bupropion SR (105 mg) matching tablet, oral 
AXS-05 is a fixed-dose combination tablet of 105 mg bupropion hydrochloride SR and 45 mg 
dextromethorphan hydrobromide monohydrate IR, in the form of a bilayer, film-coated tablet. 
Bupropion SR tablets contain 105 mg bupropion hydrochloride SR, in the form of a film-coated 
tablet that matches the visual appearance and weight of the AXS-05 tablets. 
AXS-05 and bupropion SR supplied for this study are manufactured by 
 
. 
8.2 
Labeling and Packaging 
8.2.1 Labeling 
Clinical labeling of the study drug will be performed by 
. The 
bottles of study drug will have a label that meets the applicable regulatory requirements and may 
include the following: subject identifier, dosage strength, lot number, package number, protocol 
number, specified number of tablets, caution statement, storage, manufacture or expiration date, 
and Sponsor/manufacturer identification and dosing instructions. 
8.2.2 Packaging 
AXS-05 and bupropion SR tablets will be supplied and bottled by 
 
and labeled at 
. The study drug will be packaged in 50 cc bottles 
and labeled to blind the Investigator, the study clinic personnel, and subjects. 
8.3 
Study Drug Administration 
All subjects will receive either AXS-05 or bupropion SR according to the kit number assigned by 
a randomization scheme. Eligible subjects will be assigned a unique kit that contains 4 bottles of 
study drug.  Bottles from the assigned kits should be dispensed to the subject per the pharmacy 
manual and/or subject dosing instructions provided. The kit must remain on-site at all times and 
only the appropriate number of bottles should be dispensed to the subject at each study visit.  
Designated staff at each site will dispense study drug bottles. Subjects will be instructed to take 
the study drug per the Treatment Period part of Section 6.1. Subjects should be instructed to return 
bottle(s) and any unused study drug at each study visit in order to record compliance. All study 
drug will be supplied and administered in a double-blind manner throughout the entire duration of 
the study. 
8.4 
Dispensing and Storage 
The study drug is to be used exclusively in this clinical study according to the instructions of this 
protocol. The Investigator is responsible for dispensing the study drug according to the dosage 
scheme and for ensuring its proper storage. The Investigator or designee must confirm the receipt 
of study drug with a signature. A copy of this receipt must be kept by the Investigator and another 
copy will be stored at Axsome and/or its designee.  


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All study drug must be stored in an appropriate secure area (e.g., a locked cabinet in a locked 
room) at controlled room temperature (with a permitted range of 15°C-30°C or 59°F-86°F) and 
must be protected from heat and moisture. Any excursions below or above this temperature range 
should be communicated to Axsome Therapeutics, Inc., or its designee as soon as possible. The 
key to the storage area is to be kept by the Investigator or designee responsible for the study drug. 
The storage area will be accessible only to those persons authorized by the Investigator. 
The key to the storage area is to be kept by the Investigator or designee responsible for the study 
drug. The storage area will be accessible only to those persons authorized by the Investigator. 
8.5 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet study entry criteria will be randomly assigned in a 1:1 ratio to AXS-05 or 
bupropion SR, respectively. The randomization schedule will be computer generated using a 
permuted block algorithm that will randomly allocate study drug to randomization numbers. The 
randomization numbers will be assigned sequentially. Study center will not be a blocking factor in 
the randomization schedule. 
The randomization schedule will be prepared before the start of the study. No one involved in the 
study performance will have access to the randomization schedule before official unblinding of 
treatment assignment. No subject will be randomized into this study more than once. 
8.6 
Blinding and Unblinding Treatment Assignment 
All subjects, Investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment with the exception of a specified 
independent unblinded statistician, and clinical supply manager who will have access to the 
randomization code. The unblinded study personnel will not otherwise participate in study 
procedures or data analysis before unblinding of the study data to all study related personnel. 
Sponsor personnel involved in the management and monitoring of the study will be blinded to the 
treatment assignment. 
Study personnel will strive to safeguard the integrity of the study blind to minimize bias in the 
conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. Unblinding should be discussed in advance with the medical 
monitor if possible. For emergency unblinding, the site will access the randomization code. If the 
Investigator is not able to discuss treatment unblinding in advance, then he or she must notify the 
medical monitor as soon as possible about the unblinding incident without revealing the subject’s 
treatment assignment. To unblind the treatment group, the Investigator will open the envelope in 
which the randomization code was received. The Investigator or designee must record the date and 
reason for study drug discontinuation on the appropriate CRF for that subject. In all nonemergency 
cases, the Investigator must discuss the event with the medical monitor before unblinding the 
subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding those of the remaining subjects in the 
study. Thus, the overall study blind will not be compromised. If a subject’s treatment assignment 
is unblinded, he or she may or may not be asked to withdraw from the study. The Investigator will 
make this decision after consultation with the medical monitor. 


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8.7 
Selection of Doses in the Study 
The dose of AXS-05 (105 mg bupropion, 45 mg DM), titrated to twice daily, was selected based 
on the results of three completed Axsome-sponsored, pharmacokinetic Phase 1 trials of the 
combination of bupropion and DM. The selected dose combination resulted in an increase in DM 
plasma concentrations into a potentially therapeutic range. 
The dose of bupropion SR is 105 mg, titrated to twice-daily administration. This dose was selected 
because it is equal to the dose of bupropion in AXS-05. 
8.8 
Selection of Timing of Dose 
A significant food effect has not been reported for the individual components of AXS-05. AXS-
05 and bupropion SR tablets are dosed on an empty stomach (at least 2 hours pre- or 2 hours post-
prandial) in this trial to match the dosing in the completed Phase 1 trials of AXS-05. 
8.9 
Dose Adjustment Criteria 
Dose adjustment is not recommended in this study.  If a subject misses a dose, or if a dose is 
skipped due to AEs, if possible the subject should continue in the study and take study drug at the 
designated times.   
8.10 Drug Accountability 
The Investigator must maintain adequate records showing the receipt, dosing, or other disposition 
of the study drug provided, including the date, quantity, batch or code number, and identification 
of subjects (subject number and initials) who received it. An inventory of study drug should be 
performed by authorized personnel upon receipt to confirm contents match the packing slip and 
that the all product packaging is received and in good condition.  If product received does not 
correspond to the packing slip or is damaged, the Axsome study team should be contacted 
immediately and the inventory quarantined until further instructions are provided. 
The Investigator will not supply the study drug to any person except those named as Sub-
Investigators on the Form FDA 1572, designated study personnel, and subjects in this study. The 
Investigator will not dispense the study drug from any study sites other than those listed on the 
Form FDA 1572. The study drug may not be relabeled or reassigned for use by other subjects. If 
any of the study drug is not dispensed; is lost, stolen, spilled, unusable; or is received in a damaged 
container, this information must be documented and reported to Axsome and appropriate 
regulatory agencies, as required. 
Upon completion of the study, the study drug (partly used, unused, and empty packaging) must be 
left in the original packaging and returned to Axsome or its designee for destruction. 
8.11 Treatment Compliance 
Study drug compliance will be closely monitored by counting the number of tablets dispensed and 
returned 
.  
Subjects will be instructed to bring any unused study drug and empty containers to the clinic on 
Days 7, 14, 21, 28 and 42 (Visits 4 – 8), or at the time of early study discontinuation. Before new 
study drug is dispensed at each visit, every effort will be made to collect the unused study drug to 
confirm compliance. Investigators will perform drug accountability of study drug at each visit to 
determine a subject’s usage. Study drug compliance will be assessed at the 80% level. 


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If non-compliance is determined, the site will be notified in writing and noncompliant subjects 
may be discontinued from the study. Discontinued subjects should return for an Early Termination 
visit, performing all the study assessments for Visit 8/ET and then complete the follow-up visit 
one week after the final dose of study drug (Visit 9).  
8.12 Prior and Concomitant Therapies 
Medication history during the previous 1 year (5 years in the case of psychiatric drug history) will 
be recorded at Screening (Visit 1) in the CRF. Thereafter, any changes in concomitant medications 
or new medications added will be recorded in the CRF.  
At each visit, subjects will be queried as to whether or not they have taken any concomitant 
medications and, if so, the Investigator will record the medications taken and the reasons for their 
use. All concomitant medications and treatments used (including over-the-counter medications 
and herbal supplements) will be recorded in the source document and on the appropriate CRF. 
8.12.1 Prohibited Therapies 
 
 The investigator should consult with the 
Axsome Medical Monitor if he/she is unsure whether a certain medication is prohibited. 
Psychotherapy for depression may not be initiated, terminated, or changed during the course of the 
study (Support meetings or counseling [e.g., marital counseling] are allowed provided they are no 
more frequent than weekly and do not have treatment of depression as their objective). 
Phototherapy is prohibited during the course of the study and may not have been initiated or 
terminated within 1 month of Visit 1. 
Subjects who receive excluded therapies will be ineligible for continuation in the study at the 
discretion of the Sponsor and medical monitor. 
8.13 Treatment after the End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 


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9. STUDY PROCEDURES 
Subjects will provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of 
Assessments (Section 17.2). Throughout the study, every reasonable effort should be made by 
study personnel to follow the timing of assessments and procedures in the schedule of assessments 
for each subject. If a subject misses a study visit for any reason, the visit should be rescheduled as 
soon as possible. 
9.1 
Study Periods, Visits, and Procedures 
9.1.1 Visit 1, Screening (Days −28 to −1) 
Subjects will be screened within 28 days before randomization in the study. The following 
procedures will be performed at Screening: 
 Provide the subject with the informed consent document and explain the rationale for the 
study, providing ample time for participants and authorized representatives to ask 
questions. Consent will be obtained before any subsequent screening related procedures 
are performed. 
 Review inclusion/exclusion criteria.  
 Review and record: Patient medical/psychiatric history and demographics. 
 Review and record: Medications currently being taken or taken within the previous 1 year 
(5 years in the case of psychiatric drug history) of Screening (including OTC medications, 
vitamins, and supplements). Determine medication washout requirements and duration. 
Subjects who are receiving prohibited medications (e.g., antipsychotics, antidepressants, 
anticonvulsants/mood stabilizers, anxiolytics, and sedatives/hypnotics) except as 
specifically allowed, will require a washout period. All prohibited medications should be 
washed out before Visit 2. 
 Perform a complete physical examination (excluding breast and genitourinary 
examination) with review of body systems. 
 Record vital signs: Blood pressure, pulse, respiratory rate, and oral temperature after 
subject has been seated for 5 minutes. 
 Measure height and weight. 
 Collect blood and urine samples for central clinical laboratory tests (hematology, serum 
chemistry, urinalysis, thyroid panel, and serum ethanol); see Section 9.3.3.2.1 for a 
complete list of required laboratory tests. 
 Collect urine for an on-site urine drug screen and urine pregnancy test (if female). 
 Conduct SCID-5-CT interview to confirm MDD diagnosis. 
 Administer evaluations: 
o MADRS ( ≥ 25 inclusive) 
o CGI-S ( ≥ 4 inclusive) 
o QIDS-SR-16 
o Columbia – Suicide Severity Rating Scale (C-SSRS) (lifetime) 


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 
 
9.1.2 Visit 2, Baseline (Day 0) 
Subjects will return for Visit 2 up to 28 days after Visit 1. The interval may be extended, if 
necessary and after discussion with the Axsome Medical Monitor, to accommodate medication 
washout or repeat screening procedures.  The following procedures will be performed at Baseline 
(Day 0): 
 Review and confirm inclusion/exclusion criteria. 
 Record vital signs, including: Blood pressure, pulse, respiratory rate, and oral temperature 
after subject has been seated for 5 minutes. 
 Review and record AEs since last visit. 
 Review and record any current concomitant medication use (including OTC, vitamins, and 
supplements). 
 Collect urine sample for on-site drug screening and urine pregnancy test (if female). 
 
