Conditions: Dysmenorrhea
Keywords: Primary dysmenorrhea of at least moderate severity
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 201
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the maximum single dose of Aleve® (two tablets, equivalent to 440 mg of naproxen sodium) to the maximum single dose of Tylenol Extra Strength (two caplets, equivalent to 1000 mg of acetaminophen) in the treatment of menstrual pain associated with primary dysmenorrhea.

Detailed description:

Arms:
arm 1: Subjects received one single oral dose of 440 mg naproxen sodium in treatment period 1, followed by one single oral dose of 1000 mg acetaminophen in treatment period 2 arm 2: Subjects received one single oral dose of 1000 mg acetaminophen in treatment period 1, followed by one single oral dose of 440 mg naproxen sodium in treatment period 2

Interventions: intervention 1: Naproxen Sodium, (Aleve, BAY117031) intervention 2: Acetaminophen (Tylenol Extra Strength)
Intervention descriptions: intervention 1: 220 mg \*2 tablets, orally, single dose intervention 2: 500 mg \*2 caplets, orally, single dose

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
A Double-Blind, Randomized, Crossover Study to Assess Menstrual 
Cramp Pain Associated with Primary Dysmenorrhea 
NCT Number: 
NCT03448536 
Document Date: 
2018-04-16 
 


Clinical Study Protocol 19737 
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Reference Number: BHC-RD-OI-107 
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1. Title page 
 
A Double-Blind, Randomized, Crossover Study to Assess Menstrual Cramp Pain Associated with 
Primary Dysmenorrhea 
Test drugs: 
BAY 117031 / Naproxen Sodium 
Study purpose: 
Clinical efficacy 
Clinical study phase: 
Phase 4 
Date: 
16-Apr-2018 
Registration: 
Not Applicable 
Version no.: 
2.0 
IMPACT Number: 
19737 
 
 
Sponsor: 
Bayer HealthCare LLC, Consumer Health 
100 Bayer Boulevard 
Whippany, NJ 07981-0915, USA 
Sponsor’s medical expert: 
 
Bayer HealthCare LLC, Consumer Health 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical investigation 
or its use for any other purpose without the prior written consent of the sponsor is not 
permitted. 
 
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.   
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
 
 
PPD


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Signature of the sponsor’s medically responsible person 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
 
 
Role:   
 
 
  
 
Date: 
 
 
Signature: 
 
 
 
 
PPD
PPD
PPD


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Signature of principal investigator 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
 
Affiliation:  
Date: 
 
 
Signature:  
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file. 
In the protocol document, this page may remain unsigned. 
 
 


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2. 
Synopsis - amended 
 
Title 
A Double-Blind, Randomized, Crossover Study to Assess Menstrual Cramp Pain 
Associated with Primary Dysmenorrhea 
IMPACT 
19737 
Clinical study phase 
4 
Study objective(s) 
To evaluate the analgesic efficacy of a maximum single dose of two tablets of 
Aleve (2 x naproxen sodium 220 mg; total dose 440 mg) as compared to two 
tablets of Tylenol Extra Strength (2 x acetaminophen 500 mg; total dose 1000 
mg) for the treatment of menstrual cramping pain associated with primary 
dysmenorrhea 
Test drug(s) 
Name of active ingredient 
 
Naproxen sodium 
Dose(s) 
220 mg 
Route of administration 
Oral 
Duration of treatment 
12 hours 
Reference drug(s) 
 
Name of active ingredient 
 
Acetaminophen 
Dose(s) 
500 mg 
Route of administration 
Oral 
Duration of treatment 
12 hours 
Background treatment 
Not applicable 
Indication 
Primary dysmenorrhea of at least moderate severity 
 
 


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Diagnosis and main criteria for 
inclusion /exclusion 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria 
 
Ambulatory healthy female patients between 15 and 35 years of age; 
 
Patient has a history of OTC analgesic use for treatment of primary 
dysmenorrhea. 
 
Patient has a history of regular menstrual cycles that typically occurs between 
every 21 to 35 days; 
 
Patient has a self-reported history of primary dysmenorrhea (onset <5 years 
after menarche) with at least moderate menstrual cramp pain (based on the 
categorical pain intensity scale) occurring during four of the past six menstrual 
cycles; 
 
Patient has a self-reported history of primary dysmenorrhea with other causes 
of dysmenorrhea having been excluded; 
 
Patient typically requires at least one dose of a OTC analgesic medication such 
as naproxen, aspirin, acetaminophen, or ibuprofen taken on at least 1 day of her 
menstrual cycle for the treatment of moderate or severe menstrual cramp pain, 
and normally experiences pain relief from these medications; 
 
Patient is of child-bearing potential and is using one of the following methods 
of contraception and agrees to continue this same method for the duration of 
the study: 
- 
Abstinence for at least the last 60 days AND willingness to use double 
barrier method should the patient become sexually active during the 
study; 
- 
Double barrier method (condom with contraceptive foam, diaphragm 
with contraceptive gel); 
- 
Permanent sterilization of patient or her spouse/partner; 
- 
Oral contraceptive (must have been using the same oral contraceptive for 
at least three months prior to study entry and agrees to remain on the 
same type and method throughout the course of the study). 
 
Patient is willing to participate in the study and return to the study site within 
approximately 1 week after her menstrual cycle to return the study medication, 
urine pregnancy test, and for review of the completed patient e-diary;  
 
Patient is willing to abstain from alcohol consumption throughout the 12-hour 
Treatment Period; 
 
Patient is willing to abstain from caffeine consumption throughout the 12-hour 
Treatment Period; 
 
Patient is willing to ingest the overencapsulated tablets throughout the study. 
 
Exclusion Criteria - amended 
 
Patient has a known history of allergic, idiosyncratic or serious adverse 
reaction, to acetaminophen, naproxen, aspirin, ibuprofen, or any other 
nonsteroidal anti-inflammatory drug (NSAID); 
 
Patient has a known allergy to any of the excipients in any of the study 
medication products; 
 
Patient has experienced asthma, urticaria, or allergic-type reactions after taking 
aspirin, acetaminophen or other NSAIDs; 
 
Patient has significant co-existing illness, including gastrointestinal, hepatic, 
renal, neurologic, cardiovascular, psychiatric, endocrine, respiratory, surgical 
procedure or other condition that, in the Investigator’s judgment, 
contraindicates administration of the study medication; 
 
Patient has a current or past history of severe gastritis, gastrointestinal bleeding 
or ulceration; 
 
Patient has a current or past history of one or more of the following conditions: 
secondary dysmenorrhea, pelvic inflammatory disease, urinary tract infection 
(currently acute or recurrent [defined as more than three per year]), prior 
history of an urinary tract infection is eligible for enrollment, adnexal masses, 
uterine fibroids, endometriosis, adenomyosis that in the opinion of the 
Investigator would impact patient safety and/or the study data; 
 
Patient has an ongoing sexually transmitted disease (except for a history of 
genital herpes or Human Papillomavirus) or has abnormal vaginal discharge; 


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 
Patient requires prescription analgesics, narcotic, non-NSAID (i.e., defined as 
oral use of 5 or more times per week for greater than 3 weeks) or has routinely 
taken OTC medications in excess of label recommended instructions for 
control of dysmenorrhea symptoms; 
 
Patient is taking mood-altering agents (e.g., antidepressants, sedatives, 
phenothiazines, or anti-anxiety agents). Patients who are on a stable dose for at 
least 3 months, and not taking this medication for dysmenorrhea or 
premenstrual syndrome are eligible for enrollment; 
 
Patient does not agree to abstain from taking any analgesic and/or anti-
inflammatory medication (with the exception of low dose aspirin [defined as no 
greater than 100 mg daily] taken for cardioprotective purposes) approximately 
72 hours prior to the anticipated treatment period and throughout the 
dosing/assessment period.  All pain and anti-inflammatory medications 
including supplements, topical heat or cold, and other products of topical 
application will be discontinued approximately 72 hours prior to the anticipated 
dosing for each treatment period and throughout the dosing/assessment period;  
 
Patient does not agree to abstain from using transcutaneous electrical nerve 
stimulation devices that are used to treat dysmenorrhea throughout each 
treatment period; 
 
Patient is taking piroxicam (Feldene®) or oral corticosteroids. Patients taking 
inhaled or topical corticosteroids are eligible for enrollment; 
 
Patient is pregnant, lactating , or less than 6 months postpartum; 
 
Patient is currently using an intra-uterine devices (IUD), or using hormonal 
implants (e.g., Norplant) or injections (e.g., Depo-Provera) for contraception or 
used within the past 6 months; 
 
Patient is currently using an oral contraceptive for less than 3 months, has been 
on a unstable dose within the last 3 months or has switched from one oral 
contraceptive to another within the last 3 months or intends to do so in the 
course of the study; 
 
Patient has a history of chronic abuse of alcohol (regularly consumes 3 or more 
alcoholic drinks per day), analgesics, narcotic analgesics, ergot alkaloids, 
tranquilizers, or opioids or other substances known to produce dependence; in 
the judgement of the investigator within the past 3 years; 
 
Positive drug screen at screening and Visit 2 for illegal drug substances, or 
non-prescribed controlled substances; 
 
Positive pregnancy test or breast feeding at screening and prior to dosing in 
each Treatment Period; 
 
Patients with a medical disorder, condition or history such that could impair the 
patient’s ability to participate or complete this study in the opinion of the 
investigator. 
Study design 
A multi-center, randomized, double-blind, two treatment cycle, crossover study in 
adolescent and adult female patients with primary dysmenorrhea of at least moderate 
pain.  The study consists of a 21 day Screening Phase and two Treatment Periods 
within Treatment Phase.  Qualified patients will be randomized in a 1:1 crossover 
fashion (A:B or B:A) to a single dose of naproxen sodium 440 mg (two tablets of 220 
mg [Treatment A]) and a single dose of acetaminophen 1000 mg (two tablets of 500 
mg [Treatment B]) 
Methodology 
Total pain relief scores (TOTPAR) over 12 hours, will be calculated by multiplying 
the pain relief score at each post-dose time point by the duration (in hours) since the 
preceding time point and then summing these values 
Type of control 
Active (acetaminophen) 
Data Monitoring Committee 
No 
Number of patients 
200 
Primary variable(s) 
TOTPAR0-12 
Time point/frame of 
measurement for primary 
variable(s) - amended 
0-4 categorical pain relief scale at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours 
post-dose 
Plan for statistical analysis 
TOTPAR0-12 will be analyzed using analysis of variance (ANOVA) for the 
cross-over study design 


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Table of contents 
1. 
Title page ............................................................................................................................. 1 
2. 
Synopsis - amended ............................................................................................................. 4 
3. 
Introduction ....................................................................................................................... 11 
4. 
Study objectives ................................................................................................................ 12 
5. 
Study design ...................................................................................................................... 13 
6. 
Study population ............................................................................................................... 17 
6.1 
Inclusion criteria .................................................................................................... 17 
6.2 
Exclusion criteria - amended ................................................................................. 18 
6.3 
Justification of selection criteria ............................................................................ 20 
6.4 
Withdrawal of patients from study ........................................................................ 20 
6.4.1 
Withdrawal .............................................................................................. 20 
6.4.2 
Replacement ............................................................................................ 21 
6.5 
Patient identification .............................................................................................. 21 
7. 
Treatment(s) ...................................................................................................................... 22 
7.1 
Treatments to be administered .............................................................................. 22 
7.2 
Identity of study treatment .................................................................................... 23 
7.3 
Treatment assignment ............................................................................................ 24 
7.4 
Dosage and administration .................................................................................... 24 
7.5 
Blinding ................................................................................................................. 24 
7.5.1 
Blinding measures ................................................................................... 24 
7.5.2 
Unblinding ............................................................................................... 25 
7.5.3 
Emergency unblinding by the investigator ............................................. 25 
7.6 
Drug logistics and accountability .......................................................................... 25 
7.7 
Treatment compliance ........................................................................................... 25 
8. 
Non-study therapy ............................................................................................................. 26 
8.1 
Prior and concomitant therapy .............................................................................. 26 
8.2 
Post-study therapy ................................................................................................. 26 
9. 
Procedures and variables ................................................................................................... 27 
9.1 
Tabular schedule of evaluations ............................................................................ 27 
9.2 
Visit description .................................................................................................... 27 
9.2.1 
Screening phase visit 1 (Day -21 to -1) ................................................... 27 
9.2.2 
Treatment period 1 .................................................................................. 28 
9.2.3 
Visit 2 - amended .................................................................................... 29 
9.2.4 
Treatment period 2 (after the completion of visit 2) ............................... 29 
9.2.5 
End of study – visit 3 .............................................................................. 30 
9.2.6 
Rescue medication .................................................................................. 30 
9.3 
Population characteristics ...................................................................................... 31 
9.3.1 
Demographic ........................................................................................... 31 
9.3.2 
Medical history ........................................................................................ 31 


