Clinical trial NCT03881852
Conditions: Narcolepsy Cataplexy Narcolepsy Excessive Sleepiness
Keywords: CONCERT AXS-12 EDS Cataplexy Narcolepsy Axsome Reboxetine
Sponsor: Axsome Therapeutics, Inc.
Start date: 2019-01-30; Completion date: 2019-11-27
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
CONCERT (Clinical Outcomes in Narcolepsy and Cataplexy: An Evaluation of Reboxetine Treatment) is a Phase 2, double-blind, randomized, placebo-controlled, crossover, multicenter trial of AXS-12 in patients with narcolepsy. Subjects meeting the entry criteria will be randomized in a 1:1 ratio either to placebo for three weeks followed by AXS-12 (up to 10 mg daily) for three weeks, or to AXS-12 (up to 10 mg daily) for three weeks followed by placebo for three weeks. Efficacy assessments will include the frequency of cataplexy attacks, and measures of other symptoms of narcolepsy.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: AXS-12 (Reboxetine) intervention 2: Placebo
Intervention descriptions: intervention 1: Dosed orally, twice daily for up to 3 weeks intervention 2: Dosed orally, twice daily for up to 3 weeks

Protocol documents:
Prot_SAP_000.pdf: 
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. 
  
 
 
 
 








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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. 





SAP_001.pdf: 
Document Type: Statistical Analysis Plan
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: November 12, 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.






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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 ................................................................................................................................. 6 
4.4 
Randomization and Blinding.................................................................................................... 8 
5.0 
ANALYSIS POPULATIONS ................................................................................................................. 8 
5.1 
Randomized Population ............................................................................................................ 8 
5.2 
Safety Population ........................................................................................................................ 8 
5.3 
Modifed Intent-to-Treat Population ....................................................................................... 8 
5.4 
Per Protocol Population............................................................................................................. 8 
6.0 
GENERAL CONVENTIONS ................................................................................................................ 8 
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 .......................................................................... 9 
7.3 
Medical History ........................................................................................................................... 9 
8.0 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 10 
9.0 
EFFICACY ANALYSES ...................................................................................................................... 10 
9.1 
Primary Efficacy Variable ..................................................................................................... 10 
9.1.1 
Derivation of Primary Efficacy Variable .......................................................................... 10 
9.1.2 
Primary Analysis ...................................................................................................................... 11 
9.1.3 
Handling of Missing Values ................................................................................................. 11 
9.2 
Secondary Efficacy Outcomes ............................................................................................... 11 
9.3 
Interim Analyses ...................................................................................................................... 12 
9.4 
Adjustments for Multiplicity ................................................................................................. 12 
9.5 
Power and Sample Size Justification ................................................................................... 12 
10.0 
SUMMARIES OF MEASURES OF SAFETY ................................................................................ 12 
10.1 
Extent of Exposure .................................................................................................................. 13 
10.2 
Adverse Events ......................................................................................................................... 13 
10.3 
Vital Signs .................................................................................................................................. 13 
10.4 
Physical Exam ........................................................................................................................... 13 


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11.0 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS .............................. 14 
12.0 
DATA QUALITY ASSURANCE ....................................................................................................... 14 
13.0 
REFERENCES ....................................................................................................................................... 14 
14.0 
APPENDICES ......................................................................................................................................... 15 
14.1 
Appendix A - List of Tables, Listings, and Figures ......................................................... 15 
14.2 
Appendix B - Imputation Algorithm for Partial and Missing Dates ........................... 15 
 




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3.0 
INTRODUCTION 
This statistical analysis plan (SAP) is based on Protocol AXS-12-201, Amendment 2, dated 25 Apr 2019. 
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 the 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-12 as compared to placebo on the 
number of cataplexy attacks as recorded in a Sleep and Symptom Daily Diary. 
The secondary objectives of the study are to assess the the effect of AXS-12 as compared to placebo on 
the following measures: 
• 
Epworth Sleepiness Scale (ESS) 
• 
Ability to Concentrate in the Sleep and Symptom Daily Diary 
• 
Number of inadvertent naps or sleep attacks in the Sleep and Symptom Daily Diary 
• 
Individual items of the Narcolepsy Symptom Assessment Questionnaire (NSAQ) 
• 
 
• 
Hamilton Rating Scale for Depression (HAM-D) 
4.2 
STUDY TREATMENTS  
In this crossover study all subjects will be randomized in a 1 : 1 ratio to Sequence 1 or Sequence 2. 
Subjects in Sequence 1 will receive AXS-12 in Period 1 and placebo in Period 2. Subjects in Sequence 2 
will receive placebo in Period 1 and AXS-12 in Period 2.  
4.3 
STUDY DESIGN 
This study is a three-week, crossover, multi-center, randomized, double-blind, placebo-controlled proof-
of-concept Phase 2 trial to assess the safety and efficacy of AXS-12 in narcoleptic subjects with cataplexy 
and excessive daytime sleepiness (EDS). Eligible subjects must have a diagnosis of narcolepsy per the 
International Classification of Sleep Disorders, Third Edition (ICSD-3) criteria, and exhibit symptoms of 
both cataplexy and EDS. Subjects meeting the entry criteria will be randomized in a 1:1 ratio either to 
placebo for three weeks followed by AXS-12 (up to 10 mg daily) for three weeks, or to AXS-12 (up to 10 
mg daily) for three weeks followed by placebo for three weeks. Study medication will be down-titrated 
during the third week of each three-week treatment period.  
The primary endpoint will be the change in the number of cataplexy attacks as recorded in a Sleep and 