 
 Administer evaluations: 
o MADRS ( ≥ 25 inclusive) 
o CGI-S ( ≥ 4 inclusive) 
o QIDS-SR-16 
o C-SSRS (since last visit) 
 Randomize subject once it is determined that subject satisfies all of the inclusion and 
exclusion criteria (on the basis of the screening and baseline assessments described above). 
Eligible subjects will be randomized sequentially and assigned the corresponding kit 
number. 
 Dispense 1 study drug bottle from the subject assigned kit. 
 Instruct subject to begin to dose 1 tablet the following morning for the next three days, on 
an empty stomach (at least 2 hours pre- or 2 hours post-prandial), orally with water. 
 Schedule Visit 3 telephone call for Day 3. 
 
. 
9.1.3 Visit 3 (Day 3) 
The following procedures will be performed via telephone at Visit 3 (Day 3): 
 Review and record AEs since last visit. 
 Review and record any current concomitant medication use (including OTC, vitamins, and 
supplements). 
 Review study drug compliance and confirm QD dosing for 3 days.  
 Instruct subject to begin BID dosing on Day 4 (the day after the call or the day of if calling 
on Day 4). Confirm doses will be taken at least 8 hours apart, orally on an empty stomach 
(at least 2 hours pre- or 2 hours post-prandial) with water. 
 
 


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9.1.4 Visit 4, 5, 6, and 7 (Days 7, 14, 21, and 28) 
The following procedures will be performed at Visits 4 – 7 (Days 7, 14, 21, and 28): 
 Record vital signs, including: Blood pressure, pulse, respiratory rate, and oral temperature 
after subject has been seated for 5 minutes. 
 Review and record AEs since last visit. 
 Review and record any current concomitant medication use (including OTC, vitamins, and 
supplements). 
 
 
 
 Collect all unused study drug dispensed at previous visit. 
 Assess study drug compliance via drug accountability. Noncompliant subjects may be 
discontinued. 
 Dispense and/or redispense study drug bottle(s) to subject from the previously assigned kit. 
 
 
 Administer evaluations: 
o MADRS 
o QIDS-SR-16 
o CGI-S 
o CGI-I 
o C-SSRS (since last visit) 
 Remind subject to continue dosing BID at least 8 hours apart, orally on an empty stomach 
(at least 2 hours pre- or 2 hours post-prandial) with water. 
 
 
9.1.5 Visit 8 (Day 42) / Early Termination 
The following procedures will be performed at Visit 8 (Days 42) or the Early Termination Visit: 
 Record vital signs, including: Blood pressure, pulse, respiratory rate, and oral temperature 
after subject has been seated for 5 minutes. 
 Record weight. 
 Review and record AEs since last visit. 
 Review and record any current concomitant medication use (including OTC, vitamins, and 
supplements). 
 Perform a physical examination (excluding breast and genitourinary examination) with 
review of body systems. 
 Collect blood and urine samples for central clinical laboratory tests (hematology, serum 
chemistry, urinalysis, thyroid panel, and serum ethanol); see Section 9.3.3.2.1 for a 
complete list of required laboratory tests. 
 Collect urine for an on-site urine pregnancy test (if female). 
 
  


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 Collect all unused study drug dispensed at previous visit. 
 Assess study drug compliance via drug accountability. Noncompliant subjects may be 
discontinued. 
 
 
 Administer evaluations: 
o MADRS 
o QIDS-SR-16 
o CGI-S 
o CGI-I 
o C-SSRS (since last visit) 
9.1.6 Visit 9 (Day 49) / 1-Week Follow-up Phone Call 
Visit 9 will be conducted by telephone. Any clinical findings observed during Visit 8 including 
clinically significant laboratory abnormalities, will be followed until the condition returns to pre-
study status, has resolved or stabilized, or can be explained as being unrelated to the study drug. 
An in-clinic follow-up visit, if one should be necessary, will take place within 30 days of study 
drug termination. 
If a subject is not able to continue treatment with study drug for any reason, he or she will be 
discontinued from treatment and if possible the procedures as listed in Visit 9 will be completed 1 
week after the last dose of study drug. 
At Visit 9, the following procedures will be performed: 
 Review and record AEs since last visit. 
 Review and record any current concomitant medication use (including OTC, vitamins, and 
supplements). 
 Administer C-SSRS (since last visit). 
9.2 
Study Duration 
The study will last up to approximately 11 weeks (including a Screening period up to 4 weeks, 6 
weeks of treatment, and a 1-week follow-up period). 
9.3 
Assessments 
The assessments listed below will be administered at the time points specified in the Schedule of 
Assessments in Section 17.2. 
9.3.1.1 Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-CT) 
The SCID-5-CT [9] is a clinician-rated diagnostic assessment that will be administered at Visit 1 
and will be considered a source document in this study. The SCID-5 is an interview guide for 
making DSM-5 diagnoses and has been adapted for use in this protocol. The interview will be 
administered by the Investigator or a Sub-Investigator who is a psychiatrist, a doctoral or masters 
level clinical psychologist or a psychiatric nurse with sufficient experience in the diagnosis of 
mental illness.  


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9.3.1.2 Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS [10] is a clinician-rated scale. The MADRS is used to assess depressive 
symptomatology during the previous week. Subjects are rated on 10 items to assess feelings of 
sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty 
concentrating and lack of interest. Each item is scored on a 7-point scale. A score of 0 indicates 
the absence of symptoms, and a score of 6 indicates symptoms of maximum severity. 
9.3.1.3 Quick Inventory of Depressive Symptomology – Self-Rated (QIDS-SR-16) 
The 16-item QIDS-SR-16 [11], a patient-rated scale, is an abbreviated version of the 30-item 
Inventory of Depressive Symptomatology (IDS) and is designed to assess the severity of 
depressive symptoms.  The QIDS-SR-16 assesses criterion symptom domains to diagnose a major 
depressive episode.   
The QIDS-SR will be used to assess the subject’s depressive symptomatology over the past 7 days.  
Subjects report severity of symptoms on 10 items assessing sleep, feelings of sadness, appetite, 
weight change, concentration, self-regard, suicidality, general interest level, energy level, 
psychomotor retardation, and restlessness.  Each item will be scored on a 4-point scale with a score 
of 0 reflecting no symptoms and a score of 3 reflecting symptoms of maximum severity. 
9.3.1.4 Clinical Global Impression – Severity (CGI-S) 
The CGI-S scale [12] is a clinician-rated scale used to rate the severity of the subject’s current 
state of mental illness compared with a subject population with MDD. The subject is rated on a 
scale from 1 to 7, with 1 indicating a “normal state” and 7 indicating “among the most extremely 
ill subjects.” The CGI-S will be administered by the Investigator or a Sub-Investigator with 
extensive professional training and experience in assessing mental illness. 
9.3.1.5 Clinical Global Impression – Improvement (CGI-I) 
The CGI-I scale [12] is a clinician-rated scale that is used to rate total improvement or worsening 
of mental illness regardless of whether the Investigator considers it to be a result of drug treatment 
or not. The subject is rated on a scale from 1 to 7, with 1 indicating that the subject is very much 
improved and 7 indicating that the subject is very much worse. The CGI-I will be administered by 
the Investigator or a Sub-Investigator with extensive professional training and experience in 
assessing mental illness. 
 
 
 
 
 
 
 
9.3.2 Clinical Pharmacology 
 
 
 
 


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9.3.3 Safety 
Safety assessments will include the evaluation of TEAEs; clinical laboratory test results; vital sign 
measurements; and physical examination findings. 
9.3.3.1 Adverse Events 
The definitions and management of and special considerations for AEs are provided in Section 10. 
9.3.3.2 Clinical Laboratory Safety Assessments 
9.3.3.2.1 Clinical Laboratory Tests to Be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
Schedule of Assessments (Section 17.2). 
Hematology 
Hemoglobin, hematocrit, red blood cell count, red blood cell indices 
(mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration), platelet count (or estimate), and 
white blood cell count (including differential), absolute and % 
Neutrophil, Lymphocyte, Basophil, Monocyte, and Eosinophils 
Serum Chemistry 
Albumin, total bilirubin, direct bilirubin, total protein, calcium, alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, 
blood urea nitrogen, creatinine, random glucose, sodium, potassium, 
chloride, C-reactive protein (CRP), cholesterol 
Urinalysis 
pH, specific gravity, blood, glucose, protein, ketones, and leukocyte 
esterase 
Thyroid Panel 
TSH, Free T3, Free T4 
Urine Drug Screen 
Benzoylecgonine 
(cocaine), 
barbiturates, 
amphetamines, 
benzodiazepines, cannabinoids, opiates, methadone, phencyclidine, 
ecstasy (MDMA) 
Serum Ethanol Level 
 
Repeat Urine Drug 
Screen 
May be performed at random during the study upon request of the 
investigator 
Repeat Serum Ethanol 
Level 
May be performed at random during the study upon request of the 
investigator 
Other laboratory assessments may be repeated at any visit if there was an abnormal finding at the 
most recent previous evaluation or if additional information is clinically necessary to appropriately 
follow up and/or manage an adverse experience. 
All blood and urine samples will be sent to a central laboratory for analyses. 
9.3.3.2.2 Pregnancy Testing 
Female subjects will be required to have an onsite urine pregnancy test at Visit 1, Visit 2 and Visit 
8/ET. 
A positive pregnancy test will exclude a subject from participating further in the study. In the event 
that a false positive is suspected, a repeat pregnancy test may be performed. Investigators should 
inquire at every study visit about the continued use of acceptable methods of contraception in 