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9.3.3 
Other baseline characteristics .................................................................. 31 
9.4 
Efficacy analysis .................................................................................................... 31 
9.4.1 
Primary efficacy parameter ..................................................................... 32 
9.4.2 
Secondary efficacy parameters ............................................................... 32 
9.4.3 
Safety analysis ......................................................................................... 32 
9.5 
Pharmacokinetics / pharmacodynamics ................................................................ 33 
9.5.1 
Pharmacodynamics ................................................................................. 33 
9.6 
Safety ..................................................................................................................... 33 
9.6.1 
Adverse events ........................................................................................ 33 
9.6.1.1 
Definitions ............................................................................ 33 
9.6.1.2 
Classifications for adverse event assessment ....................... 34 
9.6.1.2.1 
Seriousness ........................................................................... 34 
9.6.1.2.2 
Intensity ................................................................................ 35 
9.6.1.2.3 
Causal relationship ............................................................... 35 
9.6.1.2.4 
Action taken with study treatment ........................................ 36 
9.6.1.2.5 
Other specific treatment(s) of adverse events ....................... 36 
9.6.1.2.6 
Outcome ............................................................................... 37 
9.6.1.3 
Assessments and documentation of adverse events ............. 37 
9.6.1.4 
Reporting of serious adverse events and pregnancy ............. 37 
9.6.1.5 
Expected adverse events ....................................................... 38 
9.6.2 
Pregnancies ............................................................................................. 38 
9.6.3 
Safety Examinations ................................................................................ 39 
9.7 
Other procedures and variables ............................................................................. 39 
9.8 
Appropriateness of procedures / measurements .................................................... 40 
10. Statistical methods and determination of sample size ....................................................... 41 
10.1 
General considerations .......................................................................................... 41 
10.2 
Analysis sets .......................................................................................................... 41 
10.3 
Variables and planned statistical analyses ............................................................. 41 
10.3.1 
Imputation of missing values .................................................................. 41 
10.3.2 
Primary endpoint ..................................................................................... 42 
10.3.3 
Secondary endpoint ................................................................................. 42 
10.4 
Determination of sample size ................................................................................ 43 
10.5 
Planned interim analyses ....................................................................................... 43 
11. Data handling and quality assurance ................................................................................. 44 
11.1 
Data recording ....................................................................................................... 44 
11.2 
Monitoring ............................................................................................................. 45 
11.3 
Data processing ..................................................................................................... 45 
11.4 
Missing data .......................................................................................................... 45 
11.5 
Audit and inspection .............................................................................................. 45 
11.6 
Archiving ............................................................................................................... 46 
12. Premature termination of the study ................................................................................... 47 
13. Ethical and legal aspects ................................................................................................... 48 


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13.1 
Investigator(s) and other study personnel ............................................................. 48 
13.2 
Funding and financial disclosure ........................................................................... 48 
13.3 
Ethical and legal conduct of the study ................................................................... 48 
13.4 
Patient information and consent/assent ................................................................. 49 
13.5 
Publication policy and use of data ......................................................................... 50 
13.6 
Compensation for health damage of patients / insurance ...................................... 50 
13.7 
Confidentiality ....................................................................................................... 51 
14. Reference list ..................................................................................................................... 52 
15. Protocol amendments - amended ...................................................................................... 53 
16. Appendices ........................................................................................................................ 54 
16.1 
Study Flow Chart ................................................................................................... 54 
16.2 
Subjective Assessments ......................................................................................... 55 
 
Table 1: Treatments administered ............................................................................................ 22 
Table 2: Study treatments ......................................................................................................... 23 
Table 3: Urine drug screen panel ............................................................................................. 39 
Table 4: Study schema ............................................................................................................. 54 
 
Figure 1 – Design Overview .................................................................................................... 16 


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List of abbreviations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
COX 
Cyclooxygenase 
CSR 
Clinical Study Report 
(e)CRF 
(electronic) Case Report Form  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
Intent-to-Treat 
IUD 
intra-uterine device 
IV/WRS 
Interactive Voice/Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OTC 
Over-the-Counter 
PID 
Pain Intensity Differences 
PP 
Per Protocol 
QA 
Quality Assurance 
RNR 
Randomization Number 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SNR 
Screening Number 
SOC 
System Organ Class 
SPID 
Summed Pain Intensity Difference 
SUSAR 
Serious Unexpected Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TOTPAR 
Total Pain Relief 


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3. Introduction 
Background 
Primary dysmenorrhea (painful menstrual cramping that occurs during menses) is a common 
problem experienced by women in their reproductive years. In a study to determine the 
prevalence of dysmenorrhea in reproductive-age women, 36% reported always or often 
having pain with their menstrual periods and 90% of the women reported to have some degree 
of dysmenorrhea.[1] This type of pain can interfere significantly with their daily activities. 
The pathophysiology of the condition is primarily prostaglandin driven. At the beginning of 
menses, prostaglandins are released and play a major role in inducing uterine contractions 
within the female reproductive system. These contractions lead to uterine ischemia which 
stimulates pain neurons resulting in pain. The severity of pain has been studied and correlated 
with the level of menstrual prostanglandin.[2]  
 
Naproxen sodium is a non-selective cyclooxygenase inhibitor and ultimately inhibits 
prostaglandins. Aleve® (naproxen sodium) is available over-the-counter and is indicated for 
temporary relief of minor aches and pains due to various pain states, including menstrual 
cramps. Tylenol® Extra Strength (acetaminophen) is also available over-the-counter and is 
indicated to temporarily relieve minor aches and pains due to premenstrual and menstrual 
cramps.  
 
The purpose of this study is to compare the maximum single dose of Aleve® (two tablets, 
equivalent to 440 mg of naproxen sodium) to the maximum single dose of Tylenol Extra 
Strength (two tablets, equivalent to 1000 mg of acetaminophen) in the treatment of primary 
dysmenorrhea. 
Benefit-risk assessment 
 
Patients with at least moderate pain due to primary dysmenorrhea who would typically take 
over-the-counter NSAIDs for pain relief will be enrolled in this study.  The two menstrual 
cycle treatment design falls within established treatment guidelines.  Patients who experience 
a treatment failure have the option of taking rescue medication for pain relief. 
 
During the study, patients will be closely monitored for the occurrence of adverse events.  
Weighing between the potential risks of OTC analgesics associated with the study, and given 
the ability to mitigate risks through close monitoring, this study is considered clinically and 
ethically acceptable. 
 
 


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4. 
Study objectives 
Primary 
 The primary objective of this study is to evaluate the analgesic efficacy of a maximum 
single dose of two tablets of Aleve (2 x naproxen sodium 220 mg; total dose 440 mg) 
as compared to two tablets of Tylenol Extra Strength (2 x acetaminophen 500 mg; 
total dose 1000 mg) for the treatment of menstrual cramping pain associated with 
primary dysmenorrhea. 
Secondary 
 To evaluate the safety and tolerability of naproxen sodium and acetaminophen. 
 
 


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5. 
Study design 
Design Overview 
This is a multi-center, randomized, double-blind, two treatment cycle, crossover study in 
adolescent and adult female patients with primary dysmenorrhea.  At the completion of the 
Screening phase, eligible patients will be randomized in a 1:1 crossover fashion (A:B or B:A) 
to a single dose of naproxen sodium 440 mg (two tablets of 220 mg [Treatment A]) and a 
single dose of acetaminophen 1000 mg (two tablets of 500 mg [Treatment B]). 
The study consists of a 21 day Screening Phase and two Treatment  Periods within the 
Treatment Phase.  The study center may schedule screening testing on multiple days as 
needed, provided all screening tests are done within 21 days.  Qualified patients will be 
randomized into one of two treatment sequences.  Approximately 260 patients will be 
screened prior to the first Treatment period during the Treatment Phase.  Approximately 200 
patients will be randomized to a specific treatment sequence. 
 
Screening Phase Visit 1 - (Day -21 to -1) 
 
Eligible patients will be selected within a screening period of 21 days prior to the start of the 
first Treatment Period within the Treatment Phase of the study.  Patients will be questioned in 
order to determine the severity of menstrual pain (at least moderate pain on a categorical pain 
intensity scale in order to be included) experienced in past menstrual cycles prior to 
randomization in the study. 
 
After the successful completion of screening procedures, patients will be randomized into one 
of two treatment sequences.  In addition, each patient will receive a treatment kit, pregnancy 
test kits and e-diary. The patients will receive training on the use of the e-diary in addition to 
instructions on how to take their assigned medication.  Automatic reminders will be set up in 
the e-diary to instruct patients to complete the assessments as needed.   
 
During both Treatment Periods, patients will be instructed to discontinue use of all pain 
medications including supplements, topical heat or cold, and other products of topical 
application approximately three days before the expected first day of menstruation of their 
menstrual cycle and throughout the dosing/assessment period.  
 
Treatment Period 1 
 
After completion of screening and randomization, patients will start the first of two Treatment 
Periods.  This part of the Treatment Phase will vary from patient to patient depending on the 
duration of their menstrual cycle (in days) and when the menstrual cycle started with respect 
to randomization.  Patients will be instructed to use their e-diary when they think they are 
close to approaching the first day of their menstrual cycle.  Patients will discontinue the use of 
all pain medications including supplements, topical heat or cold, and other products of topical 
application approximately three days before the expected first day of menstruation and 
throughout the treatment/assessment period. Once the patient has reached qualifying pain, the 
patient will notify the site through a phone call to the study center before beginning treatment.  
Patients are only required to call and leave a voice message.  Approval is not needed to 
proceed with the next steps. Patients will then perform a urine pregnancy test and will take the 
designated treatment only if the pregnancy test is negative and when they feel their pain is ≥5 


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on the NRS scale. After taking the study medication the patient will complete the pain/pain 
relief assessment (0-10 NRS and the 0-4 categorical pain relief scale) at the designated time 
intervals using the e-diary over the next 12 hour time period. At 12 hours after taking the 
study medication, patients will complete the Global Evaluation of the overall satisfaction with 
the effectiveness of the study medication. If the patient decides to take rescue medication 
prior to the 12 hours, the patient will be instructed to complete the Global Evaluation prior to 
taking the rescue medication. 
 
If the patient does not have sufficient menstrual pain intensity, has taken prohibited 
medications within the specified period of 3 days, developed other confounding pain 
conditions, or is not able to complete all assessments for the next 12 hours, then Treatment 
Period 1 can be extended to the next menstrual cycle. Patients must inform study staff if they 
require an extension and only one extension for Treatment Period 1 is possible. If the patient 
does not dose the study medication within the next menstrual cycle (as part of the extension), 
then the patient will contact the study center immediately. The patient will proceed to Visit 2 
and if eligible, the patient will proceed to Treatment Period 2. 
 
Visit 2 (after the completion of Treatment Period 1) 
 
Patients will return to the study center approximately one week after use of study medication.   
On visit 2, the patients will bring their used/unused pregnancy test kit/s, treatment kit and e-
diary for review. Patients will be given the instructions for treatment period 2 if still eligible 
to participate in the study. 
 
Treatment Period 2 
 
Patients will be instructed to use their e-diary when they think they are close to approaching 
the first day of their menstrual cycle.  Patients will discontinue use of all pain medications 
including supplements, topical heat or cold, and other products of topical application 
approximately three days before the expected first day of menstruation and throughout the 
treatment /assessment period. Once the patient has reached qualifying pain, the patient will 
notify the site before beginning treatment by phone call to the study center.  Patients are only 
required to call and leave a voice message.  Approval is not needed to proceed with the next 
steps. Patients will then perform a urine pregnancy test and take the designated treatment only 
if the pregnancy test is negative and when they feel their pain is ≥5 on the NRS scale. After 
taking the study medication, the patient will complete the pain/pain relief assessment (0-10 
NRS and the 0-4 categorical pain relief scale) at the designated time intervals using the e-
diary over the next 12 hour time period.  At 12 hours after taking the study medication, 
patients will complete the Global Evaluation of the overall satisfaction with the effectiveness 
of the study medication.  If the patient decides to take rescue medication prior to the 12 hours, 
the patient will be instructed to complete the Global Evaluation prior to taking the rescue 
medication. 
 
If the patient does not have sufficient menstrual pain intensity, has taken prohibited 
medications within the specified period of 3 days, developed other confounding pain 
conditions, or is not able to complete all assessments for the next 12 hours, then Treatment 
Period 2 can be extended to the next menstrual cycle.  Patients must inform study staff if they 
require an extension and only one extension for Treatment Period 2 is possible. If the patient 


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does not dose the study medication within the next menstrual cycle (as part of the extension), 
then the patient will contact the study center immediately. The patient will proceed to Visit 3. 
 
Visit 3 End of Study (after the completion of Treatment Period 2) 
 
Patients will return to the study center approximately one week after use of study medication.  
Patient will return their used/unused pregnancy test kit/s, treatment kit and e-diary for review.  
Upon completion of all study procedures, patients will be discharged from the clinical site and 
be considered completed. 
 
The duration of each patient’s participation will be approximately 77 days for 2 menstrual 
cycles and 133 days for 4 menstrual cycles (if it was required for evaluation using an average 
cycle time of 28 days). For an overview on the study design and study procedures see Figure 
1. 
 
 
 


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Figure 1 – Design Overview 
Justification of the design 
The study was designed to capture menstrual pain in patients who could benefit from the 
administration of an OTC analgesic.  OTC analgesics are commonly used to treat the pain of 
dysmenorrhea (3,4).  The dysmenorrhea pain model has been widely studied in the approval 
of both prescription and OTC medications.  In this study, as in all pain studies, should a 
patient not get sufficient pain relief from the investigational medical product (IMP), then 
rescue medication may be used. 
 
 
Screening 
Phase 
 
Treatment Phase 
 
Study days 
Visit 1 
Screening 
Days -21 to -1 
Treatment     
Period 1 
After Screening 
Visit 2       
After Period 1 
Treatment     
Period 2          
After Visit 2 
Visit 3         
End of Study   
Sequence 1 
Urine 
pregnancy test 
Treatment kit 
e-diary training 
& distribution 
Categorical 
pain intensity  
(0-3) 
A 
approx.         
1 week after 
dosing of 
period 1       
 
e-diary, 
pregnancy and 
treatment kit 
check 
B 
approx.        
1 week after 
dosing of 
period 2       
 
e-diary, 
pregnancy 
and treatment 
kit returned 
 
Patient 
discharged 
Urine pregnancy 
test done prior to 
dosing 
 
NRS pain (0-10) 
Categorical        
pain relief (0-4) 
Global evaluation 
(0-4) 
Urine pregnancy 
test done prior to 
dosing 
 
NRS pain (0-10) 
Categorical       
pain relief (0-4) 
Global evaluation 
(0-4) 
 
 
 
 
 
Sequence 2 
Urine 
pregnancy 
test 
Treatment kit 
e-diary 
training & 
distribution 
Categorical 
pain intensity 
(0-3) 
B 
approx.        
1 week after 
dosing of 
period 1       
 
e-diary, 
pregnancy 
and treatment 
kit check 
A 
approx.        
1 week after 
dosing of  
period 2 
 
e-diary, 
pregnancy 
and treatment 
kit returned  
 
Patient 
discharged 
 
 
Urine pregnancy 
test done prior to 
dosing 
 
NRS pain (0-10) 
Categorical        
pain relief (0-4) 
Global evaluation 
(0-4) 
Urine pregnancy 
test done prior to 
dosing 
 
NRS pain (0-10) 
Categorical        
pain relief (0-4) 
Global evaluation 
(0-4) 
 
 = Randomization of a treatment sequence                                              
 = Onset of dysmenorrhea pain 
A = naproxen sodium 440 mg (220 mg x 2 tablets) 
B = acetaminophen 1000 mg (500 mg x 2 tablets) 
Note:  Treatment Period 1 and 2 may each be extended by one additional 
 
menstruation cycle if the patient does not elect to take the treatment 
 
due to insufficient pain, has taken prohibited medications,  
           developed other confounding pain conditions, or do not have 
 
adequate time for pain assessments. 


