Clinical trial NCT04039022
Conditions: Major Depressive Disorder Treatment Resistant Depression Depression
Keywords: Depression AXS-05 Dextromethorphan Bupropion Dopamine Reuptake Inhibitor NMDA Receptor Antagonist Nicotinic Acetylcholine Receptor Antagonist Serotonin Reuptake Inhibitor Axsome Therapeutics Norepinephrine Reuptake Inhibitor Sigma-1 Receptor Agonist Glutamate Modulator Antidepressant
Sponsor: Axsome Therapeutics, Inc.
Start date: 2019-07-08; Completion date: 2020-10-23
Enrollment: 876 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
An open-label, long-term, safety study of AXS-05 in patients with major depressive disorder (MDD), including treatment resistant depression.

Detailed description:
A multi-center, open-label, long-term study to evaluate the safety and efficacy of AXS-05 in patients with major depressive disorder, including treatment resistant depression, treated for up to one year.

Arms: arm 1: None
Interventions: intervention 1: AXS-05 (dextromethorphan and bupropion) oral tablets
Intervention descriptions: intervention 1: Oral tablets, taken twice daily for up to 12 months.

Protocol documents:
Prot_SAP_000.pdf: 
Document Type: Protocol 
Protocol Title: An Open-Label Study to Assess the Long-term Safety and Efficacy of AXS-05 in 
Subjects with Major Depressive Disorder
ClinicalTrials.gov Identifier:  NCT04039022
Document Date: July 9, 2020
Certain information within this protocol has been redacted to protect either personally identifiable 
information (PII) or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
•
Named persons or organizations associated with the study.
•
Proprietary information, such as scales or coding systems, which are considered confidential
information.
•
Other information as needed to protect the confidentiality of Axsome Therapeutics, personal
information, or to otherwise protect the integrity of the clinical study.


Axsome Therapeutics, Inc. 
Confidential 
 
AXS-05-303 
Version Date (Amendment 3): July 9, 2020 
Page 1 
 
 
PROTOCOL 
 
COMPOUND NAME/NUMBER: 
 
AXS-05 
PROTOCOL NUMBER: 
 
AXS-05-303 
 
 
 
DEVELOPMENT PHASE: 
 
Phase 3 
PROTOCOL TITLE: 
An Open-Label Study to Assess the Long-term Safety and 
Efficacy of AXS-05 in Subjects with Major Depressive 
Disorder  
 
PROTOCOL VERSION: 
 
Amendment 3 
PROTOCOL DATE: 
 
July 9, 2020 
 
 
 
 
 
 
This study will be performed in compliance with Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of Axsome Therapeutics, Inc. 
 
 








Axsome Therapeutics, Inc. 
Confidential 
 
AXS-05-303 
Version Date (Amendment 3): July 9, 2020 
Page 5 
 
5. If female and of childbearing potential, has a negative urine pregnancy test result at Visit 1, is 
practicing at least two adequate methods of birth control (i.e., oral or parenteral contraceptives, 
intrauterine device, condoms, spermicides), and is not currently pregnant or breastfeeding nor 
plans to become pregnant during the course of the study.  
a. 
Long-term abstinence is acceptable when it is in line with the subjects preferred and usual 
lifestyle.  
b. 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.  
c. 
Female subjects may be enrolled without a negative urine pregnancy test if they are 
surgically sterile or at least 2 years post-menopausal.  
d. Male subjects and their female sexual partners should use an acceptable method of birth 
control (as noted above) during the study.  
 
Exclusion Criteria: 
A subject will be excluded from the study if the subject meets any of the following criteria: 
1. 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). 
2. Is considered by the investigator, for any reason (including, but not limited to, the risks 
described as precautions, warnings, and contraindications in the current version of the 
investigator’s brochure for AXS-05 tablets), to be an unsuitable candidate to receive AXS-05. 
3. If the subject is currently receiving or plans to use drugs with known bupropion interactions 
(as listed in the Wellbutrin SR package insert), PI is aware of any potential drug interaction 
and has deemed the subject acceptable to participate. 
4. 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.  
5. History of allergy or hypersensitivity to bupropion, dextromethorphan, opiate drugs (e.g. 
codeine, etc.), or any other ingredient in the study medication. 
6. History of intolerance to bupropion or dextromethorphan. 
7. 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. 
8. Previously received treatment with any investigational drug (other than AXS-05) or device 
within 30 days of Visit 1. 
Test Product, Dosage, 
and Mode of 
Administration 
AXS-05 (105 mg bupropion, 45 mg dextromethorphan) tablet, oral 


Axsome Therapeutics, Inc. 
Confidential 
 
AXS-05-303 
Version Date (Amendment 3): July 9, 2020 
Page 6 
 
Treatment Regimen 
Doses will be titrated as follows: 
• 
Days 1 – 3: AXS-05 (105 mg bupropion, 45 mg DM) tablet, once daily, in the morning  
• 
Days 4 – end of study (maximum of 12 months): AXS-05 tablet, twice daily  
All doses should be taken orally on an empty stomach (at least 2 hours pre- or 2 hours post-
prandial) with water. Twice daily doses should 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 
The duration of participation will be up to 12 months. 
Criteria for 
Evaluation 
Primary Safety Measures: 
• 
Incidence of treatment-emergent AEs (TEAEs) following dosing with AXS-05. 
Additional Safety Measures: 
• 
Change in vital signs (blood pressure and heart rate) over time 
• 
Change in ECG findings over time 
• 
Change in clinical laboratory measures over time 
• 
Incidence of suicidal behavior, as identified via the C-SSRS 
Efficacy Measures: 
• 
Change in MADRS over time  
• 
Change in SDS over time 
• 
Change in Q-LES-Q-SF over time 
• 
CGI-S 
• 
CGI-I 
Statistical Methods 
Analysis Populations:  
The following analysis populations are planned for this study: 
 Safety Population—the Safety Population will include all subjects who receive at least 1 dose 
of the study medication. 
 Intent-to-Treat (ITT) Population—the ITT Population will include all subjects who receive at 
least 1 dose of the study medication and report at least one efficacy measurement. 
Descriptive statistics will be used for all variables and all data over time. 
Sample Size 
Determination 
This study will enroll approximately 1100 subjects, with 300 subjects treated for at least 6 months 
and 100 for 12 months.  The study will be considered completed once 300 subjects are treated for 
at least 6 months and 100 for 12 months. This sample size will provide an adequate number of 
subjects exposed to assess the long-term safety of AXS-05.