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females of child-bearing potential and perform a repeat pregnancy test if there is any question of 
non-compliance with contraception. 
9.3.3.2.3 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist about the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the study laboratory manual. The Investigator is responsible 
for ensuring that all study samples that are to be transported to another location are appropriately 
packed and shipped according to the applicable regulations.  
9.3.3.2.4 Evaluation of Clinical Laboratory Values 
The normal ranges of values for clinical laboratory assessments in this study will be provided by 
the responsible laboratory and submitted to Axsome or its designee before the start of the study. 
These will be regarded as the reference ranges on which decisions will be made. 
If a clinical laboratory value is out of the reference range, it is not necessarily clinically relevant. 
The Investigator is responsible for determining whether these occurrences are considered as AEs. 
All clinical laboratory values that in the Investigator’s opinion show clinically relevant or 
pathological changes during or after termination of the treatment must be reported as AEs and 
followed as described in Section 10.2.5. 
All measurements described in this section are recognized standard methods. 
9.3.3.3 Clinical Examinations 
9.3.3.3.1 Vital Signs 
Vital signs will include seated blood pressure, pulse, respiratory rate, and oral temperature. Seated 
blood pressure and other vital signs will be measured after the subject has been in a sitting position 
for 5 minutes.  
9.3.3.3.2 Physical Examination 
A complete physical examination (excluding breast and genitourinary examination) will be 
performed at Screening by a licensed physician or clinician (NP, DO, PA) and at the final on-site 
visit (Visit 8/ET). Physical examination will include assessments of head, eyes, ears, nose, throat, 
lymph nodes, skin, extremities, respiratory, gastrointestinal, musculoskeletal, cardiovascular, and 
nervous systems. The physical examination should be performed by the same person each time, 
whenever possible. Physical examination abnormalities determined by the Investigator to be 
clinically significant at Screening should be recorded as medical history. The thoroughness of the 
Visit 8/ET physical examination is at the discretion and judgment of the Investigator, but should 
include a brief review of systems to ensure there have been no changes since Screening. 


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9.3.3.3.3 Other Safety Assessments 
9.3.3.3.3.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS [14] is a clinician-rated instrument that reports the severity of both suicidal ideation 
and behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific 
active suicidal thoughts), 3 (active suicidal ideation with any methods [not plan] without intent to 
act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active suicidal 
ideation with specific plan and intent). The C-SSRS also captures information about the intensity 
of ideation, specifically the frequency, duration, controllability, deterrents, and reasons for the 
most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 0 (no suicidal 
behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), and 4 
(actual attempt). More than 1 classification can be selected provided they represent separate 
episodes. For actual attempts only, the actual or potential lethality is classified for the initial, most 
lethal, and most recent attempts.  
The C-SSRS will be completed at Visits 1, 2, and 4 – 9. At Visit 1 (Screening) the C-SSRS will 
be completed for the subject’s lifetime history of suicidal ideation and behavior, along with a recent 
recall period. At all other visits the C-SSRS will be completed for ideation and behavior with a 
recall period since the last visit. 
The C-SSRS will be administered by the Investigator.   
10. ADVERSE EVENTS 
10.1 Definitions 
10.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the product. An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically important abnormal laboratory finding), symptom, or disease, temporally associated 
with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events that occur in subjects treated with active comparator or during treatment-free periods of the 
study are also considered AEs. 
Clinical AEs should be described by diagnosis and not by symptoms when possible (e.g., cold, 
seasonal allergies, instead of “runny nose”). 
Please note medical procedures scheduled prior to consenting, but occurring during the study 
should not be captured as AEs, but should be listed in the medical history if related to a pre-existing 
condition. 
10.1.2 Adverse Drug Reaction 
All noxious and unintended responses to a study drug related to any dose should be considered 
adverse drug reactions (ADRs). 


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The phrase “responses to a study drug” means that a causal relationship between a study drug and 
an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. All AEs judged 
by either the reporting Investigator or the Sponsor as having a reasonable causal relationship to a 
study drug qualify as ADRs. 
All AEs for which the judgment of relationship to the study drug is “possible” or higher will be 
considered ADRs. If a relationship to the study drug is not given, then the AE must be treated as 
if the relationship to the study drug were “possible.”  
10.1.3 Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is an event for which the nature or severity is consistent with the known 
AE profile of the product. For a study drug, the known information is contained in the IB and in 
the current package inserts for marketed drugs that contain the same active moiety. For a marketed 
product, the known information is contained in the current package insert for the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is an event for 
which the specificity or severity is not consistent with the current IB. For example, hepatic necrosis 
would be unexpected (greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. 
Likewise, cerebral thromboembolism and cerebral vasculitis would be unexpected (greater 
specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events. Examples would be a) acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
(interstitial nephritis would be unexpected) and b) hepatitis with a first occurrence of fulminant 
hepatitis (fulminant hepatitis would be unexpected.) 
10.1.4 Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death. 
 Is life-threatening. 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the study 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE. Further, an overnight stay in the hospital that is only due to 
transportation, organization, or accommodation problems and without medical 
background does not need to be considered an SAE. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly. 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the study 
drug during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject who 
has received a study drug is not considered an SAE unless it is suspected that the study 
drug(s) interacted with a contraceptive method and led to the pregnancy.  


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 Is an important medical event. 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. The occurrence of 
malignant tumors is also to be considered serious. 
10.1.5 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first 
administration of the study drug and not more than 30 days after the last study visit. 
10.2 Management of Adverse Events 
Adverse events will be collected from the time of signing the ICF through 30 days after the last 
study visit or Early Termination, whichever occurs first. Only Serious adverse events will be 
collected for subjects who screen fail. 
10.2.1 Collection of Adverse Events 
The Investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The Investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as: 
 “How are you feeling?” 
 “Have you experienced any issues since your last visit?” 
 “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
10.2.2 Evaluation of Adverse Events 
10.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 10.1.4. 


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10.2.2.2 Seriousness 
The Investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 10.1.4. 
10.2.2.3 Action(s) Taken 
Action(s) taken may consist of: 
Dose increased 
An indication that a medication schedule was modified by addition; either 
by changing the frequency, strength, or amount. 
Dose not changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength, or amount. 
Drug interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn 
An indication that a medication schedule was modified through termination 
of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
10.2.2.4 Outcome at the Time of Last Observation 
The outcome, including Fatal, at the time of last observation will be classified per CRF completion 
instructions.  Only select fatal as an outcome when the AE results in death. If more than 1 AE is 
possibly related to the subject’s death, the outcome of death should be indicated for each such AE. 
Although “fatal” is usually an event outcome, events such as sudden death or unexplained death 
should be reported as SAEs. 
10.2.2.5 Adverse Event Relationship to the Study Drug 
The Investigator will also assess the relationship (if any) between the AE and the study treatment 
(not related, unlikely, possibly, probably or definitely). 
The Investigator will use the following definitions to classify the relationship of an AE to study 
drug: 
Not related: 
AEs which, after careful consideration, are clearly and undeniably unrelated 
because of extraneous causes (e.g. disease, environment); 
Unlikely: 
This category can generally be considered applicable to those AEs which, after 
careful medical consideration at the time they are evaluated, are judged to be 
unrelated to the test drug. An AE may be considered unlikely to be related if or 
when at least two of the following criteria are fulfilled: 
1) The event does not follow a reasonable temporal sequence from administration 
of the test drug; 
2) The event could readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject; 
3) The event does not follow a known pattern of response to the test drug; 
4) The event does not reappear or worsen when the drug is re-administered. 


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Possibly:  
This category applies to those AEs for which, after careful medical consideration at 
the time they are evaluated, a connection with the test drug administration appears 
unlikely, but cannot be ruled out with certainty. An AE may be considered possibly 
related if or when at least two of the following criteria are fulfilled: 
1) The event follows a reasonable temporal sequence from administration of the 
drug; 
2) The event could not readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject; 
3) The event follows a known pattern of response to the test drug. 
Probably: 
This category applies to those AEs which, after careful medical consideration at the 
time they are evaluated, are felt with a high degree of certainty to be related to the 
test drug. An AE may be considered probably related if or when least three of the 
following criteria are fulfilled: 
1) The event follows a reasonable temporal sequence from administration of the 
drug; 
2) The event could not be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject; 
3) The event disappears or decreases on stopping or reducing the dose. There are 
important exceptions when an AE does not disappear upon discontinuation of 
the drug, but drug-relatedness clearly exists, e.g. bone marrow depression, fixed 
drug eruptions, tardive dyskinesia; 
4) The event follows a known pattern of response to the test drug. 
Definitely: 
This category applies to those AEs, which the Investigator feels are undeniably 
related to the test drug. An AE may be assigned an attribution of definitely related 
if or when all the following criteria are fulfilled: 
1) The event follows a reasonable temporal sequence from administration of the 
drug; 
2) The event could not be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject; 
3) The event disappears or decreases on stopping or reducing the dose and reappears 
with re-exposure to study drug (Note: this does not mean that the subject is to be 
re-exposed to study drug, however, a category of definitely related can only be 
used when recurrence is observed); 
4) The event follows a known pattern of response to the test drug. 
10.2.3 Documentation 
All AEs occurring within the period of observation for the study must be documented in the CRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 10.2.) 
 AE name or term. 
 When the AE first occurred (start date and time). 
 When the AE stopped (stop date and time or an indication of “ongoing”). 