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6. 
Study population 
6.1 
Inclusion criteria 
Patients will be allowed to participate in the study if they meet the following eligibility 
criteria: 
1. Patient has given written informed consent to participate in the study prior to admission to 
the study; 
2. Ambulatory healthy female patients between 15 and 35 years of age; 
3. Patient has a history of OTC analgesic use for treatment of primary dysmenorrhea. 
4. Patient has a history of regular menstrual cycles that typically occurs between every 21 to 
35 days; 
5. Patient has a self-reported history of primary dysmenorrhea (onset <5 years after 
menarche) with at least moderate menstrual cramp pain (based on the categorical pain 
intensity scale) occurring during four of the past six menstrual cycles; 
6. Patient has a self-reported history of primary dysmenorrhea with other causes of 
dysmenorrhea having been excluded; 
7. Patient typically requires at least one dose of a OTC analgesic medication such as 
naproxen, aspirin, acetaminophen, or ibuprofen taken on at least 1 day of her menstrual 
cycle for the treatment of moderate or severe menstrual cramp, and normally experiences 
pain relief from these medications; 
8. Patient is of child-bearing potential and is using one of the following methods of 
contraception and agrees to continue this same method for the duration of the study: 
a. Abstinence for at least the last 60 days AND willingness to use double 
barrier method should the patient become sexually active during the study; 
b. Double barrier method (condom with contraceptive foam, diaphragm with 
contraceptive gel); 
c. Permanent sterilization of patient or her spouse/partner; 
d. Oral contraceptive (must have been using the same oral contraceptive for at 
least three months prior to study entry and agrees to remain on the same 
type and method throughout the course of the study). 
9. Patient is willing to participate in the study and return to the study site within 
approximately 1 week after her menstrual cycle to return the study medication, urine 
pregnancy test, and for review of the completed patient e-diary;  
10. Patient is willing to abstain from alcohol consumption throughout the 12-hour Treatment 
Period; 
11. Patient is willing to abstain from caffeine consumption throughout the 12-hour Treatment 
Period; 
12. Patient is willing to ingest the overencapsulated tablets throughout the study; 
13. Patient is willing and able to participate in all scheduled visits, treatment plan, laboratory 
tests and other study procedures according to the clinical protocol. 


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6.2 
Exclusion criteria - amended 
Patients presenting with any of the following will not be included in the study: 
1. Patient has a known history of allergic, idiosyncratic or serious adverse reaction, to 
acetaminophen, naproxen, aspirin, ibuprofen, or any other nonsteroidal anti-inflammatory 
drug (NSAID); 
2. Patient has a known allergy to any of the excipients in any of the study medication 
products; 
3. Patient has experienced asthma, urticaria, or allergic-type reactions after taking aspirin, 
acetaminophen, or other NSAIDs; 
4. Patient has significant co-existing illness, including gastrointestinal, hepatic, renal, 
neurologic, cardiovascular, psychiatric, endocrine, respiratory, surgical procedure or other 
condition that, in the Investigator’s judgment, contraindicates administration of the study 
medication; 
5. Patient has a current or past history of severe gastritis, gastrointestinal bleeding or 
ulceration; 
6. Patient has a current or past history of one or more of the following conditions: secondary 
dysmenorrhea, pelvic inflammatory disease, urinary tract infection (currently acute or 
recurrent [defined as more than three per year]), prior history of an urinary tract infection 
is eligible for enrollment, adnexal masses, uterine fibroids, endometriosis, adenomyosis 
that in the opinion of the Investigator would impact patient safety and/or the study data; 
7. Patient has an ongoing sexually transmitted disease (except for a history of genital herpes 
or Human Papillomavirus) or has abnormal vaginal discharge; 
8. Patient requires prescription analgesics, narcotic, non-NSAID (i.e., defined as oral use of 
5 or more times per week for greater than 3 weeks) or has routinely taken OTC 
medications in excess of label recommended instructions for control of dysmenorrhea 
symptoms; 
9. Patient is taking mood-altering agents (e.g., antidepressants, sedatives, phenothiazines, or 
anti-anxiety agents). Patients who are on a stable dose for at least 3 months, and not taking 
this medication for dysmenorrhea or premenstrual syndrome are eligible for enrollment; 
10. Patient does not agree to abstain from taking any analgesic and/or anti-inflammatory 
medication (with the exception of low dose aspirin [defined as no greater than 100 mg 
daily] taken for cardioprotective purposes) approximately 72 hours prior to the anticipated 
treatment period and throughout the dosing/assessment period. All pain and anti-
inflammatory medications including supplements, topical heat or cold, and other products 
of topical application will be discontinued approximately 72 hours prior to the anticipated 
dosing for each treatment period and throughout the dosing/assessment period;  
11. Patient does not agree to abstain from using transcutaneous electrical nerve stimulation 
devices that are used to treat dysmenorrhea throughout each treatment period; 
12. Patient is taking piroxicam (Feldene®) or oral corticosteroids. Patients taking inhaled or 
topical corticosteroids are eligible for enrollment; 
13. Patient is pregnant, lactating, or less than 6 months postpartum; 


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14. Patient is currently using an intra-uterine devices (IUD), or using hormonal implants (e.g., 
Norplant) or injections (e.g., Depo-Provera) for contraception or used within the past 6 
months; 
15. Patient is currently using an oral contraceptive for less than 3 months, has been on a 
unstable dose within the last 3 months or has switched from one oral contraceptive to 
another within the last 3 months or intends to do so in the course of the study; 
16. Patient has a history of chronic abuse of alcohol (regularly consumes 3 or more alcoholic 
drinks per day), analgesics, narcotic analgesics, ergot alkaloids, tranquilizers, or opioids or 
other substances known to produce dependence; in the judgement of the investigator 
within the past 3 years; 
17. Positive drug screen at screening and Visit 2 for illegal drug substances, or non-prescribed 
controlled substances; 
18. Positive pregnancy test or breast feeding at screening and prior to dosing in each 
Treatment Period; 
19. Patients with a medical disorder, condition or history such that could impair the patient’s 
ability to participate or complete this study in the opinion of the investigator; 
20. Current participation in any other studies involving investigational or marketed products 
within 30 days prior to the Screening Visit;  
21. Unwilling or unable to comply with all requirements outlined in the protocol;  
22. Member or relative of study staff or the Sponsor directly involved in the study. 
 
In addition to the above stated inclusion/exclusion criteria and restrictions, patient selection in 
this study is to be made consistent with all the warnings, precautions, and contraindications 
associated with the use of Aleve and Tylenol Extra Strength. The Investigator should review 
and be familiar with the information available on these marketed products and the information 
in the package label. 


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6.3 
 Justification of selection criteria 
The selection criteria are chosen to ensure that patients with specific risks for administration 
of the study medication and/or patients with conditions which may have an impact on the 
safety of the patient or data integrity during their participation in the study are excluded. 
6.4 
Withdrawal of patients from study 
6.4.1 
Withdrawal 
Withdrawal criteria 
Patients must be withdrawn from the study if any of the following occurs: 
 At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a patient may decline to participate 
further.  The patient will not suffer any disadvantage as a result. 
Patients may be withdrawn from the study if any of the following occurs: 
 Serious adverse events; 
 If, in the Investigator's opinion, continuation of the study would be harmful to the 
patient's well-being; 
 At the specific request of the Sponsor and in liaison with the Investigator (e.g., 
obvious non-compliance, safety concerns); 
 Protocol violation: if the patient develops conditions which would have prevented her 
entry into the study according to the inclusion/exclusion criteria, she must be 
withdrawn immediately if safety is concerned; in other cases, the investigator will 
decide whether there is a conflict with the study objectives 
Depending on the time point of withdrawal, a withdrawn patient is referred to as either a 
“screening failure” “Inadequate pain reporter” or “dropout” as specified below: 
Screening failure 
A patient who, for any reason (e.g., failure to satisfy the selection criteria), terminates the 
study prior to randomization is regarded as a “screening failure”. 
Re-starting the defined set of screening procedures (re-screening) to enable the “screening 
failure” patient’s participation at a later time point is not allowed – with the following 
exceptions: 
 The patient had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule. 
 Initial screening occurred too early to complete the required washout period after prior 
therapy. 
 The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment). 


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 Other situations where the patient had to withdraw consent due to “life circumstances” 
though they otherwise qualified.  These situations will be considered on a case by case 
basis by the sponsor or sponsor representative in consultation with the investigator. 
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the patient to an unjustifiable health risk.  In addition, for re-screening, the patient has 
to re-sign the informed consent form, even if it was not changed after the patient’s previous 
screening. 
Inadequate pain reporter 
A patient who is successfully screened and eligible for treatment but does not meet the 
minimum NRS pain threshold (≥5). 
Dropout 
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has been randomized and administered at least one dose of study 
medication. 
General procedures 
In all cases, the reason for withdrawal must be recorded in the case report form/electronic 
case report form (CRF/eCRF) data collection system and progress noted in the patient's 
medical records.  
The patient may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4. 
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (Premature termination of the Study). 
6.4.2 
Replacement 
Patients who prematurely discontinue participation after randomization will not be replaced. 
6.5 
Patient identification 
Each patient is identified by the study site’s unique patient identification code. After informed 
consent procedure every patient is given a screening number (SNR). At the time point of 
randomization, patients who meet the entry criteria will be sequentially assigned to a four-
digit number in ascending order (randomization number, RNR).  See Section 7.3. 
 
 


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7. 
Treatment(s) 
The study center will dispense a blinded treatment sequence (A/B or B/A) after successfully 
completing screening procedures.  The overencapsulated tablets (IMP) for each treatment 
sequence will be dispensed using an Interactive Voice/Web Response System (IV/WRS) to 
maintain a balanced stratification amongst the study centers participating in the study. 
 
7.1 
Treatments to be administered 
The treatments to be administered during the study are displayed in Sections 7.2 and 7.3. 
Table 1: Treatments administered 
Treatment (condition) 
Dose / route 
Amount / form 
Frequency of 
administration 
A: Naproxen sodium 440  mg (menstrual 
pain) 
220 mg / orally 
2 / tablets 
single dose 
B: Acetaminophen 1000 mg (menstrual 
pain) 
500 mg / orally 
2 / tablets 
single dose 
 
 
 


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7.2 
Identity of study treatment 
Table 2: Study treatments 
Treatment 
Treatment A 
Treatment B 
Dose 
Naproxen sodium 440 mg/day  
(220 mg x 2 single dose) 
Acetaminophen 1000 mg/day 
(500 mg x 2 single dose) 
Pharmaceutical Form 
over-encapsulated tablet 
over-encapsulated tablet 
Strength 
220 mg 
500 mg 
Formulation 
naproxen sodium 
FD&C blue #2 lake 
hypromellose 
magnesium stearate 
microcrystalline cellulose 
polyethylene glycol 
povidone 
talc 
titanium dioxide 
 
Swedish orange opaque 
DBcaps® size AA-el capsules* 
micro crystalline cellulose* 
 
acetaminophen 
carnauba wax 
castor oil 
corn starch 
FD&C red #40 aluminum lake 
hypromellose 
magnesium stearate 
polyethylene glycol 
powdered cellulose, 
pregelatinized starch 
propylene glycol 
shellac 
sodium starch glycolate 
titanium dioxide  
 
Swedish orange opaque 
DBcaps® size AA-el capsules* 
micro crystalline cellulose* 
Route of 
administration / 
Dosing instructions 
orally with a full glass of water 
orally with a full glass of water 
Batch Number 
available in the study file 
available in the study file 
Manufacturer 
Bayer                        
Bitterfeld, Germany 
McNeil Consumer Healthcare 
Fort Washington, PA USA 
*components of the over-encapsulation and filler material. 
 
All study medications will be labeled according to the requirements of local law and 
legislation.  Label text will be approved according to the sponsor’s agreed procedures, and a 
copy of the labels will be made available to the study site upon request. 
For all study medications, a system of numbering in accordance with all requirements of 
Good Manufacturing Practice (GMP) will be used, ensuring that each dose of study 
medication can be traced back to the respective bulk batch of the ingredients.  Lists linking all 
numbering levels will be maintained by the sponsor’s clinical supplies Quality Assurance 
(QA) group.  
A complete record of batch numbers and expiry dates of all investigational products as well as 
the labels will be maintained in the clinical supply file. 
The source of test and reference products will be documented in the clinical supply file. 