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4.4 
RANDOMIZATION AND BLINDING 
Subjects meeting the entry criteria will be randomized in a 1:1 ratio either to placebo for three weeks 
followed by AXS-12 (up to 10 mg daily) for three weeks, or to AXS-12 (up to 10 mg daily) for three 
weeks followed by placebo for three weeks. Study
 
 
Detailed blinding and unblinding procedures can be found in the protocol. 
5.0 
ANALYSIS POPULATIONS 
5.1 
RANDOMIZED POPULATION 
The randomized population will consist of all subjects who complete the Screening Phase and are 
randomized to a treatment sequence.  
5.2 
SAFETY POPULATION 
The safety population will include all subjects who have received study medication. All safety analyses 
will use the safety population. 
5.3 
MODIFED INTENT-TO-TREAT POPULATION 
The Modified Intent-to-Treat (mITT) population will be the primary efficacy analysis population and will 
consist of all subjects who are randomized, subsequently take at least 1 dose of the study drug, and have 
at least 1 post-dose efficacy assessment. 
5.4 
PER PROTOCOL POPULATION 
The Per Protocol population will include all subjects in the mITT population with no major protocol 
violations. Major protocol violation criteria will be established prior to the database lock. Protocol 
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 
 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.  


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6.1 
DEFINITION OF BASELINE 
Unless otherwise stated, the last observed measurement prior to randomization will be considered the 
baseline measurement.  
6.2 
SOFTWARE 
  
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, Per Protocol or Safety) 
in the title. 
7.1 
DISPOSITION 
Subject disposition summaries will be presented by treatment sequence and will include the number of 
subjects randomized, the number and percentage of randomized subjects in the safety, ITT, 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, mITT, 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, 
region (US and ex-US), 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. 
 
Clinical baseline characteristics summarized will include Narcolepsy Disease Related History. 
7.3 
MEDICAL HISTORY 
Medical history will be coded using MedDRA dictionary. A medical history listing will be presented.  


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8.0 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications recorded on the CRFs will be coded using the WHO DRUG Dictionary Enhanced 
September 2018. 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 7 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 were clearly stopped prior to the 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 
the 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 medication will be summarized for the safety population. 
 
9.0 
EFFICACY ANALYSES 
The number of partial and complete cataplexy attacks, as well as the total number of attacks, are recorded 
daily. In addition, the rating of the ability to concentrate (1=Very Good, 2=Good, 3=Average, 4=Poor, 
5=Very Poor) and the total number of inadvertent naps or sleep attacks are recorded daily. Unless 
otherwise stated, for these daily captured efficacy variables, the weekly average will be used in the 
analyses. The weekly average is derived by the average of the non-missing scores captured during the 7 
days prior to the given visit. For example, the baseline score will be derived by the average of the non-
missing scores captured during the 7 days prior to randomization date. 
9.1 
PRIMARY EFFICACY VARIABLE 
9.1.1 DERIVATION OF PRIMARY EFFICACY VARIABLE 
 
Primary Efficacy Variable 
The primary efficacy variable will be the change from baseline in the total number of cataplexy attacks. 
The change will be calculated as Baseline – Post Baseline. A positive change is indicative of 
improvement. 
 






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10.1 EXTENT OF EXPOSURE 
Summary statistics of exposure to study drug will be tabulated by treatment group, and by duration (in 
days) of exposure. The duration will be calculated as last dosing date – first dosing date + 1. 
10.2 ADVERSE EVENTS 
Each AE and serious adverse event (SAE) term recorded on the case report forms (CRFs) by primary 
system organ class (SOC) will be mapped to a preferred term using the MedDRA dictionary. The 
investigator will assess AE severity and relationship to the study treatment. 
 
A treatment emergent adverse event (TEAE) is defined as any AE that occurs within the TEAE window. 
This window starts on the randomization date and ends 7 days after the last dosing date for non-serious 
AEs and 30 days after the last dosing for SAEs. All AEs that are considered by the Investigator as 
treatment related will be treated as TEAEs. Only TEAEs will be summarized in tables (unless otherwise 
stated AEs in tables are TEAEs). However, all AEs recorded will be listed. For the purpose of calculating 
treatment emergence and inclusion in summary tables, incomplete onset dates will be imputed as detailed 
in Appendix B. 
 
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, SAEs 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.  
 
Frequencies for deaths and hospitalizations will also be summarized by treatment group and overall. 
 
Other safety analyses will be performed as appropriate 
10.3 VITAL SIGNS 
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. Vital sign values will be 
summarized by sequence and period. 
10.4 PHYSICAL EXAM 
Number and percent of subjects with abnormal physical exam findings at Screening will be summarized 
by body system, sequence and overall. Physical Exam data for each subject will also be presented in a 
listing. 
 


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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 crosscheck 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 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.0 APPENDICES 
14.1 APPENDIX A - LIST OF TABLES, LISTINGS, AND FIGURES  
List of Tables, Figures, and Listings will be documented separately. 
14.2 APPENDIX B - 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.