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 Severity of the AE. 
 Seriousness (e.g., hospitalization or death). 
 Actions taken. 
 Outcome. 
 Investigator opinion regarding the AE relationship to the study drug(s). 
10.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated if necessary by established standards of 
care. If such treatment constitutes a deviation from the protocol, the subject may continue in the 
study at the discretion of Axsome after consultation with the Investigator and/or medical monitor. 
Any time a subject reports an AE that is considered to be serious, he or she should be encouraged 
to return to the site to be evaluated, which will include having blood and urine samples taken for 
drug concentrations. Recent dietary information will be collected. 
If AEs occur in a subject that are not tolerable, or for which continued administration of the study 
drug is not reasonable in view of the potential benefit to the subject, the Investigator must decide 
whether to stop the study and/or treat the subject. Special procedures may be recommended for the 
specific study drug, such as the collection of a blood sample for plasma concentrations of the study 
drug, specific tapering procedures, or treatment regimens, as appropriate. 
For double-blinded studies, it is not necessary to unblind a subject’s treatment assignment in most 
circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 8.6 for a 
description of the unblinding procedures. 
10.2.5 Follow-up of Adverse Events 
Any AE will be followed to a satisfactory resolution, until it becomes stable, or until it can be 
explained by another known cause(s) (i.e., concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted. All findings relevant to the final 
outcome of an AE must be reported in the subject’s medical record and recorded on the appropriate 
CRF. 
10.2.6 Notification 
10.2.6.1 Serious Adverse Events 
The Investigator or designee must report all SAEs promptly to 
 within 24 hours of first 
becoming aware of the event by completing the SAE Report Form and faxing or emailing it to 
number or email shown below. Axsome’s Medical Monitor may also be notified by telephone. 
Even if an initial report is made by telephone, the SAE Report Form must be completed with all 
available details and faxed within 24 hours of knowledge of the event at the study site. 
At the time of first notification, the Investigator or designee should provide the following 
information, if available: 
 Protocol number. 
 Reporter (study site and Investigator). 
 Subject’s study number and initials. 
 Subject’s date of birth. 
 Subject’s gender. 
 Date of first dose of study drug(s). 


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 Date of last dose of the study drug(s), if applicable. 
 Adverse event term. 
 Time and date of occurrence of the event. 
 A brief description of the event, outcome to date, and any actions taken. 
 The seriousness criteria (on) that were met. 
 Concomitant medication at onset of the event. 
 Relevant past history information. 
 Relevant laboratory test findings. 
 Investigator’s opinion of the relationship to the study drug(s).  
 Whether and when the Investigator was unblinded as to the subject’s treatment 
assignment. 
 
 
 
 
 
 
 
The Investigator must fax or e-mail a written SAE Report Form that describes the SAE to the 
recipient(s) of the initial information, who will forward the information to Axsome. The 
Investigator must also immediately deliver any available supporting information requested on the 
SAE Report Form or by Axsome. 
Any missing or additional relevant information concerning the SAE should be provided to the 
recipient(s) of the initial information in a written, follow-up SAE Report Form. Supplemental 
information should be submitted as soon as available and may include laboratory results, radiology 
reports, progress notes, hospital admission and emergency room notes, holding and observation 
notes, discharge summaries, autopsy reports, and death certificates. 
The Investigator is expected to take all therapeutic measures necessary for resolution of the SAE. 
Any medications or procedures necessary for treatment of the SAE must be recorded on the 
appropriate pages of the subject’s CRF. All SAEs are to be followed by the study staff until 
resolution or until the SAE is deemed stable. Axsome Therapeutics, Inc. may contact the study site 
to solicit additional information or follow up on the event. 
The Investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/Independent Ethics Committee (IEC), principal and coordinating Investigators, study 
Investigators, and institutions. The detailed reporting duties and division of responsibilities 
between Axsome and designated vendors will be provided in a separate document (see the Safety 
Management Plan). Each Investigator is obligated to learn about the reporting requirements for 
Investigators in his or her country. The study monitor may be able to assist with this. 


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10.2.6.2 Adverse Drug Reactions 
Axsome will report all ADRs related to the study drug to the proper health authorities; serious 
ADRs will be reported immediately and nonserious ADRs will be reported after completion of the 
study. Suspected serious adverse drug reactions must be reported to Axsome immediately, 
regardless of the time that has elapsed since the end of the period of observation. 
10.2.6.3 Nonserious Adverse Events 
Axsome will review nonserious AEs that are recorded in the CRFs on a regular basis. 
10.3 Special Considerations 
10.3.1 Adverse Events of Special Interest 
No AEs of special interests have been defined for this study. 
10.3.2 Pregnancy 
In the rare chance that a pregnancy occurs or is suspected, women should be instructed to contact 
the Investigator or study staff immediately. 
A woman who becomes pregnant during study drug treatment or within 30 days of discontinuing 
the study drug will be immediately discontinued from study participation. The Investigator must 
report the pregnancy as if it were an SAE within 24 hours of learning of the pregnancy. The 
Investigator should contact the designated individual(s) who receive SAE notification and record 
information related to the pregnancy on a Pregnancy and Lactation Exposure Form/other 
designated form provided by Axsome or its designee. 
Early termination visit assessments are required as soon as possible after learning of the pregnancy. 
The Investigator is also responsible for following the pregnancy until delivery or termination. 
Findings must be reported on the Pregnancy and Lactation Exposure Form/other designated form 
and forwarded to the designated individual(s). The event meets the SAE criterion only if it results 
in a spontaneous abortion or a congenital anomaly. If the pregnancy is associated with an SAE 
(e.g., if the mother is hospitalized for hemorrhage), a separate SAE Form must be filed with the 
appropriate serious criterion (e.g., hospitalization) indicated in addition to the aforementioned 
designated form. 
10.3.3 Overdose 
The dose of study drug specified in the protocol should not be exceeded during the study. 
Overdose that occurs during the study will be treated and documented as an AE/UAE/SAE if it 
fulfills the criteria. If the overdose does not result in an AE, it should be reported in written form 
to the designated individual(s) who receive SAE notification. The information contained therein 
should include study site identification, reporter identification, subject identification, study drug, 
dose, action taken (e.g., administration of antidote [if available] or supportive measures or 
therapy), and any comments. 
11. DATA SAFETY MONITORING BOARD 
No Data Safety Monitoring Board will be convened during the study.   
12. STATISTICS 
The final analysis plan will be documented in a formal statistical analysis plan (SAP) that must be 
finalized before database lock. The SAP will include details on how variables will be derived, how 
missing data will be handled, and how data will be presented as well as the details on statistical 


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methods to be used for safety and other analyses. The final clinical study report will discuss 
deviations from the SAP, if any. 
12.1.1 Safety Endpoints 
Safety endpoints include the following: 
 Adverse Events (AE)  
 Adverse Dropouts (ADOs) 
 Incidence of Treatment Emergent Adverse Events (TEAEs) 
 Clinical laboratory test results 
 Vital sign measurements 
 Physical examination findings 
 Columbia – Suicide Severity Rating Scale (C-SSRS) 
12.2 Sample Size Determination 
Approximately 60 subjects (30 per arm), who are compliant and who complete the 6-week 
treatment period, are planned for this study. The sample was determined based on prior reported 
experience with trials of a similar stage, in a similar patient population, with a similar objective. 
A sufficient number of subjects will be screened to achieve the planned number of subjects.   
12.3 Analysis Populations 
The following 3 analysis populations are planned for this study:  
 Modified Intent-to-Treat (mITT) Population—the mITT population and will include data 
from all subjects who receive at least 1 dose of study drug and provide at least 1 post-
Baseline 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.  
Membership in the analysis populations will be determined before unblinding. 
12.4 Statistical Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant. 
Furthermore, the baseline will be the last assessment before the first dosing of the study drug. 
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum. For categorical variables, these statistics will 
typically include the number and percentage of subjects in each category. 
12.4.1 Study Subjects and Demographics 
12.4.1.1 Disposition and Withdrawals 
The numbers of subjects screened, randomized, completing, discontinuing treatment, and 
withdrawing, along with reasons for discontinuation or withdrawal, will be tabulated overall and 
by treatment group. The number of subjects in each analysis population will be reported. 


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12.4.1.2 Protocol Deviations 
Major protocol deviations will be classified and documented by Axsome before database lock and 
will be discussed in the CSR.  All protocol deviations, both minors and majors, will be presented 
in a data listing. 
12.4.1.3 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, weight, and height) will be 
summarized for each treatment group and for the overall population by descriptive statistics. 
12.4.1.4 Medical History and Clinical Laboratory 
Medical history and clinical laboratory tests will be listed. Prior and concomitant medications will 
be summarized by treatment group, by the number and percentage of subjects taking each 
medication, classified using World Health Organization (WHO) Drug Dictionary Anatomical 
Therapeutic Chemical (ATC) classes and preferred terms. 
12.4.2 Exposure and Compliance 
Study drug administration will be summarized in terms of exposure and dose taken. Descriptive 
statistics for these quantities, including the mean, SD, minimum, and maximum, will be provided 
by treatment group. 
Overall study drug compliance based on tablet count will be defined as the actual dose taken 
divided by the intended dose times 100. 
12.4.3 Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 12.3).  
Safety and tolerability will be assessed through TEAEs; hematologic, biochemical, and urinalysis 
laboratory parameters; physical examination findings; and vital signs measurements.  
No formal statistical comparisons will be performed for safety endpoints. 
12.4.3.1 Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities reporting system. Treatment-emergent AEs are defined as any 
of the following: 
 Non-serious AEs with onset on the date of first dose of treatment with the study drug 
through follow up (7 days after the last dose of study drug);  
 Serious AEs with onset on the date of first dose of treatment with the study drug through 
30 days after the last dose of study drug; 
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. 
12.4.3.2 Clinical Laboratory Evaluations 
For continuous laboratory parameters, descriptive statistics will be presented for each visit and for 
the changes from Baseline to each subsequent visit by treatment group.  


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Additionally, clinical laboratory parameters will be categorized as low, normal, or high according 
to laboratory range specifications and the number and percentage of subjects in each category will 
be presented in shift tables. 
Laboratory values that are outside the normal range will also be flagged in the data listings, along 
with corresponding normal ranges. 
12.4.3.3 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for systolic blood pressure, diastolic blood pressure, 
pulse, respiratory rate, and oral temperature. 
12.4.3.4 Physical Examination Findings 
Physical examination data will be presented in the listings. 
12.4.3.5 Other Safety Parameters – C-SSRS 
The number and percentage of subjects with suicidal ideation or suicidal behavior based on the  
C-SSRS will be summarized by treatment group. The distribution of responses for most severe 
suicidal ideation and most severe suicidal behavior during the patient’s lifetime, during the double-
blind treatment period, and during the safety follow-up period will also be presented by treatment 
group for the Safety Population. Supportive listings will be provided and will include the subject 
number, study center number, lifetime history, and post-baseline values. Intensity of suicidal 
ideation, suicidal behavior type, and lethality of suicidal behavior will also be included in these 
listings. A listing of all AEs occurring in subjects who have suicidal ideation or suicidal behavior 
will also be provided. 
 