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7.3 
Treatment assignment 
At the beginning of the first treatment period, after completion of the pre-treatment baseline 
procedures/assessments, patients who meet the entry criteria will be sequentially assigned to a 
unique number in ascending order (randomization number, RNR) according to the 
randomization schedule prepared prior to the study.  
Patients will be numbered according to the following scheme: 
14001XXXX 
Whereas the “Xs” will be replaced with a four digit sequentially assigned number as each 
patient enters the study (e.g., first patient number will be 140011001). 
Once a number has been assigned to a patient, it cannot be reassigned to another patient.   
Patients entering the Treatment Phase are randomized in a 1:1 fashion into one of two blinded 
treatment sequences: 
 Naproxen sodium 440 mg (two tablets of naproxen sodium 220 mg) for Treatment 
Period 1 and acetaminophen 1000 mg (two tablets of acetaminophen 500 mg) for 
Treatment Period 2 (treatment sequence A/B); 
 Acetaminophen 1000 mg (two tablets of acetaminophen 500 mg) for Treatment Period 
1 and naproxen sodium 440 mg (two tablets of naproxen sodium 220 mg) for 
Treatment Period 2 (treatment sequence B/A). 
 
Patients will be reminded to discontinue use of all pain medications including supplements, 
use of topical heat or cold, and other products of topical application approximately 72 hours 
before the patient’s anticipated initiation of the first day of menstruation of their cycle in each 
Treatment Period.  Patients will take the e-diary and treatment kit home and complete the 
questionnaires when they think they are close to approaching the first day of menstruation of 
their menstrual cycle. 
7.4 
Dosage and administration 
Each patient will self-administer the treatment at the onset of dysmenorrhea during their 
menstrual cycle.  Depending upon which treatment in the sequence, they could be either 
taking naproxen sodium (220 mg x 2) or acetaminophen (500 mg x 2).  Patients will 
administer the study medication with a full glass of non-refrigerated, non-carbonated water 
(about 8 ounces or 240 mL).  The patient will enter the dosing date and time into the e-diary 
at the time of study medication administration. 
7.5 
Blinding 
7.5.1 
Blinding measures 
Patients enrolled in the study, investigators and their staff involved in protocol procedures or 
data collection analysis will be blinded to the identity of the treatment sequence. The study 
monitor will conduct product accountability during and after database lock. To preserve the 
blinding, all investigational products will be over encapsulated and prepackaged according to 
the randomization schedule and managed using IV/WRS. 


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7.5.2 
Unblinding  
In the case of a medical emergency, such as serious adverse events (SAE), breaking the blind 
may become necessary during the study.  Randomization code-break envelopes are securely 
maintained at the study site and with the Sponsor. 
In compliance with applicable regulations, in the event of a SUSAR related to the blinded 
treatment, the patient’s treatment code will usually be unblinded before reporting to the health 
authorities, ethic committees and investigators (see Section 9.6.1.4). 
7.5.3 
Emergency unblinding by the investigator 
The investigator will be provided with code-break envelopes that can be used to break the 
blinding of the study medication.  Any patient who was unblinded using the code-break 
envelopes must have this occurrence documented in the patient’s medical record.  The 
investigator should notify the sponsor or sponsor medical monitor prior to unblinding if at all 
possible, unless a delay in doing so will deleteriously affect the patient’s well being. The 
investigator must report the blind break in conjunction with a SAE as defined in Section 9.6.1.  
Patients that have been unblinded will not be included in the ITT or PP efficacy analysis. 
The Sponsor will collect all code-break envelopes at the end of the study. 
7.6 
Drug logistics and accountability 
The Sponsor will provide sufficient quantity of the IMP to the study site.  All study centers 
will dispense IMP according to the randomization schedule entered in the IV/WRS. 
All study medication will be stored at the investigational site in accordance with GCP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/CRO), and will be inaccessible to unauthorized personnel. Special storage 
conditions and a complete record of batch numbers and expiry dates can be found in the 
Sponsor’s study file; the site-relevant elements of this information will be available in the 
investigator site file. On the day of receipt, the responsible site personnel will confirm receipt 
of IMP in writing. The personnel will use the IMP only within the framework of this clinical 
study and in accordance with this protocol. Receipt, distribution, return and destruction (if 
any) of the study medication must be properly documented according to the sponsor’s agreed 
and specified procedures. 
7.7 
Treatment compliance 
The distribution of the study medication will be supervised by a member of the Investigator’s 
team. Patients will self-adminster IMP at their discretion and document the dosing in the e-
diary system.  The study center will monitor used and unused IMP for compliance.  Any 
discrepancies between actual and expected amount of returned study medication must be 
discussed with the patient at the time of the visit, and any explanation must be documented in 
the source records. 
 
 


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8. 
Non-study therapy 
8.1 
Prior and concomitant therapy 
 
The following treatments are prohibited:  
 
Use of all pain medications and/or anti-inflammatory medications (with the 
exception of low dose aspirin [defined as no more than 100 mg daily] taken for 
cardioprotective purposes) including supplements, topical heat or cold, and other 
products of topical application approximately three days before the expected first 
day 
of 
menstruation 
of 
their 
menstrual 
cycle 
and 
throughout 
the 
dosing/assessment period.  
 
Use of transcutaenous electrical nerve stimulation devices that are used to treat 
dysmenorrhea throughout each treatment period.  
 
The use of mood-altering agents (antidepressants, sedatives, phenothiazines, or 
anti-anxiety agents). Patients who are on a stable dose for at least 3 months, and 
are not taking this medication for dysmenorrhea or premenstrual syndrome are 
eligible for enrollment. 
 
Piroxicam (Feldene®) and corticosteroids. However, patients taking inhaled or 
topical corticsteroids will be eligible for enrollment. 
 
Intra-uterine devices, hormonal implants (e.g., Norplant) or injections (e.g., 
Depo-Provera) used throughout the study or used within the past 6 months. 
 
Patient is currently using an oral contraceptive for less than 3 months, has been on 
an unstable dose within the last 3 months or has switched from one oral 
contraceptive to another within the last 3 months or intends to do so in the course 
of the study. 
 
Patients will be asked to abstain from caffeine and alcohol throughout the 12-hour treatment 
period. 
All medications (oral or topical) prescription and nonprescription products, supplements and 
herbal products, as well as topical heat or cold taken or used by the patient from 30 days prior 
to Screening will be documented. The reported medications will be reviewed and evaluated 
by the Principal Investigator or designee to determine if they affect the patient’s eligibility to 
participate in the study. 
8.2 
Post-study therapy 
This a blinded two period, two treatment crossover study for patients with primary 
dysmenorrhea and therefore no additional treatment after the second treatment period will be 
allocated.  Patients will be discharged upon their completion of Visit 3. 
 
 


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9. 
Procedures and variables 
9.1 Tabular schedule of evaluations 
See flow chart in Section 16.1 
Regarding protocol deviations, the processes and responsibilities defined by the Sponsor will 
be followed. Respective details (e.g., identification and classification of protocol deviations) 
are described separately. 
9.2 
Visit description 
If not stated otherwise, the measures / actions listed in the following Sections 9.2.1 to 9.2.5 
will be performed by or under the supervision of the investigator. 
9.2.1 
Screening phase visit 1 (Day -21 to -1) 
At the Screening visit, the Principal Investigator or appropriate designee will discuss with 
each patient the nature of the study, its requirements and its restrictions.  Written informed 
consent will be obtained prior to performance of any protocol-specific procedures.   
The Screening Period will be up to 21 days.  The following will be determined during the 
Screening Visit: 
 Signed Informed Consent; 
 Review Inclusion and Exclusion Criteria; 
 Patient demographics; 
 Medical History (primary dysmenorrhea is based on the patient’s self-reported 
history)  
 Medication history of all prescription and over-the-counter drugs (including 
topicals, herbal products, vitamins and nutritional supplements), use of topical heat 
or cold, and other products of topical application and investigational drugs, taken 
within 30 days prior to screening; 
 History of drug, alcohol and tobacco use; 
 Height, weight, and Body Mass Index (BMI); 
 Physical examination (general routine); 
 Urine drug screen; 
 Urine pregnancy test; 
 History of Categorical pain intensity (0-3 scale) of moderate or severe for 
menstrual cramp pain during four of the past six menstrual cycles; 
 Vital signs (blood pressure, heart rate, respiratory rate and body temperature after 
at least 5 minutes in a sitting position); 
 Discuss the procedure to report adverse events; 
 e-diary distribution and training; 
 Pregnancy test kits (2); 
 Rescue medication; 
 Treatment kit (randomized patients only). 
 
The Principal Investigator or his/her designee must review all screening results before 
proceeding to the Treatment phase of the study.  Eligible patients will receive their allotted 
treatment kit as per randomization, pregnancy test kits and e-diary and be trained on how to 


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use the e-diary, treatment and pregnancy kits prior to starting the first Treatment Period.  The 
study center will dispense Investigational Medicinal Product (IMP or treatment kit) using the 
Interactive Voice / Web Response System (IV/WRS). 
 
9.2.2 
Treatment period 1  
After screening, all Patients will start the first Treatment Period.  The start of treatment will 
vary based on when the patient’s last menstrual cycle occurred. Once the patient has reached 
qualifying pain, the patient will notify the site by a phone call to the study center and begin 
treatment.  Patients are only required to call and leave a voice message.  Approval is not 
needed to proceed with the next steps. The patient takes the assigned study medication when 
menstrual cramp pain is ≥5 in severity using the 0-10 Numerical Rating Scale (NRS) 
questionnaire.  
 
“My menstrual cramp pain at this time is …?” 
 
If the patient designates that her menstrual cramp pain is <5 on the NRS, has taken prohibited 
medications, developed other confounding pain conditions or does not have adequate time to 
finish 12 hours of evaluation, the patient should stop all activities and inform the study center 
immediately. 
 
Patients are allowed to continue on the study and Treatment Period 1 can be extended to their 
next menstrual cycle.  Patients must inform study staff if they require an extension and only 
one extension for Treatment Period 1 is possible. If the patient does not dose within the next 
menstrual cycle (as part of the extension), then the patient will immediately contact the study 
center. The patient will proceed to Visit 2 and if eligible, the patient will proceed to Treatment 
Period 2.  
 
Prior to dosing all patients MUST perform a urine pregnancy test and verify that the 
results are negative (not pregnant).  Any patient who has a positive pregnancy test or is not 
sure of the results must contact the study center immediately.  Patients with a verified positive 
pregnancy test will be withdrawn from the study. 
 
Before dosing, the patient will complete a baseline (immediately before dosing) 0-10 NRS 
menstrual cramp pain intensity evaluation.  After dosing, patients will complete the 0-10 NRS 
menstrual cramp pain intensity questionnaires at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 
hours post-dose. All post-dose time point assessments have an allowable window of ± 10 
minutes for the 30 and 60 minute assessments.  Subsequent to the 1 hour reading, assessments 
from hours 2-12 will have an allowable window of ± 15 minutes. 
 
Additionally, patients will complete menstrual cramp pain relief (0-4 pain relief scale) 
questionnaires at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours post-dose.  All post-dose 
time point assessments have an allowable window of ± 10 minutes for the 30 and 60 minutes 
assessments. Subsequent to the 1 hour reading, assessments from hours 2-12 will have an 
allowable window of ± 15 minutes.   
 
At 12 hours post-dose, patients will complete the Global Evaluation of the overall satisfaction 
with the effectiveness of the study medication. If the patient decides to take rescue medication 
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taking the rescue medication. Patients will be encouraged to complete the 12 hour Treatment 
Period. 
 
If the patient dosed the study medication before the onset of menstrual flow, then flow must 
start within 48 hours of dosing. Patients who took study medication and did not start 
menstrual flow within 48 hours of dosing will not be included in the primary efficacy 
analysis.  Patients will contact the study center to schedule their next visit (Visit 2) after the 
prescribed treatment period. 
9.2.3 
Visit 2 - amended 
Patients will return to the study center approximately one week after the completion of 
Treatment Period 1 dosing and all assessments.  The following activities will be performed: 
 
 Review concomitant medications; 
 Urine drug screen 
 Vital signs (blood pressure, heart rate, respiratory rate and body temperature after 
at least 5 minutes in a sitting position); 
 Review e-diary data for completeness; 
 Review treatment kit (drug accountability); 
 Review used pregnancy test kit; 
 Adverse Event assessment. 
9.2.4 
Treatment period 2 (after the completion of visit 2) 
The start of treatment for the second Treatment Period will vary based on when the patient’s 
last menstrual cycle occurred. Once the patient has reached qualifying pain, the patient will 
notify the site by a phone call to the study center and begin treatment.  Patients are only 
required to call and leave a voice message.  Approval is not needed to proceed with the next 
steps.  The patient takes the assigned study medication when menstrual cramp pain is at ≥5 in 
severity using the 0-10 Numerical Rating Scale (NRS) questionnaire. 
 
“My menstrual cramp pain at this time is …?” 
 
If the patient designates that her menstrual cramp pain is <5 on the NRS, has taken prohibited 
medications, developed other confounding pain conditions or does not have adequate time to 
finish 12 hours of evaluation, then the patient should stop all activities and inform the study 
center immediately.  
 
Patients are allowed to continue on the study and Treatment Period 2 can be extended to their 
next menstrual cycle.  Patients must inform study staff if they require an extension and only 
one extension for Treatment Period 2 is possible. If the patient does not dose within the next 
menstrual cycle (as part of the extension), then the patient will contact the study center 
immediately. The patient will proceed to Visit 3. 
 
Prior to dosing all patients MUST perform a urine pregnancy test and verify that the 
results are negative (not pregnant).  Any patient who has a positive pregnancy test or is not 
sure of the results must contact the study center immediately.  Patients with a verified positive 
pregnancy test will be withdrawn from the study. 
 


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Before dosing, the patient will complete a baseline (immediately before dosing) 0-10 NRS 
menstrual cramp pain intensity evaluation.  After dosing, patients will complete the 0-10 NRS 
menstrual cramp pain intensity questionnaires at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 
hours post-dose. All post-dose time point assessments have an allowable window of ± 10 
minutes for the 30 and 60 minute assessments.  Subsequent to the 1 hour reading, assessments 
from hours 2-12 will have an allowable window of ± 15 minutes. 
 
