A Multi-center, Randomized, Double-blind, Placebo-controlled, 3-Week Crossover Study to Assess the Efficacy and Safety of AXS-12 in Subjects With Cataplexy and Excessive Daytime Sleepiness in Narcolepsy
Phase: PHASE2
Conditions: Narcolepsy, Cataplexy Narcolepsy, Excessive Sleepiness
Sponsor: Axsome Therapeutics, Inc.

Document Type: Protocol 
Protocol Title: A Multi-center, Randomized, Double-blind, Placebo-controlled, 3-Week Crossover 
Study to Assess the Efficacy and Safety of AXS-12 in Subjects with Cataplexy and Excessive 
Daytime Sleepiness in Narcolepsy
ClinicalTrials.gov Identifier:  NCT03881852
Document Date: April 25, 2019 
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-12-201 
Version: Amendment 2 (25 Apr 2019) 
Page 1 
 
PROTOCOL 
COMPOUND NAME/NUMBER: AXS-12 
PROTOCOL NUMBER: 
AXS-12-201 
DEVELOPMENT PHASE: 
Phase 2 
PROTOCOL TITLE: 
A 
Multi-center, 
Randomized, 
Double-blind, 
Placebo-
controlled, 3-Week Crossover Study to Assess the Efficacy and 
Safety of AXS-12 in Subjects with Cataplexy and Excessive 
Daytime Sleepiness in Narcolepsy 
PROTOCOL VERSION: 
Amendment 2 
PROTOCOL DATE: 
25 Apr 2019 
 
 
 
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-12-201 
Version: Amendment 2 (25 Apr 2019) 
Page 2 
 
 
APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
AXS-12-201 
PROTOCOL TITLE: 
A Multi-center, Randomized, Double-blind, Placebo-controlled, 3-
Week Crossover Study to Assess the Efficacy and Safety of AXS-12 
in Subjects with Cataplexy and Excessive Daytime Sleepiness in 
Narcolepsy 
Protocol Version:  
Amendment 2 
Protocol Date: 
25 Apr 2019  
 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study. 
  
 
 
 
 

Axsome Therapeutics, Inc. 
Confidential 
 
AXS-12-201 
Version: Amendment 2 (25 Apr 2019) 
Page 6 
 
 
Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal 
contraceptives for a minimum of 1 full cycle (based on the subject's usual menstrual cycle 
period) before study drug administration.  
 
Total abstinence from sexual intercourse since the last menses before study drug 
administration, abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle.  
 
Intrauterine device.  
 
Vasectomized partner. 
 
Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or cream). 
7. Is willing and able to attend study visits, including overnight sleep stays, comply with study drug 
dosing, complete the daily cataplexy diary and all other study-related assessments. 
8. Is able to provide written informed consent to participate in the study and able to understand the 
procedures and study requirements. 
9. Is willing to voluntarily sign and date an informed consent form that is approved by a human research 
ethics committee before the conduct of any study procedure. 
Exclusion criteria: 
A subject will not be eligible for study entry if any of the following exclusion criteria are met: 
1. Current or prior use of reboxetine. 
2. Concomitant sleep disorder. Subjects with untreated mild sleep apnea (< 15 events per hour) are 
allowed.  Subjects receiving treatment for mild to moderate sleep apnea (< 30 events per hour) are 
allowed if the subject is receiving stable treatment. 
3. Concurrent use of any of the following medications:  sodium oxybate, stimulants, anticonvulsants, 
clonidine, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine re-uptake 
inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), 
hypnotics, anxiolytics, sedating antihistamines, antipsychotics, or any other experimental medications 
designed to treat narcolepsy, cataplexy or any other condition.  A longer screening period will be 
allowed, as needed, to ensure subjects have withdrawn any of the above medications for at least 5 half-
lives, or 5 days, whichever is longer. Note: Modafinil and armodafinil are allowed provided the dose 
is stable for at least 3 weeks before treatment start and maintained through the study duration.  
4. History of seizure or other convulsive disorder. 
5. Diagnosis of cancer (other than basal cell carcinoma) within the last 5 years. Subjects who have 
received definitive treatment, such as curative surgery more than 6 months ago, with no known 
recurrence may be included following consultation with the Sponsor. 
6. Bilirubin, alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase levels >2 
times the upper limit of normal. 
7. Clinically significant hypertension (as defined by the PI), uncontrolled hypertension, or a history of 
cardiovascular disease (e.g., myocardial infarction, angina, dysrhythmias, cardiac failure). 
8. Current sign or symptom of severe and/or progressive or uncontrolled: hepatic, renal, gastrointestinal, 
endocrine, hematological, pulmonary, or neurological disease.  
9. Clinically significant psychiatric disorder (eg, schizophrenia, bipolar disorder, or panic disorder) 
including a lifetime history of manic or psychotic episodes or who are at significant risk of self-injury, 
suicide, or aggression towards others.  Significant risk of suicide is determined by the subject 
responding “yes” to question 4 or question 5 on the screening C-SSRS at Visit 1 or Visit 2, and the 
most recent episode occurred in the last 12 months. 
10. History of narrow angle glaucoma. 
11. Any other clinically significant medical condition or clinical laboratory abnormality that would in the 
investigator’s judgment interfere with the subject’s ability to participate in the study. 
12. Gastric bypass or any condition that would be expected to affect drug absorption (lap band procedures 
are acceptable if there is no problem with absorption). 
13. History of intolerance, allergy, or hypersensitivity to reboxetine or any other ingredient in the study 
medication. 
14. Has a known or suspected history of alcoholism or drug abuse or misuse within 6 months of Screening. 
15. Previously participated in another clinical study or received any investigational drug or device or 
investigational therapy within 30 days or 5 half-lives, whichever is longer, of Baseline.