 
13. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified Investigators 
and appropriate study sites, review of protocol procedures with the Investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
13.1 Sponsor and Investigator Responsibilities 
13.1.1 Sponsor Responsibilities 
Axsome is obligated to conduct the study in accordance with strict ethical principles (Section 15). 
Axsome reserves the right to withdraw a subject from the study (Section 7.3), to terminate 
participation of a study site at any time (Section 13.6), and/or to discontinue the study 
(Section 13.5.2). 
Axsome agrees to provide the Investigator with sufficient material and support to permit the 
Investigator to conduct the study according to the study protocol. 
13.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.1), the Investigator indicates that he or she 
has carefully read the protocol, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol. 


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The Investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities (Section 15.1 and Appendix  B). While delegation 
of certain aspects of the study to Sub-Investigators and study coordinators is appropriate, the 
Investigator will remain personally accountable for closely overseeing the study and for ensuring 
compliance with the protocol and all applicable regulations and guidelines. The Investigator is 
responsible for maintaining a list of all persons that have been delegated study-related 
responsibilities (e.g., Sub-Investigators and study coordinators) and their specific study-related 
duties. 
Investigators should ensure that all persons who have been delegated study-related responsibilities 
are adequately qualified and informed about the protocol, study drugs, and their specific duties 
within the context of the study. Investigators are responsible for providing Axsome with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by Axsome and the relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person. The 
Investigator agrees, by written consent to this protocol, to cooperate fully with compliance checks 
by allowing access to all study documentation by authorized individuals. 
13.2 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from Axsome or its designee that the study can be initiated at the study site. The study site will not 
be authorized for study initiation until: 
 The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
 All regulatory/GCP documents have been submitted to and approved by Axsome or its 
designee. 
 The study site has a Clinical Trial Agreement in place. 
 Study site personnel, including the Investigator, have participated in a study initiation 
meeting/visit. 
13.3 Study Documents 
All documentation and material provided by Axsome for this study are to be retained in a secure 
location and treated as confidential material. 
13.3.1 Investigator’s Regulatory Documents 
The regulatory documents are listed as follows: 
 Signed original protocol; (i.e., Investigator’s Agreement). 
 Curricula vitae of all Investigators and Sub-Investigators. 
 Name and address of the laboratories. 
 List of laboratory reference ranges, and if available, a quality certificate. 
 Form Signature Log/Delegation of Study-related Duties. 
 Any other relevant GCP documents. 
The regulatory documents must be received from the Investigator and reviewed and approved by 
Axsome or its designee before the study site can initiate the study and before Axsome will 
authorize shipment of study drug to the study site. Copies of the Investigator’s regulatory 
documents must be retained at the study site in a secure location. Additional documents, including 


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a copy of the protocol and applicable amendment(s), the AXS-05 IB, CRF completion guidelines, 
copies of regulatory references, copies of IRB/IEC correspondence, and study product 
accountability records should also be retained as part of the Investigator’s regulatory documents. 
It is the Investigator’s responsibility to ensure that copies of all required regulatory documents are 
organized, current, and available for inspection. 
13.3.2 Case Report Forms 
By signing the Investigator’s Agreement (Section 17.1), the Investigator agrees to maintain 
accurate CRFs and source documentation as part of the case histories for all participating subjects. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. Axsome or its designee will provide the necessary training on the use of the specific 
CRFs used during the study to ensure that the study information is captured accurately and 
appropriately. 
To ensure data accuracy, CRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered on the CRFs according to the 
completion guidelines provided by Axsome or its designee. 
The Investigator will sign off each subject casebook. These signatures serve to attest that the 
information contained in the CRFs is accurate and true. 
13.3.3 Source Documents 
All information recorded in the CRFs must be supported by corresponding source documentation. 
Examples of acceptable source documentation include, but are not limited to, hospital records, 
clinic and office charts, laboratory notes, and recorded data from automated instruments, 
memoranda, and pharmacy dispensing records. 
During the study, select CRF data may be used as original data collection tools as long as a 
description of this documentation process is maintained in the Investigator’s study files. Before 
the study starts, a list identifying any data to be recorded directly on the CRFs (i.e., no prior written 
or electronic record of data) and considered to be source data will be provided. 
Clinical laboratory data required by the protocol will be electronically transferred from the central 
laboratory to Axsome or its designee as well as the Investigator. A copy of the laboratory results 
should be retained with each subject’s source data. 
13.4 Data Quality Control 
Axsome and its designees will perform quality control checks on this clinical study. 
13.4.1 Monitoring Procedures 
Axsome and/or its designee will conduct site visits to monitor the study and ensure compliance 
with the protocol, GCP, and applicable regulations and guidelines. The assigned clinical research 
associate(s) (CRA[s]) will visit the Investigator and study site at periodic intervals and maintain 
periodic communication. The Investigator agrees to allow the CRA(s) and other authorized 
Axsome personnel access. The CRA(s) will maintain current personal knowledge of the study 
through observation, review of study records and source documentation, and discussion of the 
conduct of the study with the Investigator and staff. While on site, the CRA(s) will review the 
following: 
 Regulatory documents, directly comparing entries in the CRFs with the source documents. 
 Consenting procedures. 
 AE procedures. 


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 Storage and accountability of the study drug and study materials. 
 Maintenance of study blind. 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting the CRFs are described in the CRF completion guidelines. As representatives of 
Axsome, CRAs are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.1), the Investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the Investigator 
agrees to allow Axsome or designee auditors or inspectors from regulatory agencies to review 
records and to assist the inspectors in their duties, if requested. 
13.4.2 Data Management 
Axsome or its designee will be responsible for activities associated with the data management of 
this study. The standard procedures for handling and processing records will be followed per GCP 
and Axsome or its vendors’ standard operating procedures.  
Study site personnel will be responsible for providing resolutions to all data queries. The 
Investigator will be required to document data review to ensure the accuracy of the corrected 
and/or clarified data. Procedures for soliciting and documenting resolution to data queries are 
described in the CRF completion guidelines. 
13.4.3 Quality Assurance/Audit 
This study will be subject to audit by Axsome or its designee. The audits will be undertaken to 
check compliance with GCP guidelines and will include a minimum of: 
 In-house study file audit. 
 Audit of computer database quality control. 
 Audit of clinical report quality control. 
Axsome or its designee may conduct additional audits on a selection of study sites, requiring access 
to subject notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The Investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the Investigator that it intends to conduct an inspection, the 
Investigator shall notify Axsome immediately. 
13.5 Study Termination 
The study may be terminated at Axsome’s discretion at any time and for any reason. 
13.5.1 Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
Axsome or its designee will notify the IRBs/IECs and regulatory authorities on the regular 
termination of the study as required according to national laws and regulations. 


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13.5.2 Premature Study Termination 
The study may be terminated prematurely for any reason and at any time by Axsome, IRBs/IECs, 
regulatory authorities, or respective steering committees. A decision to prematurely terminate the 
study is binding to all Investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Axsome or its designee will notify 
the IRB/IEC and regulatory authorities as appropriate on the premature termination as required 
according to national laws and regulations. Axsome or its designee must clearly explain the reasons 
for premature termination. 
If the study is terminated prematurely, all Investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the subjects’ 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Early Termination Visit. 
13.6 Study Site Closure 
A study site’s participation in the study may be terminated at any time by Axsome.  At the end of 
the study, all study sites will be closed.  This will include the Investigators final approval and lock 
of all subject data, return of unused study material and investigational product unless otherwise 
provided for in writing by Axsome, and final visits by study monitors. 
13.6.1 Record Retention 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should be 
separated into two categories: Investigator’s study file and subject clinical source documents. 
 The Investigator’s study file will contain the protocol and protocol amendments (if 
applicable), CRF guidelines, CRF query forms, IRB/IEC and governmental approval with 
correspondence, informed consent, drug records, staff curriculum vitae and authorization 
forms and other appropriate documents and correspondence. 
 Subject clinical source documents (which are usually defined by the project in advance to 
record key parameters independent of the CRF) may include subject and/or hospital clinical 
records, physician’s and nurse’s notes, appointment book, original laboratory reports, X-
ray, pathology and special assessment reports, consultant’s letters, screening and 
enrollment log, etc. 
The subject’s involvement in the study should be clearly documented in the study site’s clinical 
records. Details should include the study protocol number, the subject’s screening and 
randomization number, the subject’s consent to take part in the study (including the date of 
consent), the dates of all study visits, details of any treatments withdrawn because of study 
participation, the dates of dispensing study drug, details of any AEs (including any SAEs), and 
changes in concomitant medications. 
Study documents should not be destroyed without prior written agreement between the Sponsor 
and the Investigator. If the Investigator wishes to assign the study records to another party or move 
them to another location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement for any or all the documents at the 
investigational site, arrangements must be made between the Investigator and the Sponsor to store 
these in a sealed container(s) outside the site. The sealed container(s) can therefore be returned to 


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the Investigator in case of a regulatory audit. Where source documents are required for the 
continued care of the subject, appropriate copies should be made for storing outside the site. 
13.7 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Axsome. The protocol amendment must be signed by the 
Investigator and approved by the IRB or IEC before it may be implemented at a site. Protocol 
amendments will be filed with the appropriate regulatory agencies having jurisdiction over the 
conduct of the study. 
13.8 Use of Information and Publication 
All information concerning AXS-05, Axsome’s operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information supplied by Axsome 
or its designee to the Investigator and not previously published, is considered confidential and 
remains the sole property of Axsome. Case report forms also remain the property of Axsome. The 
Investigator agrees to use this information for purposes of study execution through finalization and 
will not use it for other purposes without the written consent of Axsome. 
The information developed in this study will be used by Axsome in connection with the continued 
development of AXS-05 and thus may be disclosed as required to other clinical Investigators or 
government regulatory agencies. 
The information generated by this study is the property of Axsome. Publication or other public 
presentation of AXS-05 data resulting from this study requires prior review and written approval 
of Axsome. Abstracts, manuscripts, and presentation materials should be provided to Axsome for 
review and approval at least 30 days before the relevant submission deadline. Data from individual 
study sites must not be published separately, unless otherwise agreed to in writing by the Sponsor. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the Investigator until Axsome has reviewed and commented on such 
a presentation or manuscript for publication. 
14. FINAL CLINICAL STUDY REPORT 
Axsome will retain ownership of the data generated from the study. 
The final clinical study report will be written within 1 year of completion of the clinical part of the 
study. This report will include a summary of the study results based on a statistical evaluation and 
clinical assessment of the protocol-defined endpoints. 