Additionally, patients will complete menstrual cramp pain relief (0-4 pain relief scale) 
questionnaires at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours post-dose.  All post-dose 
time point assessments have an allowable window of ± 10 minutes for the 30 and 60 minute 
assessments. Subsequent to the 1 hour reading, assessments from hours 2-12 will have an 
allowable window of ± 15 minutes  
 
At 12 hours post-dose, the patient will complete the Global Evaluation of her overall 
satisfaction with the effectiveness of the study medication.  If the patient decides to take 
rescue medication prior to the 12 hours, the patient will be instructed to complete the Global 
Evaluation prior to taking the rescue medication.  Patients will be encouraged to complete the 
12 hour Treatment Period. 
 
If the patient dosed study medication before the onset of menstrual flow, then flow must start 
within 48 hours of dosing.  Patients who took study medication and did not start menstrual 
flow within 48 hours of dosing will not be included in the primary efficacy analysis.   
 
Patients will contact the study center to schedule their final visit (Visit 3). 
 
9.2.5 
End of study – visit 3 
Patients will return to the study center approximately one week after the completion of 
Treatment Period 1 dosing and all assessments.  The following activities will be performed: 
 
 Review of concomitant medications; 
 Vital signs (blood pressure, heart rate, respiratory rate and body temperature after 
at least 5 minutes in a sitting position); 
 Return and review e-diary for completeness; 
 Return and review treatment kit (drug accountability);  
 Return and review used/unused pregnancy test kits for signs of use; 
 Adverse Event assessment. 
9.2.6 
Rescue medication 
If adequate pain relief was not achieved, then patients are permitted to take rescue medication 
at their discretion, though they will be encouraged to wait for at least 2 hours after dosing of 
study medication prior to use of rescue.  The rescue medication will be ibuprofen 400 mg and 
only one dose for each Treatment Period will be provided. All rescue medication taken must 
be documented on the patient’s medical record and the CRF/e-CRF data collection system.   
Patients should only use the rescue medication during the 12 hour Treatment Period. 
Patients will be queried in a nonspecific fashion for any adverse events.  All observed and 
reported AEs will be collected and recorded on the case report form.  The information 


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recorded will be based on signs and symptoms reported by the patient or observed by the 
research coordinator/Investigator during clinical evaluation. 
9.3 
Population characteristics 
9.3.1 Demographic 
For basic patient assessment prior to screening, some demographic information may be 
collected before obtaining written informed consent: 
 Year of birth (approximate age); 
 Sex; 
 Native language. 
Collection of demographic information is subject to all applicable local regulations. 
9.3.2 
Medical history 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator: 
 Start before signing of the informed consent; 
 Considered relevant for the patient’s study eligibility. 
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1. 
9.3.3 
Other baseline characteristics 
Information on smoking, as well as drug and alcohol consumption will be collected. 
9.4 
Efficacy analysis 
Patients may be invalid for one period but valid for another period. Therefore, invalidity for 
either period does not make them invalid for both. For example, if a patient did not dose in 
Treatment Period 1, but did dose in Treatment Period 2, then the data from Treatment Period 
2 will be analyzed. The following incidences will be considered as a protocol violation and 
excluded from the PP analysis if any one of the following occurred during the treatment 
period: 
 Patient vomited within 30 minutes of ingesting the study medication; 
 
 Patient took rescue medication before the 2-hour evaluation; 
 
 Patient does not have a baseline (predose) pain evaluation; 
 
 Patient dosed with study medication despite having a NRS <5; 
 
 Patient took a prohibited concomitant medication preceding or during the study 
Treatment Period; 
 


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 Patient did not start menstrual flow within 48 hours of dosing; 
 
 Patient failed to continue to meet the inclusion/exclusion criteria prior to the 
Treatment Period; 
 
 Patient had more than 50% evaluations that were missed during the 0 through 12-hour 
evaluation period in those who did not use rescue medication; 
 
 Patient missed more than 2 evaluations from hours 6-12 in those who did not use 
rescue medication. 
 
 
9.4.1 
Primary efficacy parameter 
All efficacy analyses will be based on the PP population.  
 Sum of Total Pain Relief (TOTPAR) over 0-12 hours (TOTPAR0-12) after Time 0 
9.4.2 
Secondary efficacy parameters 
The secondary efficacy variables include: 
 Summed Pain Intensity Difference (SPID) over the 12-hour study period (SPID0-12) 
using 0-10 NRS 
 SPID over 0-6 hours (SPID0-6)  
 SPID 6-12 hours (SPID6-12) 
 TOTPAR over 0-6 hours (TOTPAR0-6) 
 TOTPAR 6-12 hours (TOTPAR6-12) 
 Time to first intake of rescue medication 
 Pain Intensity Difference (PID) scores at each evaluation 
 Global Evaluation at 12 hours post-dose or immediately before first intake of rescue 
medication 
 
9.4.3 
Safety analysis 
Safety measures will be analyzed for all patients in the safety population. 
Adverse events will be collected throughout the treatment and safety follow-up periods and 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
Only treatment-emergent AEs will be included, i.e., AEs that begin or worsen after the first 
dose of the investigational products in the treatment period.  The number and percent of 
patients who experience any event, by System Organ Class (SOC), and by Preferred Term 
will be displayed by treatment group.  Tables will also be produced by severity and 
relationship to investigational product. Seriousness, severity, relationship to investigational 
product, duration, and outcome will also be listed. 


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9.5 
Pharmacokinetics / pharmacodynamics 
Not applicable 
9.5.1 
Pharmacodynamics 
Not applicable 
9.6 
Safety 
9.6.1 
Adverse events 
9.6.1.1 
Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product.  
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE). 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g., physical examination findings, symptoms, diseases. 
 Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g., seasonal allergy without acute complaints); 
 Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g., allergic pollinosis); 
 Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses. 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition refers to an event in which the patient 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. 


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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours 
- The admission is pre-planned  
(e.g., elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2) 
- The admission is not associated with an AE  
(e.g., social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 
d. Results in persistent or significant disability / incapacity 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
e. Is a congenital anomaly / birth defect 
f. Is another serious or important medical event as judged by the investigator 
9.6.1.2 Classifications for adverse event assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.   
9.6.1.2.1 Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1. 


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9.6.1.2.2 Intensity 
The intensity of an AE is classified according to the following categories: 
 Mild: Presents with signs and symptoms easily tolerated, does not need treatment, or 
prolonged hospitalization and does not necessarily require stopping the drug; 
 Moderate:  A type of adverse event that is 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 research participant; 
 Severe: A type of adverse event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects clinical status. The event 
possesses a significant risk of harm to the research participant and hospitalization may be 
required. 
 
9.6.1.2.3 Causal relationship  
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF/eCRF data collection system. 
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question. 
Possible answers are “yes” or “no” 
An assessment of “no” would include: 
1. The existence of a highly likely alternative explanation, e.g., mechanical bleeding at 
surgical site. 
or 
2. Non-plausibility, e.g., the patient is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration. 
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment. 
Important factors to be considered in assessing the relationship of the AE to study treatment 
include: 
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event. 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge):  Patient’s response after de-challenge or re-challenge should be considered 
in view of the usual clinical course of the event in question. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 


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- Concomitant medication or treatment:  
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in question. 
- Known response pattern for this class of drug: Clinical/preclinical 
- Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event 
- The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual patient’s pharmacodynamics should be 
considered. 
- The assessment is not possible 
Causal relationship to protocol-required procedure(s) 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s). 
Possible answers are “yes” or “no” 
9.6.1.2.4 Action taken with study treatment  
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
The study treatment action should be recorded separately for each study treatment as detailed 
in the CRF/eCRF data collection system. 
- Drug withdrawn 
- Drug interrupted 
- Dose reduced 
- Dose not changed 
- Dose increased 
- Not applicable 
- Unknown 
9.6.1.2.5 Other specific treatment(s) of adverse events 
- None 
- Remedial drug therapy 
- Other 


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9.6.1.2.6 Outcome 
The outcome of the AE is to be documented as follows:  
- Recovered/resolved 
- Recovering/resolving 
- Recovered/resolved with sequelae 
- Not recovered/not resolved 
- Fatal 
- Unknown 
9.6.1.3 
Assessments and documentation of adverse events 
AEs observed, mentioned upon open questioning by a member of the investigator’s team or 
spontaneously reported by the patient will be documented. The observation phase for AEs 
will start with signing the informed consent form and will end in general with the last visit of 
follow-up. After the end of follow-up there is no requirement to actively collect AEs. 
In case of ongoing AEs after the last follow-up visit – especially when related to treatment 
with the study medication – the respective AE will be followed until resolution, if possible. 
The type of information that should be assessed and recorded by the investigator for each AE 
is listed in Section 9.6.1.2. 
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to treatment with the study medication. 
The investigator has to record on the respective CRF/eCRF data collection system all adverse 
events occurring in the period between the signing of the informed consent and the end of the 
Follow-up Visit, there is no requirement to actively collect AEs including deaths.  The type of 
information that should be assessed and recorded by the investigator for each AE is listed in 
Section 9.6.1.2.   
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s). 
For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study medication. 
9.6.1.4 Reporting of serious adverse events and pregnancy 
The definition of serious adverse events (SAEs) is given in Section 9.6.1.1.  Each SAE must 
be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient. 
Investigator’s notification of the sponsor 
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed. 
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
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detailed in the instructions for SAE reporting included in the Investigator File.  For this, an 
AE page in the CRF/eCRF data collection system as well as the complementary pages 
provided in the Investigator File must be completed for each SAE.   
Pregnancy occurring during a clinical investigation, although not considered a serious adverse 
event, must be reported to Bayer within the same timelines as a serious adverse event on a 
Pregnancy Monitoring Form.  The outcome of a pregnancy should be followed up carefully 
and any abnormal outcome of the mother or the child should be reported.  This also applies to 
pregnancies following the administration of the investigational product to the father prior to 
sexual intercourse.  Send the completed SAE or pregnancy forms to: 
 or Fax: 
 (in the USA) 
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations. 
Notification of the IRB 
Notification of the Institutional Review Board (IRB) about all relevant events (e.g., SAEs, 
suspected, unexpected, serious adverse reactions [SUSARs]) will be performed by the 
sponsor and/or by the investigator according to all applicable regulations. 
Notification of the authorities 
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations. 
Sponsor’s notification of the investigational site 
The sponsor will inform the investigational site about reported relevant events (e.g., SUSARs) 
according to all applicable regulations. 
9.6.1.5 Expected adverse events 
For this study, the applicable reference document is the most current version of the package 
insert for naproxen, acetaminophen and ibuprofen.  If relevant new safety information is 
identified, the information will be integrated into an update of the safety information and 
distributed to all participating sites. 
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations. 
9.6.2 
Pregnancies 
A patient’s participation is to be terminated immediately if a pregnancy is supposed (i.e. 
in case her pregnancy test becomes positive).   
The investigator must report to the sponsor any pregnancy occurring in a female patient 
during her participation in this study.  The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported. 
For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as an SAE (see Section 9.6.1.4.).  Send the completed pregnancy forms to: 
 or Fax: 
 (in the USA) 
PPD
PPD
PPD
PPD


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9.6.3 
Safety Examinations 
The following safety examinations will be performed at the time points specified in the study 
flowchart, see Section 16.1. 
 Physical examination 
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician at the study site covering at least the organs of the cardiovascular, respiratory, 
and abdominal system. 
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1). 
 Body weight and height, BMI 
Body weight will be measured by a member of the investigator’s team under the following 
conditions: 
 Patient without shoes after having emptied her bladder 
 Scale measurement units of 0.1 kg 
The patient’s height will be measured (without shoes) to calculate the BMI. 
 Blood pressure / heart rate 
Systolic and diastolic blood pressure and heart rate will be measured by a member of the 
investigator’s team under the following conditions: 
 Systolic blood pressure (after resting for at least 5 min in sitting position) 
 Diastolic blood pressure (after resting for at least 5 min in sitting position) 
 Heart rate (after resting for at least 5 min in sitting position) 
 Measuring site: cuff to be placed on the right / left upper arm (if possible, the same arm 
will be used for all measurements in one patient); cuff location will be documented 
 Method: oscillometric by an automatic or a manual measurement device 
 Laboratory examinations 
Urine samples will be collected to assess for illicit drugs at Screening (Visit 1) and Visit 2. 
Table 3: Urine drug screen panel 
 Urine pregnancy test 
9.7 
Other procedures and variables 
Not applicable 
Test Panel 
Parameter 
Urine Drug Screen 
Methamphetamines, Amphetamines, cannabinoids, 
cocaine, opiates, benzodiazepines, barbiturates, 
Methylenedioxymethamphetamine, methadone, 
Oxycodone, Adulterants 


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9.8 
Appropriateness of procedures / measurements 
All efficacy and safety parameters, as well as the methods to measure them, are standard 
variables / methods in clinical studies and / or clinical practice. They are widely used and 
generally recognized as reliable, accurate and relevant. 
 
 


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10. 
Statistical methods and determination of sample size 
10.1 
General considerations 
Statistical analysis will be performed using SAS and the version used will be specified in the 
Statistical Analysis Plan (SAP) and placed on file.  The SAP will contain a more 
comprehensive explanation than described below of the methodology used in the statistical 
analyses.  The SAP will also contain the rules and data handling conventions used to perform 
the analyses, and the procedure used for accounting for missing data. 
10.2 
Analysis sets 
Three populations will be identified in this study.  
Safety Population:  
 
All randomized patient who take at least one dose of IMP. Safety measures will be analyzed 
for all patients in the safety population. 
 
 
Intent to Treat (ITT) Population:  
 
All patients who are randomized and provide at least one measure of an efficacy parameter 
after the first dose of IMP.  ITT population will be used as the sensitivity analysis for the 
selected parameters.   
 
 
Per Protocol (PP) Population 
 
PP population will include all patients in ITT who do not have any major protocol violations. 
PP population will be used as the primary analysis for the efficacy parameters. 
 
10.3 
Variables and planned statistical analyses 
 
10.3.1 
Imputation of missing values 
Pain intensity differences (PID) will be derived by subtracting the pain intensity at the post-
dose time point from the baseline intensity score (baseline score – post-baseline score).  A 
positive difference is indicative of improvement.   
If a patient takes rescue medication during the 12 hour assessment period, the subsequent pain 
intensity scores following the intake of the rescue medication will be imputed by either the 
baseline score (pre-dose) or the score recorded immediately prior to taking rescue medication, 
whichever is worse.  Subsequent pain relief scores following the intake of the rescue 
medication will be imputed by “none relief” (0). 
 


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For those patients who are not rescued during the 12 hour assessment period, the 30 and 60 
minute assessments will be considered as missing in the event that pain assessment is off-
schedule by more than 10 minutes.  Subsequent to the 1 hour reading values will be 
considered as missing in the event that the pain assessment is off-schedule by more than 15 
minutes.  Any missing values during 12 hour assessment period will be imputed using linear 
interpolation (trapezoid rule) or extrapolation (last observation carried forward) approach 
depending on availability of data surrounding the missing value.  
 
10.3.2 
Primary endpoint 
 
Total pain relief scores (TOTPAR) over 12 hours, will be calculated by multiplying the pain 
relief score at each post-dose time point by the duration (in hours) since the preceding time 
point and then summing these values. 
 
TOTPAR0-12 will be analyzed using analysis of variance (ANOVA) for the cross-over study 
design. 
 
10.3.3 
Secondary endpoint 
The secondary efficacy variables include: 
 Summed Pain Intensity Difference (SPID) over the 12-hour study period (SPID0-12) 
using 0-10 NRS 
 SPID over 0-6 hours (SPID0-6)  
 SPID 6-12 hours (SPID6-12) 
 TOTPAR over 0-6 hours (TOTPAR0-6) 
 TOTPAR 6-12 hours (TOTPAR6-12) 
The above mentioned secondary endpoints will be analyzed similarly as the primary endpoint. 
 Time to first intake of rescue medication. If a patient did not take the rescue 
medication during the treatment period, she will be censored at the time of last 
assessment. Time to first use of rescue medication will be estimated and plotted using 
Kaplan-Meier method and analyzed using log-rank test. 
 Pain Intensity Difference (PID) scores at each evaluation. PIDs will be summarized 
descriptively by treatment group and plotted over time. 
 Global Evaluation at 12 hours post-dose or immediately before first intake of rescue 
medication. This variable will be analyzed using CMH method with modified ridit 
score.   
Safety and Tolerability 
AEs will be collected from screening throughout the Treatment Phase and Follow-up Phase 
and will be coded using the Medical Dictionary for Regulatory Activities. Only treatment-
emergent AEs will be included, i.e., AEs that begin or worsen after the first dose of the 
investigational medicinal product (IMP) in the Treatment Phase.  The number and percent of 
patients who experience any event and the number of events overall, by System Organ Class, 


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and by Preferred Term will be displayed by treatment period and treatment group.  Tables will 
also be produced by severity and relationship to each IMP. Seriousness, severity, relationship 
to each IMP duration, and outcome will also be listed. 
Quantitative data for blood pressure, heart rate, laboratory data, body weight, body 
temperature will be described by summary statistics for the original data as well as for the 
differences to baseline.  Frequency tables will be provided for qualitative data. Laboratory 
data outside the reference range will be listed and highlighted with ‘L’ for low and ‘H’ for 
high. An additional table with all abnormal values will be presented. 
Listings of individual patient data (e.g., vital signs) will be provided. 
10.4 
Determination of sample size 
The proposed design of the study is to detect the treatment difference of 5.9 in TOTPAR12 
with 90% power and a type I error of 0.05.  The required sample size to meet these design 
criteria are 154 patients in the PP population.  Assuming a 23% drop out rate, approximately 
200 patients will need to be randomized. 
10.5 
Planned interim analyses 
No interim analysis is planned for this study. 
 
 


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11. 
Data handling and quality assurance 
11.1 
Data recording 
Data collection and storage 
The data collection tool for this study will be a validated electronic data capture system to be 
used at the study site. Patient data necessary for analysis and reporting will be provided to the 
Sponsor in CDISC (Clinical Data Interchange Standards Consortium) standards. 
Test results originating directly from the site (e.g., urine drug screen) will be entered into the 
CRF/eCRF data collection system by designated site personnel. 
Analytical results generated by central laboratory / -ies 
The analytical results will be provided as electronic data files using predefined data formats. 
Where appropriate, these data will be supplemented with data already available from the 
CRF/eCRF data collection system (e.g., specific time points, demographic data) before being 
evaluated by the responsible specialist(s). Data relevant for the clinical study report will be 
stored in the sponsor’s validated data repository. 
Source documentation 
Entries made in the CRF/eCRF data collection system must be either verifiable against source 
documents, or have been directly entered into the CRF/eCRF data collection system, in which 
case the entry in the CRF/eCRF data collection system will be considered as the source data 
(e.g., time points of blood sampling).  The site has to ensure the availability of all required 
documentation. 
Data recorded from screening failures 
Data of 'only screened patients' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable.  At minimum, the following data should be 
recorded in the screening log: 
 Demographic information (patient number; year of birth  or age, sex); 
 Date of informed consent; 
   Reason for premature discontinuation; 
   Date of last visit.   
For screening failures with an SAE, the following data should be collected in the CRF/eCRF 
data collection system in addition to the data specified above: 
 All information related to the SAE such as:  
- Concomitant medication 
- Medical history 
- Other information needed for SAE complementary page 


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11.2 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items. 
The sponsor/designee will monitor the site activity to verify that the: 
 Data are authentic, accurate and complete.   
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes); 
 Safety and rights of patients are being protected; 
 Study is conducted in accordance with the currently approved protocol  
(including study treatment being used in accordance with the protocol); 
 Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
11.3 
Data processing 
Data will be collected as described in Section 11.1.  Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on the CRF/eCRF data collection system as 
well as for data from other sources (e.g., laboratory, ECG). 
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used. 
11.4 
Missing data  
Reasons for missing data, especially inability to perform a test, must be documented.  
Additional parameters for missing data are detailed in Section 10.3.1. 
11.5 
Audit and inspection 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome. 
In addition, inspections by regulatory health authority representatives and IRB(s) are possible.  
The investigator should notify the sponsor immediately of any such inspection. 
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study. 


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11.6 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Study patient files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the study site.  Where the archiving procedures do not 
meet the minimum timelines required by the sponsor, alternative arrangements must be made 
to ensure the availability of the source documents for the required period. 
The investigator/institution notifies the sponsor if the archival arrangements change (e.g., 
relocation or transfer of ownership). 
The investigator site file is not to be destroyed without the sponsor’s approval. 
The contract with the investigator/institution will contain all regulations relevant for the study 
center. 
 
 


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12. 
Premature termination of the study 
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g., treatment arms; dose steps; centers]) at any time, which may be due but not limited to 
the following reasons:  
 If risk-benefit ratio becomes unacceptable owing to, for example, 
- Safety findings from this study (e.g., SAEs) 
- Results of any interim analysis 
- Results of parallel clinical studies 
- Results of parallel animal studies  
(on e.g., toxicity, teratogenicity, carcinogenicity or reproduction toxicity); 
 If the study conduct (e.g., recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the study within a reasonable 
time frame. 
The investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
 Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing; 
 All affected institutions (e.g., IRB(s); competent authority(ies); study center; head of 
study center) must be informed as applicable according to local law; 
 All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction; 
 In the event of a partial study closure, ongoing patients, including those in post study 
follow-up, must be taken care of in an ethical manner. 
Details for individual patient's withdrawal can be found in Section 6.4.1. 
 
 


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13. 
Ethical and legal aspects 
13.1 
Investigator(s) and other study personnel 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file. 
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site. 
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g., health authority, ethics committee, sponsor) 
before patient recruitment may start at the respective center.  Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center. 
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file. 
The global sponsor of this study is identified on the title page of this protocol.  If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages. 
13.2 
Funding and financial disclosure 
Funding 
This study will be funded by its sponsor. 
Financial disclosure  
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
Trial Master File. 
13.3 
Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). 
Documented approval from appropriate IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IRB approval 
must be obtained and also forwarded to the sponsor.  The responsible unit (e.g., IRB, head of 


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the study center/medical institution) must supply to the sponsor, upon request, a list of the 
EC/IRB members involved in the vote and a statement to confirm that the IRB is organized 
and operates according to GCP and applicable laws and regulations. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.   
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the study patients without prior IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator. 
Details on discontinuation of the entire study or parts thereof can be found in Section 12. 
13.4 
Patient information and consent/assent 
All relevant information on the study will be summarized in an integrated patient information 
sheet and informed consent form provided by the sponsor or the study center.  Sample patient 
information and informed consent/assent forms are provided as a document separate to this 
protocol.  Patients 15 to 17 years old who cannot legally give informed consent for research 
participation must use an IRB-approved assent form and a Parental/Guardian informed 
consent form.  Informed consent must first be obtained from the child’s parent or legal 
guardian before assent may be obtained from the child. 
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient prior to her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms). 
The investigator will also mention that written approval of the IRB has been obtained. 
Each patient will be informed about the following aspects of premature withdrawal: 
 Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision;   
 The patient’s consent covers examinations as specified in the visit description described 
in Section 9.2.5 to be conducted after withdrawal of consent; 
 The patient’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan; 
 Patient-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g., image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan.  The patient has the right to object to the 
generation and processing of this post-withdrawal data.  For this, he/she needs to sign a 
corresponding declaration of objection; alternatively, the patient’s oral objection may be 
documented in the patient’s source data. 


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Each patient will have ample time and opportunity to ask questions. 
Only if the patient agrees to sign the informed consent form and has done so, may he/she 
enter the study.  Additionally, the investigator will personally sign and date the form.  The 
patient will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient´s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
For minors or adults under legal protection, consent shall be given by the legal guardian(s). 
The consent of a minor or adult under legal protection shall also be requested where such a 
person is able to express his/her own will. His/her refusal or the withdrawal of his/her consent 
may not be disregarded. 
The informed consent form and any other written information provided to patients will be 
revised whenever important new information becomes available that may be relevant to the 
patient’s consent, or there is an amendment to the protocol that necessitates a change to the 
content of the patient information and / or the written informed consent form.  The 
investigator will inform the patient of changes in a timely manner and will ask the patient to 
confirm her participation in the study by signing the revised informed consent form.  Any 
revised written informed consent form and written information must receive the IRB`s 
approval / favorable opinion in advance of use. 
13.5 
Publication policy and use of data 
The sponsor will make the information regarding the study publicly available on the internet 
at www.clinicaltrials.gov as applicable to local regulations. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. 
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.   
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.   
13.6 
Compensation for health damage of patients / insurance 
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 


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13.7 
Confidentiality 
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Patient names will not be supplied to the sponsor.  Only the patient numbers (SNR and RNR) 
will be recorded in the CRF/eCRF data collection system, and if the patient name appears on 
any other document (e.g., pathologist report), it must be obliterated before a copy of the 
document is supplied to the sponsor.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  As part of the informed consent process, the 
patients will be informed in writing that representatives of the sponsor, IRB, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and 
in accordance with local data protection laws. 
If the results of the study are published, the patient’s identity will remain confidential. 
The investigator will maintain a list to enable patients to be identified. 
 
 


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14. 
Reference list  
 
1. Jamieson DJ, Steege JF. The prevalence of dysmenorrhea, dyspareunia, pelvic pain, and 
irritable bowel syndrome in primary care practices. Obstet Gynecol. 1995;87:55-8. 
2. Chan WY, Dawood MY, Fuchs F. Relief of dysmenorrhea with the prostaglandin synthetase 
inhibitor ibuprofen: effect on prostaglandin levels in menstrual fluid. Am J Obstet Gynecol. 
1979;153:102. 
3. Campbell MA and McGrath PJ. Use of medication by adolescents for the management of 
menstrual discomfort. Arch Pediatr Adolesc Med. 1997;151:905-13. 
4. Ortiz MI. Primary dysmenorrhea among Mexican university students: prevalence, impact and 
treatment. Eur J Obstet Gynecol Reprod Biol. 2010;152:73-7. 
 
 
 


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15. 
Protocol amendments 
 
15.1 
Amendment 1 (16-Apr-2018) 
 
15.1.1 
Overview of changes to the study 
The following sections have been modified for Amendment 1: 
 Section 2 (Synopsis, Exclusion Criteria, Time point/frame of measurement for primary 
variable(s)) 
 Section  6.2 (Exclusion Criteria) 
 Section 9.2.3 (Visit 2) 
 
 


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16. 
Appendices 
 
16.1 
Study Flow Chart 
Table 4: Study schema 
Study Procedure 
Screening 
Phase 
Treatment Phase 
Screening 
Visit 1 
Treatment 
Period 1 
Visit 2 
Treatment 
Period 2 
Visit 3 
End of Study 
 
Days -21 to -1 
 After 
Screening 
After Period 1 
After Visit 2 
After Period 2 
Signed Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
Patient Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Prior and Concomitant / Medication 
History 
X 
 
X 
 
X 
History of drug, alcohol and tobacco 
use 
X 
 
 
 
 
Body weight, height, and BMI 
X 
 
 
 
 
Physical examination (general 
routine) 
X 
 
 
 
 
Urine drug screen 
X 
 
X 
 
 
Vital signs (incl. temperature)a 
X 
 
X 
 
X 
Urine pregnancy test 
X 
X 
 
X 
 
Categorical Pain Intensity 0-3 Scale 
X 
 
 
 
 
e-diary distribution/training 
X 
 
 
 
 
Randomization/Kit assignment 
Xb 
 
 
 
 
IMP administration 
 
Xc 
 
Xc 
 
0-10 Point Pain Intensity NRS 
 
X 
 
X 
 
0-4 Categorical – pain relief 
 
X 
 
X 
 
12 hour post-dose Global 
Evaluationd 
 
X 
 
X 
 
IMP compliance 
 
 
X 
 
X 
e-diary/treatment kit return/review 
 
 
X 
 
X 
Adverse events 
 
X 
X 
X 
X 
a Vital signs (blood pressure, respiratory rate, heart rate and body temperature after 5 minutes of rest in a sitting position). 
b Randomization to treatment occurs only for eligible patients. 
c Urine pregnancy test must be performed and the results must be negative (not pregnant) before dosing. 
d If the patient decides to take rescue medication prior to the 12 hours, the patient will be instructed to complete the Global Evaluation 
 prior to taking the rescue medication. 
 