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15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1 Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry E6 
GCP (including archiving of essential study documents), the 1996 Version of the Declaration of 
Helsinki, and the applicable regulations of the countries in which the study is conducted. 
See Appendix B for regulations and guidelines. 
15.2 Subject Information and Informed Consent 
A properly constituted, valid IRB or IEC must review and approve the protocol, the Investigator’s 
informed consent document, and related subject information and recruitment materials before the 
start of the study. 
It is the responsibility of the Investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed consent before enrollment in a clinical study and before any protocol-specified 
procedures are performed. Informed consent will be obtained from each subject (if the subject is 
capable in the judgment of the Investigator to provide informed consent) or the subject’s 
authorized representative. For subjects that are not capable of providing informed consent, but are 
capable of providing assent, the subject will be asked to provide assent. If the subject is not capable 
of providing assent, the Investigator will document the reasons why and maintain that 
documentation with the other informed consent documents. The written ICF will embody the 
elements of informed consent as described in the Declaration of Helsinki and will also comply 
with local regulations.  
Each subject should be made aware by the Investigator of the nature of the study (i.e., objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the IRB/IEC. Subjects (and if necessary, legal representatives) must be 
given ample opportunity to inquire about details of the study. 
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject and to give them sufficient time 
to understand the information and to prepare questions before being asked for their consent. The 
Investigator must confirm that the text was understood by the subject or the subject’s authorized 
representative. Subjects capable of signing consent, or the subject’s authorized representative, will 
then sign and date the IRB/IEC-approved consent form indicating that they have given their 
consent to participate in the study. The signatures confirm the consents are based on information 
that has been understood. The forms will also be signed by the Investigator, or designee, obtaining 
the consents and annotated with the study subject number. Each subject’s signed ICFs must be 
kept on file by the Investigator for possible inspection by regulatory authorities, Axsome, and/or 
designated personnel. Collection of informed consent has to be documented on the CRF. 
Furthermore, the subject will be informed that if they wish to dropout or withdraw (see Section 7.3) 
at any time during the study, this will not have any negative consequences. Subjects may be 
withdrawn by the Investigator if any change related to safety or ethics precludes further 
participation in the study. Subjects will be asked to agree to a final assessment in the event of an 
early termination of the study. 


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Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their names and such data will not be revealed to any unauthorized third party. Data will be 
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate. 
15.3 Approval by Institutional Review Board and Independent Ethics Committee 
For investigational new drug studies, the minimum standards of conduct and requirements for 
informed consent are defined in the US FDA regulations. 
A valid IRB or IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be submitted by the Investigator to the Axsome monitor before 
shipment of investigational drug supplies, and will include the date of the committee’s approval 
and the chairperson’s signature.  
Until written approval by the IRB or IEC has been received by the Investigator, no subject may 
undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB or IEC. Axsome must 
receive their written approval before implementation.  
15.4 Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the Investigator 
and Axsome. 
 


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16. REFERENCES
[1] Substance Abuse and Mental Health Services Administration, "Key substance use and 
mental health indicators in the United States: Results from the 2016 National Survey on Drug 
Use and Health," Center for Behavioral Health Statistics and Quality, Substance Abuse and 
Mental Health Services Administration, September 2017. [Online]. Available: 
https://www.samhsa.gov/data/.
[2] A. J. Rush, M. H. Trivedi, S. R. Wisniewski, A. A. Nierenberg, J. W. Stewart, D. Warden, 
G. Niederehe, M. E. Thase, P. W. Lavori, B. D. Lebowitz, P. J. McGrath, J. F. Rosenbaum, 
H. A. Sackeim, D. J. Kupfer, J. Luther and M. Fava, "Acute and longer-term outcomes in 
depressed outpatients requiring one or several treatment steps: a STAR*D report," Am J 
Psychiatry, vol. 11, no. 163, pp. 1905-17, 2006 .
[3] GlaxoSmithKline, Wellbutrin SR [Package Insert], 2014.
[4] L. Nguyen, M. J. Robson, J. R. Healy, A. L. Scandinaro and R. R. Matsumoto, "Involvement 
of sigma-1 receptors in the antidepressant-like effects of dextromethorphan," PLoS One, vol. 
31, no. 4, pp. 1-9, 2014.
[5] L. E. Pope, M. H. Khalil, J. E. Berg, M. Stiles, G. J. Yakatan and E. M. Sellers, 
"Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with 
quinidine in extensive and poor metabolizers," J Clin Pharmacol, vol. 44, no. 10, pp. 
1132-1142, 2004.
 
 
 
 
 
 
 
 
 
[9] M. B. First, J. W. Williams, R. S. Karg and R. L. Spitzer, 10. MB, Williams JBW, Karg RS, 
Spitzer RL: Structured Clinical Interview for DSM-5 Disorders, Clinical Trials Version 
(SCID-5-CT)., Arlington: American Psychiatric Association, 2015.
[10] S. A. Montgomery and M. Asberg, "A New Depression Scale Designed to be Sensitive to 
Change," The British Journal of Psychiatry, vol. 134, pp. 382-389, 1979.
[11] A. J. Rush, M. H. Trivedi, H. M. Ibrahim, T. J. Carmody, B. Arnow, D. N. Klein, J. C. 
Markowitz, P. T. Ninan, S. Kornstein, R. Manber, M. E. Thase, J. H. Kocsis and M. B. Keller, 
"The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating 
(QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic 
major depression," Biological Psychiatry, vol. 54, no. 5, pp. 573-583, 2003.


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[12] W. Guy, ECDEU Assessment Manual for Psychopharmacology, Rockville: US Department 
of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental 
Health Administration, 1976.  
 
  
[14] K. Posner, G. K. Brown, B. Stanley, D. A. Brent, K. V. Yershova, M. A. Oquendo, G. W. 
Currier, G. A. Melvin, L. Greenhill, S. Shen and J. J. Mann, "The Columbia–Suicide Severity 
Rating Scale: Initial Validity and Internal Consistency Findings From Three Multisite 
Studies With Adolescents and Adults," The American Journal of Psychiatry, vol. 168, no. 
12, pp. 1266-1277, 2011.  
 
 
 


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17. ATTACHMENTS 
17.1 Investigator’s Agreement 
 
PROTOCOL NUMBER: 
 
AXS-05-MDD-201 
PROTOCOL TITLE: 
A Randomized, Double-Blind, Active-Controlled Trial of AXS-05 
Administered Orally to Subjects with Major Depressive Disorder 
PROTOCOL  
 
Version 2.0: 28Jun2018 
I have read this protocol and the Investigator’s Brochure and agree to conduct this clinical study 
as outlined herein. I will ensure that all sub-investigators and other study staff members have read 
and understand all aspects of this protocol. I agree to cooperate fully with Axsome and its 
designated vendors during the study. I carry out the study in accordance with the revised 
Declaration of Helsinki 1996. I will adhere to all FDA, ICH, and other applicable regulations and 
guidelines regarding clinical studies on a study drug during and after study completion. 
Having considered fully all the available information, I consider it is ethically justifiable to give 
the study drug to selected subjects in my care according to the study protocol. I: 
 Agree to use the study material, including the study drug, only as specified in the protocol and 
understand that changes cannot be made to the protocol without prior written approval from 
Axsome. 
 Understand that any violation of the protocol may lead to early termination of the study. 
 Agree to report to Axsome within time any clinical AE or abnormal laboratory value that is 
serious, whether or not considered related to administration of the study drug. 
 Agree to comply with Axsome and regulatory requirements for the monitoring and auditing of 
this study. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
 
Printed Name: 
 
 
 
Signature: 
  
 
Date: 
  
 
 
Investigator’s site name and address:  
 
 
 


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17.2 Schedule of Assessments 
 
Visit 
Screening 
Visit 1 
Baseline 
Visit 2 
Phone Call 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 / 
ET 
Visit 9 
Follow-upa 
Study Day 
-28 to -1 
0 
3 (+1) 
7 (±2) 
14 (±2) 
21 (±2) 
28 (±2) 
42 (±2) 
49 (±2) 
Week 
-4 to -1 
 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 6 
Week 7 
Informed Consent 
Xb 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical/Psychiatric History 
X 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
 
Vital Signs, Height/Weightc 
X 
X 
 
X 
X 
X 
X 
X 
 
Laboratory Testsd 
X 
 
 
 
 
 
 
X 
 
Urine Drug Screene 
X 
X 
 
 
 
 
 
X 
 
Serum Ethanole 
X 
 
 
 
 
 
 
X 
 
Urine Pregnancy Test (all 
female subjects) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MADRS 
X 
X 
 
X 
X 
X 
X 
X 
 
QIDS-SR-16 
X 
X 
 
X 
X 
X 
X 
X 
 
CGI-S (Severity) 
X 
X 
 
X 
X 
X 
X 
X 
 
CGI-I (Improvement) 
 
 
 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Instruct to begin BID dosing 
 
 
X 
 
 
 
 
 
 
Study Drug Dispensationh 
 
X 
 
X 
X 
X 
X 
 
 
Study Drug Accountability 
 
 
X 
X 
X 
X 
X 
X 
 
Prior and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations:  SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition, Clinical Trials Version; ET = early termination; EOS = End of Study; MADRS = Montgomery-Åsberg Depression Rating 
Scale; QIDS-SR-16 = Quick Inventory of Depressive Symptomatology-Self- Rated; CGI-I = Clinical Global Impressions–
Improvement; CGI-S = Clinical Global Impressions–Severity; C-SSRS = Columbia - Suicide Severity Rating Scale; 
 
 
 
a 
Safety follow-up visit to be performed telephonically. 
b 
Informed consent must be signed prior to any study procedures being performed. 
c 
Vital signs, including blood pressure, heart rate, respiratory rate, and oral body temperature, will be measured after the subject has 
been in a seated position for at least 5 minutes.  Height will be measured at Visit 1 and weight at Visit 1 and Visit 8 (EOS or ET). 
d 
Clinical laboratory tests will include hematology, serum chemistry, urinalysis and thyroid panel. 
e 
May be performed at other study visits per investigator judgment. Subjects with positive urine drug screen or serum ethanol levels at 
Visit 1 may be allowed in study depending on circumstances described to the Medical Monitor and a negative repeat UDS is obtained 
before Visit 2.  
f 
 
 
 
 
 
 
h 
Subjects will begin to take study drug the morning of Day 1 (morning after Visit 2). 