 
 


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16.2 Subjective Assessments 
Categorical Pain Intensity (at Screening Visit 1 only) 
 
 0 = none 
 1 = mild 
 2 = moderate 
 3 = severe 
 
0-10 pain Numerical Rating Scale (NRS) 
Assessed at baseline (predose), 30 minutes, 60 minutes and hourly from 2-12 hours post-dose. 
All post-dose time point assessments have an allowable window of ± 10 minutes for the 30 
and 60 minute assessments.  Subsequent to the 1 hour reading, assessments from hours 2-12 
will have an allowable window of ± 15 minutes. 
My menstrual cramp pain at this time is … 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No  
pain 
 
 
 
 
 
 
 
Worst 
possible 
pain 
 
Categorical Pain Relief  
Assessed at 30 minutes, 60 minutes and hourly from 2-12 hours post-dose. 
All post-dose time point assessments have an allowable window of ± 10 minutes for the 30 
and 60 minute assessments.  Subsequent to the 1 hour reading, assessments from hours 2-12 
will have an allowable window of ± 15 minutes. 
My relief from my starting menstrual cramp pain is… 
 0 = none 
 1 = a little 
 2 = some 
 3 = a lot 
 4 = complete 
 
Global Evaluation 
A question that rates the IMP as a pain reliever at 12 hours post-dose or immediately at the 
first intake of rescue medication. 
 
Overall, I would rate the effectiveness of this study medication in relieving my menstrual 
cramp pain as… 
 
 0 = poor 
 1 = fair  
 2 = good  
 3 = very good  
 4 = excellent 

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A Double-Blind, Randomized, Crossover Study to Assess Menstrual 
Cramp Pain Associated with Primary Dysmenorrhea 
NCT Number: 
NCT03448536 
Document Date: 
2018-12-07 
 


PPD
PPD
PPD


 
Confidential 
 
 
 
 
 
 
 
 
 
Bayer HealthCare 
 
Clinical Study Protocol 19737 
 
A Double-Blind, Randomized, Crossover Study to Assess Menstrual Cramp Pain 
Associated with Primary Dysmenorrhea 
 
07DEC2018 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Prepared by: 
 
PPD 
3900 Paramount Parkway 
Morrisville, NC 27560 
 
 
 


Bayer HealthCare 
 
Statistical Analysis Plan, Version  1.0 
 
19737 
 
Date Issued: 07DEC2018 
 
  
II  
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... IV 
1. 
INTRODUCTION ............................................................................................................ 5 
2. 
OBJECTIVES ................................................................................................................... 5 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 6 
3.1.  OVERALL STUDY DESIGN AND PLAN .................................................................................. 6 
FIGURE 1. DESIGN OVERVIEW ............................................................................................. 7 
3.2.  STUDY ENDPOINTS ............................................................................................................. 7 
3.2.1. 
Primary Efficacy Endpoint ......................................................................................... 7 
3.2.2. 
Secondary Efficacy Endpoints .................................................................................... 8 
3.2.3. 
Safety Endpoints.......................................................................................................... 8 
3.3.  TREATMENTS ...................................................................................................................... 8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 9 
4.1.  SAMPLE SIZE ...................................................................................................................... 9 
4.2.  RANDOMIZATION AND BLINDING ..................................................................................... 10 
4.3.  ANALYSIS SET .................................................................................................................. 10 
4.3.1. 
Intent-to-Treat (ITT) ................................................................................................. 10 
4.3.2. 
Per Protocol (PP) ..................................................................................................... 10 
4.3.3. 
Safety ......................................................................................................................... 11 
4.4.  ASSESSMENT WINDOWS ................................................................................................... 11 
4.4.1. 
Treatment Periods ..................................................................................................... 11 
5. 
SUBJECT DISPOSITION ............................................................................................. 13 
5.1.  STUDY SETS .................................................................................................................... 13 
5.2.  DISPOSITION ..................................................................................................................... 13 
5.3.  PROTOCOL DEVIATIONS AND VIOLATIONS ....................................................................... 13 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 13 
6.1.  DEMOGRAPHICS ................................................................................................................ 13 
6.2.  ALCOHOL, TOBACCO AND DRUG USAGE .......................................................................... 14 
6.3.  MEDICAL HISTORY ........................................................................................................... 14 
6.3.1. 
General Medical History .......................................................................................... 14 
6.4.  INCLUSION AND EXCLUSION CRITERIA ............................................................................. 14 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 15 
7.1.  PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 15 
7.2.  STUDY TREATMENTS ........................................................................................................ 15 
7.2.1. 
Exposure and Treatment Compliance ....................................................................... 15 
7.2.2. 
Treatment Review ...................................................................................................... 15 
8. 
EFFICACY ANALYSIS ................................................................................................. 16 
8.1.  PRIMARY EFFICACY ENDPOINT ......................................................................................... 16 
8.1.1. 
Primary Analysis ....................................................................................................... 17 


Bayer HealthCare 
 
Statistical Analysis Plan, Version  1.0 
 
19737 
 
Date Issued: 07DEC2018 
 
  
III  
 
8.1.2. 
Sensitivity Analysis.................................................................................................... 17 
8.2.  SECONDARY EFFICACY ENDPOINTS .................................................................................. 17 
8.2.1. 
Summed Pain Intensity Difference (SPID) over the 12-hour study period (SPID0-12)
 
17 
8.2.2. 
SPID over 0-6 hours (SPID0-6) ................................................................................ 18 
8.2.3. 
SPID 6-12 hours (SPID6-12) .................................................................................... 18 
8.2.4. 
TOTPAR over 0-6 hours (TOTPAR0-6) .................................................................... 19 
8.2.5. 
TOTPAR 6-12 hours (TOTPAR6-12) ........................................................................ 19 
8.2.6. 
Time to First Intake of Rescue Medication ............................................................... 19 
8.2.7. 
Pain Relief Scores at Each Evaluation ..................................................................... 20 
8.2.8. 
Global Evaluation at 12 Hours Post-Dose or Immediately Before First Intake of 
Rescue Medication ................................................................................................................. 20 
9. 
SAFETY ANALYSIS ..................................................................................................... 21 
9.1.  ADVERSE EVENTS ............................................................................................................. 21 
9.1.1. 
Incidence of TEAEs ................................................................................................... 21 
9.1.2. 
Relationship of Adverse Events to IMP .................................................................... 22 
9.1.3. 
Intensity of Adverse Event ......................................................................................... 22 
9.1.4. 
Serious Adverse Events ............................................................................................. 22 
9.1.5. 
Deaths, Adverse Events Leading to Treatment Discontinuation/Study 
Discontinuation ...................................................................................................................... 23 
9.2.  CLINICAL LABORATORY EVALUATIONS ........................................................................... 23 
9.2.1. 
Urine Drug Screen .................................................................................................... 23 
9.2.2. 
Urine Pregnancy Test ............................................................................................... 23 
9.3.  VITAL SIGN MEASUREMENTS ........................................................................................... 24 
9.4.  PHYSICAL EXAMINATION ................................................................................................. 24 
10. 
INTERIM ANALYSIS ................................................................................................... 24 
11. 
REFERENCES ................................................................................................................ 24 
12. 
APPENDICES ................................................................................................................. 25 
12.1. 
NOTABLE ABNORMAL VITAL SIGNS  ............................................................................. 25 
12.2. 
TABLE OF CONTENTS: SUMMARY TABLES, LISTINGS AND FIGURES .............................. 25 
12.3. 
SCHEDULE OF STUDY PROCEDURES .............................................................................. 29 


Bayer HealthCare 
 
Statistical Analysis Plan, Version  1.0 
 
19737 
 
Date Issued: 07DEC2018 
 
  
IV  
 
List of Abbreviations 
 
 
 
 
 
 
 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
(e)CRF 
(electronic) Case Report Form 
eDiary 
Electronic Diary 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
ITT 
Intent-to-Treat 
IxRS 
Interactive Voice/Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OTC 
Over the Counter 
PID 
Pain Intensity Differences 
PP 
Per Protocol 
PT 
Preferred Term 
PVG 
Pharmacovigilance 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SNR 
Screening Number 
SOC 
System Organ Class 
SPID 
Summed Pain Intensity Difference 
SPID0-12 
Summed Pain Intensity Difference over 12 hours 
SPID0-6 
Summed Pain Intensity Difference over 6 hours 
SPID6-12 
Summed Pain Intensity Difference from 6 to 12 hours 
TEAE 
Treatment-Emergent Adverse Events 
TOTPAR 
Total Pain Relief 
TOTPAR0-12 Total Pain Relief over 12 hours  
TOTPAR0-6 
Total Pain Relief over 6 hours 
TOTPAR6-12 Total Pain Relief from 6 to 12 hours 
WHODD 
World Health Organization Drug Dictionary 


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1. Introduction 
 
Primary dysmenorrhea (painful menstrual cramping that occurs during menses) is a 
common problem experienced by women in their reproductive years. In a study to 
determine the prevalence of dysmenorrhea in reproductive-age women, 36% reported 
always or often having pain with their menstrual periods and 90% of the women reported 
to have some degree of dysmenorrhea. This type of pain can interfere significantly with 
their daily activities. The pathophysiology of the condition is primarily prostaglandin 
driven. At the beginning of menses, prostaglandins are released and play a major role in 
inducing uterine contractions within the female reproductive system. These contractions 
lead to uterine ischemia which stimulates pain neurons resulting in pain. The severity of 
pain has been studied and correlated with the level of menstrual prostaglandin. 
  
Naproxen sodium is a non-selective cyclooxygenase inhibitor and ultimately inhibits 
prostaglandins. Aleve® (naproxen sodium) is available over-the-counter and is indicated 
for temporary relief of minor aches and pains due to various pain states, including 
menstrual cramps. Tylenol® Extra Strength (acetaminophen) is also available over-the-
counter and is indicated to temporarily relieve minor aches and pains due to premenstrual 
and menstrual cramps.  
 
The purpose of this study is to compare the maximum single dose of Aleve® (two tablets, 
equivalent to 440 mg of naproxen sodium) to the maximum single dose of Tylenol Extra 
Strength (two tablets, equivalent to 1000 mg of acetaminophen) in the treatment of primary 
dysmenorrhea. 
 
Patients with at least moderate pain due to primary dysmenorrhea who would typically 
take over-the-counter NSAIDs for pain relief will be enrolled in this study. The two 
menstrual cycle treatment design falls within established treatment guidelines. Patients 
who experience a treatment failure have the option of taking rescue medication for pain 
relief.  
 
During the study, patients will be closely monitored for the occurrence of adverse events. 
Weighing between the potential risks of OTC analgesics associated with the study, and 
given the ability to mitigate risks through close monitoring, this study is considered 
clinically and ethically acceptable. 
 
2. Objectives 
 
The primary objective of this study is to evaluate the analgesic efficacy of a maximum 
single dose of two tablets of Aleve (2 x naproxen sodium 220 mg; total dose 440 mg) as 


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compared to two tablets of Tylenol Extra Strength (2 x acetaminophen 500 mg; total dose 
1000 mg) for the treatment of menstrual cramping pain associated with primary 
dysmenorrhea.  
 
The secondary objective of this study is to evaluate the safety and tolerability of naproxen 
sodium and acetaminophen. 
 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
 
This is a multi-center, randomized, double-blind, two treatment cycle, crossover study in 
adolescent and adult female patients (15 to 35 years old) with primary dysmenorrhea. At the 
completion of the Screening phase, eligible patients will be randomized in a 1:1 crossover 
fashion (A:B or B:A) to a single dose of naproxen sodium 440 mg (two tablets of 220 mg 
[Treatment A]) and a single dose of acetaminophen 1000 mg (two tablets of 500 mg 
[Treatment B]).  
 
The study consists of a 21 day Screening Phase and two Treatment Periods within the 
Treatment Phase. The study center may schedule screening testing on multiple days as needed, 
provided all screening tests are done within 21 days. Qualified patients will be randomized into 
one of two treatment sequences. Approximately 260 patients will be screened prior to the first 
Treatment period during the Treatment Phase. Approximately 200 patients will be randomized 
to a specific treatment sequence. Duration of trial participation will be 77 to 133 days as 
detailed in Figure 1. Design Overview .   See Appendix 12.3 for complete schedule of events. 
 
In order to be evaluated for this study, patients must have at least moderate menstrual pain 
during four of the past six menstrual cycles at screening and a Numerical Rating Scale (NRS ≥ 
5) at the time of each treatment period. Each patient will enter their score on an eDiary prior to 
taking the medication for each period. If the patient’s score is < 5 or don’t have enough time to 
complete the eDiary, they will be instructed to contact the site and may be granted a maximum 
of one month’s extension for each treatment period. If the score is ≥ 5, and they have a 
negative pregnancy test, they will be instructed to take the medication for each treatment 
period. Note that concomitant pain therapies must be discontinued at least 3 days prior to 
expected menses. If a patient withdraws from the study, they will not be replaced. Once a 
patient takes their study dose, they will enter the time in the eDiary, then will be prompted to 
enter in NRS scores (0-10). At subsequent timepoints they will be prompted to enter NRS 
scores and Categorical Pain Relief scores (0-4).  The eDiary will be used to collect data 
throughout treatment phase as detailed in schedule of events. 
 