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APPENDICES 
 
B. Regulations and Good Clinical Practice Guidelines 
C. Structured Clinical Interview for DSM-5, Clinical Trials (SCID-5-CT) 
D. Montgomery and Åsberg Depression Rating Scale (MADRS) 
E. Quick Inventory of Depressive Symptomology – Self-Rated (QIDS-SR-16) 
F. Clinical Global Impression of Severity of Illness (CGI-S) 
G. Clinical Global Impression of Improvement of Illness (CGI-I) 
H. Columbia – Suicide Severity Rating Scale (C-SSRS) – Lifetime 
I. Columbia – Suicide Severity Rating Scale (C-SSRS) – Since Last Visit  
 
 
 
*Samples of these scales are provided to give the Investigators and IRB(s) an understanding of 
the content of each of the scales. The final versions used in the clinical trial are subject to 
changes in layout and formatting as appropriate for each of the validated versions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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B. Regulations and Good Clinical Practice Guidelines 
1. 
Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
 FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
 FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
 FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
2. 
Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/LOB/media/MEDIA482.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Document Type: Statistical Analysis Plan  
Protocol Title: A Randomized, Double-Blind, Active-Controlled Trial of AXS-05 Administered Orally 
to Subjects with Major Depressive Disorder 
ClinicalTrials.gov Identifier:  NCT03595579 
Document Date: December 11, 2018 
 
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 
Version 1.0—11 December 2018 
AXS-05-MDD-201 SAP 
Page 2 of 16 
 
SPONSOR APPROVAL 
 
The undersigned have reviewed the format and content of this prospective statistical analysis plan (SAP) 
and have approved it for use to analyze the AXS-05-MDD-201 data. 
 
 
AXSOME Therapeutics, Inc.  


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Page 3 of 16 
 
TABLE OF CONTENTS 
1.0 
DOCUMENT HISTORY ............................................................................................................................. 5 
2.0 
LIST OF ABBREVIATIONS ...................................................................................................................... 5 
3.0 
INTRODUCTION ........................................................................................................................................ 6 
4.0 
STUDY DESCRIPTION ............................................................................................................................. 6 
4.1 
Study Objectives ........................................................................................................................ 6 
4.2 
Study Treatments ...................................................................................................................... 6 
4.3 
Study Design ............................................................................................................................... 7 
4.4 
Randomization and Blinding ................................................................................................ 8 
5.0 
ANALYSIS POPULATIONS ...................................................................................................................... 8 
5.1 
Randomized Population ......................................................................................................... 8 
5.2 
Safety Population ...................................................................................................................... 8 
5.3 
Modified Intent-to-Treat Population ................................................................................. 8 
5.4 
Per Protocol Population ......................................................................................................... 8 
6.0 
GENERAL CONVENTIONS ...................................................................................................................... 9 
6.1 
Definition of Baseline .............................................................................................................. 9 
6.2 
Software ....................................................................................................................................... 9 
6.3 
Changes to Planned Analyses ............................................................................................... 9 
7.0 
DESCRIPTION OF THE STUDY POPULATIONS ............................................................................... 9 
7.1 
Disposition .................................................................................................................................. 9 
7.2 
Demographic and Baseline Characteristics .................................................................. 10 
7.3 
Medical History ....................................................................................................................... 10 
8.0 
PRIOR AND CONCOMITANT MEDICATIONS................................................................................. 10 
9.0 
EFFICACY ANALYSES ............................................................................................................................ 11 
9.1 
Primary Efficacy Variable: Change from Baseline in MADRS ................................. 11 
9.1.1 
Derivation of Primary Efficacy Variable ....................................................................... 11 
9.1.2 
Primary Analysis .................................................................................................................... 11 
9.1.3 
Handling of Missing Values ................................................................................................ 11 
9.2 
Secondary Efficacy Outcomes ............................................................................................ 11 
9.3 
Interim Analyses .................................................................................................................... 13 
9.4 
Adjustments for Multiplicity .............................................................................................. 13 
9.5 
Power and Sample Size Justification ............................................................................... 13 
10.0 
SUMMARIES OF MEASURES OF SAFETY ........................................................................................ 13 
10.1 
Extent of Exposure ................................................................................................................. 13 
10.2 
Adverse Events ........................................................................................................................ 13 
10.3 
Laboratory Assessments ..................................................................................................... 14 
10.4 
Vital Signs ................................................................................................................................. 14 


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10.5 
Physical Exam .......................................................................................................................... 15 
11.0 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS ........................................... 15 
12.0 
DATA QUALITY ASSURANCE ............................................................................................................. 15 
13.0 
REFERENCES ........................................................................................................................................... 15 
14.0 
APPENDICES ........................................................................................................................................... 16 
14.1 
Appendix A - Imputation Algorithm for Partial and Missing Dates ..................... 16 
 




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3.0 
INTRODUCTION 
This statistical analysis plan (SAP) is based on Protocol AXS-05-MDD-201, Amendment Final Version 
. 
The purpose of this document is to provide details on study populations and on how the variables will be 
derived, how missing data will be handled, as well as details on statistical methodologies to be used to 
analyze the safety and efficacy data from the study.   
 
The document may evolve over time, for example, to reflect the requirements of protocol amendments or 
regulatory requests.  However, the final SAP must be finalized, approved by the Sponsor, and placed on 
file before database is locked and treatment codes are unblinded.  The approved plan will be used to carry 
out all analyses for the clinical study report.  Deviations, if any, from the approved plan will be noted in 
the clinical study report. 
 
4.0 
STUDY DESCRIPTION 
4.1 
STUDY OBJECTIVES 
 
The primary objective of the study is to assess the effect of AXS-05 versus bupropion as measured 
by MADRS (Montgomery-Åsberg Depression Rating Scale). 
 
The secondary objectives of the study include assessment of the effect of AXS-05 versus bupropion 
on: 
• 
QIDS-SR-16 (Quick Inventory of Depressive Symptomatology-Self- Rated);  
• 
CGI-I (Clinical Global Impressions–Improvement);  
• 
CGI-S (Clinical Global Impressions–Severity);  
• 
 
• 
C-SSRS (Columbia - Suicide Severity Rating Scale); and 
• 
Safety as assessed by AEs, vital signs, and laboratory assessments. 
4.2 
STUDY TREATMENTS  
 
In this double blind study, subjects will be randomized, in a 1:1 ratio, to one of the following two 
treatment groups: 
Treatment Group 
Description 
1. AXS-05 
105 mg bupropion, 45 mg 
dextromethorphan tablet, oral 
2. Bupropion 
Bupropion SR 105 mg matching 
tablet, oral 
 


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4.3 
STUDY DESIGN 
 
This study is a randomized, double-blind, active-controlled, Phase 2 trial, consisting of a screening period 
of up to 4 weeks, and a 6-week treatment period. 
 
Screening Period 
Prior to randomization, all subjects will enter an up to four-week screening period (Screening) to 
determine eligibility. Eligible subjects must meet the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria for MDD without psychotic features, based on the Structured 
Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Clinical 
Trials Version (SCID-5-CT), with a current major depressive episode of at least 4 weeks in duration. 
Eligible subjects must meet all other inclusion and no exclusion criteria. 
 
Treatment Period 
Randomization 
Subjects who successfully complete Screening will be randomly assigned at the baseline visit (Baseline) 
to receive either AXS-05 or bupropion sustained release (SR) in a 1:1 ratio for 6 weeks.  The 
randomization schedule will be computer-generated using a permuted block algorithm that will randomly 
allocate the study drug to randomization numbers. 
 
The study will evaluate only subjects whose diagnosis of MDD with a current major depressive episode 
of moderate or greater severity is confirmed by an independent assessor based on clinical review 
  
. However, to maintain the blinding of the study 
investigators, all subjects will be randomized to receive study medication and be included in the safety 
analysis. 
 
Treatments 
Doses will be titrated as follows: 
• 
Days 1 - 3 
o AXS-05 group: 105 mg bupropion, 45 mg dextromethorphan QD 
o Bupropion group: 105 mg bupropion QD 
• 
Days 4 - 42 
o AXS-05 group: 105 mg bupropion, 45 mg dextromethorphan BID 
o Bupropion group: 105 mg bupropion BID 
 
All QD doses will be taken in the morning, orally on an empty stomach (at least 2 hours pre- or 2 hours 
post-prandial) with water. All BID doses will be taken at least 8 hours apart, orally on an empty stomach 
(at least 2 hours pre- or 2 hours post-prandial) with water. All study drug is of identical appearance and 
similar weight in order to maintain the integrity of the blind. 
 
Assessments and Visits 
Study visits will occur at Screening (Visit 1), Baseline (Day 0, Visit 2), and on Days 3, 7, 14, 21, 28, 42 
and 49 (Visits 3 – 9). Study procedures and assessments will be performed during study visits as outlined 
in the Schedule of Assessments. Visit 3 (Day 3) will be conducted telephonically. Subjects will be 
reminded during Visit 3 to begin BID dosing on Day 4. All subjects completing 6 weeks of treatment or 
subjects prematurely discontinuing from the study will be required to complete a follow-up visit one week 
after the last dose of study drug, Visit 9, telephonically.  Assessments will include safety parameters, 




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deviations will be presented in the clinical study report.  Efficacy analyses may also be performed based 
on the per protocol population.   
 
6.0 
GENERAL CONVENTIONS 
Unless otherwise stated, all analyses will be performed using 
 and all hypothesis tests will 
be conducted at a two-sided significance level of 0.05.  P-values will be presented with 3 decimals and p-
values that are less than 0.001 will be presented as <0.001. 
 
Continuous data will be summarized using descriptive statistics: number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum.  Frequencies and percentages will be used to 
summarize categorical (discrete) data.  Presentations of categorical data will generally suppress 
percentages for items where the count is zero in order to draw attention to the nonzero counts.  In general, 
mean, standard deviation, median, minimum, maximum, and percentages will be presented with one 
decimal. 
 
Unless otherwise stated, confidence intervals, when presented, will be constructed at the two-sided 95% 
level.  For binomial variables, the 95% confidence intervals will be constructed using the normal 
approximation without continuity correction. 
 
Data listings will present all data collected on CRFs by study drug, center, and subject number.  Unless 
otherwise stated, data will be presented by treatment and subject within treatment. 
6.1 
DEFINITION OF BASELINE 
 
Unless otherwise stated, the last observed measurement on the date of randomization will be considered 
the baseline measurement.  If multiple observations are made during baseline, the baseline will be defined 
as average of the observations obtained during the baseline phase. 
6.2 
SOFTWARE 
 
Most analyses will be conducted using 
.   
6.3 
CHANGES TO PLANNED ANALYSES 
 
Draft versions of the SAP will be numbered sequentially as Version 0.0i.  The final approved version will 
be numbered as Version 1.00.  Revisions after the “Final” version will be numbered as Version 1.0x.  The 
Clinical Study Report will document any changes made after the final version approved before 
unblinding. 
 
7.0 
DESCRIPTION OF THE STUDY POPULATIONS 
All tables, figures, and listings must include a population descriptor (e.g., mITT, safety or Per Protocol) in 
the title. 
7.1 
DISPOSITION 
 


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Subject disposition summaries will be presented by treatment arm and will include the number of subjects 
randomized, the number and percentage of randomized subjects in the safety, mITT, and Per Protocol (if 
applicable) populations, as well as the number and percentage of subjects who complete the study.  The 
summaries will also include the reasons for early discontinuation from the study.   
 
Disposition summaries will be presented for safety, Intent-to-Treat, and Per Protocol populations (if 
applicable) separately. 
7.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
 
A summary of demographics and baseline characteristics will be presented by treatment arm and overall 
for the mITT and safety populations.  The demographic characteristics will consist of age, sex, ethnicity, 
and race using descriptive statistics. 
 
Demographic data including age, race, ethnicity, region, and gender, as well as baseline clinical 
characteristics will be summarized. Age will be calculated based on the following conditional algorithm:  
• 
Has the patient had his/her birthday this year? 
o Yes, then AGE = (year of informed consent) – (year of birth). 
o No, then AGE = (year of informed consent) – (year of birth) – 1. 
 
7.3 
MEDICAL HISTORY 
 
A medical history listing will be presented.   
 
8.0 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications recorded on the CRFs will be coded using the WHO DRUG Dictionary Enhanced March 
2014.  Prior and concomitant medications will be summarized by treatment arm in the safety population 
by anatomical therapeutic chemical (ATC) Class Level 4 and WHO Drug base substance preferred name. 
 
Prior medications are defined as medications with stop dates occurring before the date of first 
administration of any study treatment component.  Concomitant medications are defined as medications 
with start dates occurring on or after the date of first administration of any study treatment component and 
no more than 30 days after the last administration of any study treatment component. Medications with 
start and stop dates that bracket the date of first administration of any study treatment component will be 
summarized as both prior and concomitant medications. 
 
Medications that clearly stopped prior to date of first administration of any study treatment component 
will be included in the prior medications table, and medications that clearly started on or after date of first 
administration of any study treatment component will be included in the concomitant medications table.  
All other medications will be included in both the prior and concomitant medications tables. 
 
Prior and Concomitant medications will be summarized for the safety population. 
 




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4. 
 
5. Percentage of responders on MADRS (response defined as ≥ 50% reduction from baseline) 
6. Percentage of responders on MADRS (response defined as ≥ 30% reduction from baseline) 
7. Percentage achieving remission on MADRS (remission defined as MADRS ≤ 10) 
8. Percentage achieving remission on MADRS (remission defined as MADRS ≤ 12) 
9. Overall treatment effects on change from baseline in MADRS (weeks 1-2, weeks 1-3, weeks 1-4, 
weeks 4-6) 
10. Change from baseline on item 1 (apparent sadness) of MADRS 
11. Change from baseline in MADRS-6 (MADRS 6-item subscale) 
12. Overall treatment effects on change from baseline in MADRS-6 (weeks 1-2, weeks 1-3, weeks 1-
4, weeks 4-6) 
13. Percentage of responders on MADRS-6 (response defined as ≥ 50% reduction from baseline) 
14. Percentage of responders on MADRS-6 (response defined as ≥ 30% reduction from baseline) 
15. Overall treatment effects on change from baseline in QIDS-SR-16 (weeks 1-2, weeks 1-3, 
weeks 1-4, weeks 4-6) 
16. Percentage of responders on QIDS-SR-16 (response defined as ≥ 50% reduction from baseline) 
17. Percentage of responders on QIDS-SR-16 (response defined as ≥ 30% reduction from baseline) 
18. Percentage achieving remission on QIDS-SR-16 (remission defined as QIDS-SR-16 ≤ 6) 
19. Percentage achieving remission on QIDS-SR-16 (remission defined as QIDS-SR-16 ≤ 5) 
20. Overall treatment effects on change from baseline in 
 (week 1, weeks 1-2, weeks 1-3, 
weeks 1-4, weeks 4-6) 
21. Percentage of responders on 
 (response defined as ≥ 50% reduction from baseline) 
22. Percentage of responders on 
 (response defined as ≥ 30% reduction from baseline) 
23. Time to clinically meaningful improvement on MADRS (reduction from baseline of ≥ 2); QIDS-
SR-16 (reduction from baseline of ≥ 10%, ≥ 20%); 
 
MADRS-6 (reduction from baseline of ≥ 10%, ≥ 20%) 
24. Time to clinical improvement based on the CGI-I (score of 3 [minimally improved] or less) 
25. Treatment effects in patients with severe depression based on MADRS (defined as MADRS ≥ 30, 
≥ 35); severe or very severe depression based on QIDS-SR-16 (defined as QIDS-SR-16 ≥ 16) 
26. Treatment effects based on MADRS in patients who had ≥1 prior antidepressant treatments 
during the current major depressive episode 
27. 
 
28. 
 
 
Efficacy variables related to change from baseline will be analyzed via the methods outlined in the 
analysis for the primary efficacy variable. 
 




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with an onset date prior to date of the final visit + 30 days will be tabulated in summary tables.  However, 
all AEs recorded will be listed.  For the purpose calculating treatment emergence and inclusion in 
summary tables, incomplete onset dates will be imputed as detailed in Appendix A.   
 
AEs will be summarized by the number and percent of subjects in each primary SOC and preferred term.  
Patients will be counted only once for each primary SOC and each preferred term. Summary tables of 
AEs by primary SOC, preferred term and severity will be provided. If a subject has more than one AE 
coded to the same preferred term, the subject will be counted only once for that preferred term by using 
the event with the highest severity. Similarly, if a subject has more than one AE within a primary SOC 
category, the subject will be counted only once in that SOC category by using the event with the highest 
severity. AEs by primary SOC, preferred term and relationship to study drug will be provided as well. If a 
subject has more than one AE coded to the same preferred term, the subject will be counted only once for 
that preferred term by using the most related event. Similarly, if a subject has more than one AE within a 
primary SOC category, the subject will be counted only once in that primary SOC category by using the 
most related event. In addition, serious adverse events (SAE) by primary SOC and preferred term will be 
provided. Deaths and SAEs will be summarized similarly to AEs. All adverse event tables will also 
include the total number of events, counting multiple events per patient. 
 
In the AE summary, preferred terms within each SOC will appear in alphabetical order as well as in 
decreasing order of total incidence.   
 
Frequencies for deaths and hospitalizations will also be summarized by treatment group and overall. 
 
Other safety analyses will be performed as appropriate 
10.3 LABORATORY ASSESSMENTS 
 
Chemistry and Hematology, Urinalysis and Coagulation Profile will be assessed at Screening and Week 
6.  Summary statistics for these parameters will be presented by visit for the actual value and change from 
baseline for each test in each laboratory category (Hematology, Chemistry, Urinalysis, and Coagulation 
Profile). Shift tables will be presented for shifts from baseline lab categories to end of study laboratory 
category.  The three laboratory categories will be:  L (below lower bound of normal range), N (within 
normal range), and H (above higher bound of normal range).    
If a lab value is reported using a non-numeric qualifier (e.g., less than (<) a certain value, or greater than 
(>) a certain value), the given numeric value will be used in the summary statistics, ignoring the non-
numeric qualifier. 
If a subject has repeated laboratory values for a given time point, the value from the first evaluation at that 
time point will be used for summarization purposes. For the purpose of determining baseline, the last 
nonmissing observation on or prior to randomization will be used.  The Week 6 values will be the last 
post-baseline value on or prior to Week 6. 
10.4 VITAL SIGNS 
 
Vital signs will consist of blood pressure (systolic and diastolic blood pressure, mmHg), pulse rate (beats 
per minute), and respiratory rate (breaths/min), collected while sitting, following a rest period of at least 3 


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minutes.  Vital sign values and change from baseline in the vital signs will be summarized for each 
treatment group. 
10.5 PHYSICAL EXAM 
 
Number and percent of subjects with abnormal physical exam findings at Screening will be summarized 
by body system for each treatment group and overall. Physical Exam data for each subject will also be 
presented in a listing. 
 
11.0 IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS 
Major protocol deviations from entry criteria and treatment compliance will be summarized as far as they 
can be extracted from numeric or coded study data. 
 
12.0 DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be ensured by verification and cross check of the CRFs against 
the investigator’s records by the study monitor (source document verification) and by the maintenance of 
a drug–dispensing log by the investigator.  Collected data will be entered into a computer database and 
subject to electronic and manual quality assurance procedures. 
 
13.0 REFERENCES 


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14.0 APPENDICES 
14.1 APPENDIX A - IMPUTATION ALGORITHM FOR PARTIAL AND MISSING 
DATES  
 
This section describes missing date imputation methods. 
 
For Adverse Events 
 
If onset date is completely missing, onset date is set to date of randomization. 
 
If (year is present and month and day are missing) or (year and day are present and month is missing): 
• 
If year = year of randomization, then set month and day to month and day of randomization 
• 
If year < year of randomization, then set month and day to December 31. 
• 
If year > year of randomization, then set month and day to January 1. 
 
If month and year are present and day is missing: 
• 
If year=year of randomization and  
• 
If month = month of randomization then set day to day of first dose 
• 
If month < month of first dose then set day to last day of month 
• 
If month > month of first dose then set day to first day of month 
• 
If year < year of randomization then set day to last day of month 
• 
If year > year of randomization then set day to first day of month 
 
For all other cases, set onset date to date of randomization. 
 
For Concomitant Medications 
 
Start Date:  If start date is completely missing and end date is not prior to randomization, then the 
medication will be classified as concomitant. If start date is completely missing and end date is prior to 
randomization, then the medication will be classified as prior. 
 
If (year is present and month and day are missing) or (year and day are present and month is missing) then 
set month and day to January 1.  If year and month are present and day is missing then set day to first day 
of month. 
 
End Date:  If end date is completely missing then the medication will be classified as concomitant. 
If (year is present and month and day are missing) or (year and day are present and month is missing) then 
set month and day to December 31.  If year and month are present and day is missing then set day to last 
day of the month. 
 
Note: that if both start and end dates are missing then the medication will be classified as concomitant.