Patients may also take a rescue medication, recommended at no earlier than 2 hours post-dose. 
The patient will record the time of rescue medication in the diary and complete the Global 
Evaluation at this time. If the patient does not take rescue medication throughout the 12 hours, 
they will be prompted to complete the Global Evaluation at the 12 hour timepoint.   


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Figure 1. Design Overview 
 
 
3.2. Study Endpoints 
3.2.1. Primary Efficacy Endpoint 
 
The primary efficacy endpoint, total pain relief scores (TOTPAR) over 12 hours 
(TOTPAR0-12), will be calculated by multiplying the pain relief score at each post-


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dose time point by the duration (in hours) since the preceding time point and then 
summing these values.  
3.2.2. Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints include  
 
• Summed Pain Intensity Difference (SPID) over the 12-hour study period 
(SPID0-12) using 0-10 NRS  
• SPID over 0-6 hours (SPID0-6)  
• SPID 6-12 hours (SPID6-12)  
• TOTPAR over 0-6 hours (TOTPAR0-6)  
• TOTPAR 6-12 hours (TOTPAR6-12)  
 
The above mentioned endpoints will be calculated in similar manner as primary on 
indicated scale and timepoints. Other endpoints will include:  
 
• Time to first intake of rescue medication  
• Pain Intensity Difference (PID) scores derived from the NRS at each 
evaluation  
• Global Evaluation at 12 hours post-dose or immediately before first intake of 
rescue medication  
3.2.3. Safety Endpoints 
 
Safety assessments will include the following: 
• Overall incidence of treatment-emergent AEs (TEAEs), serious AEs (SAEs) 
will be summarized including breakout by intensity and relationship to 
investigational medicinal product (IMP) 
• Quantitative vital signs (systolic blood pressure, diastolic blood pressure, 
heart rate, respiratory rate, and body temperature) and laboratory tests (urine 
drug screen and urine pregnancy test) will be summarized, including observed 
and change from baseline.   
3.3. Treatments 
 
The study center will dispense a blinded treatment sequence (A/B or B/A) after 
successfully completing screening procedures. The overencapsulated tablets (IMP) for 
each treatment sequence will be dispensed using an Interactive Voice/Web Response 
System (IxRS) to maintain a balanced stratification amongst the study centers participating 
in the study. 
 


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4. General Statistical Considerations 
 
All statistical analyses will be conducted using SAS Version 9.3 or higher (SAS Institute, 
Cary, North Carolina).  
 
All statistical tests will be two-sided and will be performed at the 5% level of significance 
leading to 95% (2-sided) confidence intervals (CIs), unless otherwise stated. P-values will be 
rounded to 3 decimal places. If a p-value is less than 0.001 it will be reported as “<0.001.” 
If a p-value is greater than 0.999 it will be reported as “>0.999.” 
 
Continuous data will be summarized by treatment group using descriptive statistics (n, 
mean, median, standard deviation [SD], minimum, and maximum). Categorical data will 
be summarized by treatment group using frequency tables (frequencies and percentages). 
Mean and median will be presented to one decimal place beyond the precision with which 
the data was captured. SD will be presented to two decimal places beyond the precision 
with which the data was captured. Minimum and maximum will be presented to the 
precision with which the data was captured. When count data are presented, the percentage 
will be suppressed when the count is zero in order to draw attention to the non-zero counts. 
A row denoted “Missing” will be included in count tabulations where specified on the 
shells to account for dropouts and missing values. The denominator for all percentages will 
be the number of patients in that treatment group within the analysis set of interest, unless 
otherwise specified. 
 
All study-related raw data that support the corresponding tables and figures will be 
presented in data listings. Additional data listings may be generated as needed. All table, 
listing and figure (TLF) shells will appear in landscape format employing Courier New 9 
point font. Unless otherwise noted, all tables will summarize patient results by treatment 
group sorted in the following order: Naproxen Sodium, Acetaminophen. As this is a 
crossover study, we expect that individual patients will be included in both treatment 
groups. Unless otherwise noted, all data listings will be sorted by treatment group and 
patient identification number defined as investigator identification number concatenated 
with the subject number. 
 
The baseline value for an assessment will be defined as the last non-missing measurement 
including unscheduled assessments before or on the day of treatment with IMP for each 
treatment period. Change from baseline is defined as the post-baseline value minus the 
baseline value for the given assessment. 
 
4.1. Sample Size 
 
The proposed design of the study is to detect the treatment difference of 5.9 in TOTPAR0-
12 with 90% power and a type I error of 0.05. The required sample size to meet these 


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design criteria are 154 patients in the PP set. Assuming a 23% drop out rate, approximately 
200 patients will need to be randomized. 
4.2. Randomization and Blinding 
 
Patients will be randomized in a 1:1 fashion into one of two blinded treatment sequences: 
 
 
Naproxen sodium 440 mg (two tablets of naproxen sodium 220 mg) for Treatment 
Period 1 and acetaminophen 1000 mg (two tablets of acetaminophen 500 mg) for 
Treatment Period 2 (treatment sequence A/B);  
 
Acetaminophen 1000 mg (two tablets of acetaminophen 500 mg) for Treatment Period 
1 and naproxen sodium 440 mg (two tablets of naproxen sodium 220 mg) for 
Treatment Period 2 (treatment sequence B/A).  
 
Patients enrolled in the study, investigators and their staff involved in protocol procedures or 
data collection analysis will be blinded to the identity of the treatment sequence. The study 
monitor will conduct product accountability during and after database lock. To preserve the 
blinding, all investigational products will be over encapsulated and prepackaged according to 
the randomization schedule and managed using IV/WRS. 
4.3. Analysis Set 
 
Three populations will be identified in this study. Patients’ inclusion status in each of the 
analysis sets will be presented in a data listing. 
4.3.1. Intent-to-Treat (ITT) 
 
The ITT will consist of all patients who were randomized and provided at least one 
measure of an efficacy parameter after the first dose of IMP. ITT set will be used as the 
sensitivity analysis for selected parameters. All analyses using the ITT will group 
participants according to randomized treatment.  
 
4.3.2. Per Protocol (PP) 
 
The PP will consist of all patients in ITT who do not have major protocol violations. The 
PP set will be used as the primary analysis for the efficacy parameters. Protocol deviations, 
including assessment of significance, will be identified prior to database lock and study 
unblinding. All analyses using the PP will group participants according to treatment 
sequence actually received. The following incidences will be considered as a protocol 
violation and excluded from the PP analysis if any one of the following occurred during 
the treatment period:  
 
• 
Patient vomited within 30 minutes of ingesting the study medication;  


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• 
Patient took rescue medication before the 2-hour evaluation;  
• 
Patient does not have a baseline (predose) pain evaluation;  
• 
Patient dosed with study medication despite having a NRS <5;  
• 
Patient took a prohibited concomitant medication preceding or during the study 
Treatment Period; 
 
• 
Patient did not start menstrual flow within 48 hours of dosing;  
 
• 
Patient failed to continue to meet the inclusion/exclusion criteria prior to the 
Treatment Period;  
• 
Patient had more than 50% evaluations that were missed during the 0 through 12-hour 
evaluation period in those who did not use rescue medication;  
 
• 
Patient missed more than 2 evaluations from hours 6-12 in those who did not use 
rescue medication.  
 
• 
Patient dosed more than 30 minutes before or more than 2 hours after the predose pain 
evaluation 
 
Patients may be invalid for one period but valid for another period. Therefore, invalidity 
for either period does not make them invalid for both. Protocol violations which lead to 
exclusion from the per-protocol set will be summarized and listed. 
4.3.3. Safety 
 
The Safety set is comprised of all patients who received at least one dose of IMP. The 
Safety set is usually used to tabulate all of the safety information for a study, such as 
adverse events, treatment compliance, laboratory results, and vital signs.  
4.4. Assessment Windows 
4.4.1. Treatment Periods 
 
 
For classifying AEs, the treatment periods will be defined as:  
 Treatment Period 1: The onset date of the AE is on or after the start date of study 
medication in treatment period 1 but before the start date of the study medication in 
treatment period 2. 
 Treatment Period 2: The onset date of the AE is on or after the start date of study 
medication in treatment period 2. 
 


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Partial dates will be imputed for AE start dates in order to determine the treatment period 
to which the event will be assigned.  
 If the onset date is completely missing, onset date is set to the date of first dose and 
will be considered TEAE for both treatment periods.  
 If the year is present and the month is missing, then the month is set to January. If 
the year is same as the year of the date of first dose and the AE end date is not prior 
to the date of first dose, then onset date is set to the date of first dose. 
 If the month and year are present and the day is missing, then the day is set to the 
1st day of month. If the month and year are same as the month and year of the date 
of first dose and the AE end date is not prior to the date of first dose, then onset 
date is set to the date of first dose. 
 If the AE end date is present, then the imputed start date will be no later than the 
end date. 
 
Partial dates will be imputed for medication start dates in order to determine if a 
medication is prior or concomitant.  
 Partial start dates of prior and concomitant medications will be assumed to be the 
earliest possible date consistent with the partial date. 
 If the year is present and the month is missing, then the month is set to January. 
 If the month and year are present and the day is missing, then the day is set to the 
1st day of month. 
 If the year is missing, then the year will be assumed to be the year part of the 
patient’s informed consent date. 
 
Partial or missing medication stop dates for medications that are not ongoing will be 
handled as follows: 
 Partial stop dates of prior and concomitant medications will be assumed to be the 
latest possible date consistent with the partial date. 
 If the year is present and the month is missing, then the month is set to December. 
 If the month and year are present and the day is missing, then the day is set to the 
last day of month. 
 For patients who are treated, if  the year is missing and the month or day are not 
missing, then the year will be assumed to be the year part of the patient’s last 
recorded study visit date.   
 For patients who are not treated, if the year is missing and the month or day is not 
missing, then the year will be assumed to be the year part of the patient’s 
discontinuation date. 
 If the complete stop date is missing, the stop date will be considered to be either the 
patient’s last recorded visit date for treated patients or the patient’s discontinuation 
date for non-treated patients. 
 
 


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5. Subject Disposition 
5.1. Study Sets 
 
The number of patients who were enrolled and the number of patients within each analysis 
set (ITT, PP, and Safety) will be summarized for each treatment group for all randomized 
patients. A by-patient listing indicating the patient’s inclusion in each analysis set and 
reason(s) that the patient is excluded from an analysis set will be presented. 
5.2. Disposition 
 
The counts and percentages of patients who complete or discontinue from the study 
treatment will be presented based on the number of patients in each treatment group and 
overall for all patients. The count and percentage of patients who complete or discontinue 
from the study will be summarized in a similar manner. Reasons for discontinuation of 
treatment for patients who do not complete the study treatment and reasons for not 
completing the study will be summarized for each treatment group as Treatment 
Disposition and Patient Disposition, respectively. Unless noted all percentages will be 
based on the number of patients screened. Patient disposition data will be listed as well.  
 
5.3. Protocol Deviations and Violations 
 
Protocol deviations will be tracked by the clinical team on an on-going basis. Specific 
criteria for what constitutes a significant protocol deviation will be determined by the 
clinical team. A blinded review of the deviation log collected by the clinical group will be 
conducted prior to database lock. All deviations will be listed. 
 
Protocol violations, which disqualify a patient from the per-protocol set, will also be 
tracked on an on-going basis.  These include but are not necessarily limited to the events 
listed in Section 4.3.2. This section also describes analyses related to this data.. 
6. Demographics and Baseline Characteristics 
6.1. Demographics 
 
Demographic information and baseline characteristics collected at screening will be 
summarized for the ITT, PP, and Safety sets. Continuous variables, including age (years), 
baseline weight (kg), baseline height (cm), and baseline body mass index (BMI) (kg/m2) 
will be summarized using descriptive statistics for each treatment sequence and overall. 
Categorical variables including sex (Male, Female), ethnicity (Hispanic or Latino, Not 
Hispanic or Latino), race (White, Black or African American, Asian, American Indian or 


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Alaska Native, Native Hawaiian or Other Pacific Islander, and Other), native language 
(English, Spanish, Chinese, Tagalog, Vietnamese, Arabic, French, Korean, Russian, 
German, Other), and present method of birth control (Abstinence and Double Barrier 
Method, Double Barrier Method, Permanent Sterilization, Oral Contraceptives) will be 
summarized by reporting the number and percentage of patients in each category for each 
treatment group and overall. Percentages will be based on the total number of patients in 
the ITT set. All demographic and baseline characteristics will be listed for all patients in 
the ITT set.  
 
Age will be calculated as (date of Screening visit – date of birth)/365.25. 
BMI is calculated as (body weight in kilograms) / (height in meters)2. 
 
6.2. Alcohol, Tobacco and Drug Usage 
 
Descriptive statistics will be provided for subject alcohol history (<3 drinks per day, ≥3 
drinks per day), tobacco usage (Current, Previous, Never), and whether drug use history 
was discussed with the subject. Percentages will be based on the total number of patients in 
the safety set.. 
 
6.3. Medical History 
6.3.1. General Medical History 
Medical history will be collected in the Electronic Case Report Form (eCRF) at the 
screening and baseline visits and verbatim terms will be coded classified on the basis of 
Medical Dictionary for Regulatory Activities (MedDRA) terminology, which will be 
updated whenever possible throughout the life of the study. Medical history will be 
summarized by the number and percentage of patients with any medical history reported 
by coded system organ class, preferred term, and treatment group for the safety set. A 
subject listing will also be included with start date and end date or ongoing status.  
6.4. Inclusion and Exclusion Criteria 
 
Inclusion and exclusion criteria deviations noted in the eCRF will be presented for the set 
of randomized patients in a data listing. 
 


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7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
Any medicinal product, prescribed or over-the-counter (OTC), including herbal products, 
vitamins, and minerals is considered a concomitant medication. Any medications used 
during the study will be coded with the World Health Organization Drug Dictionary 
(WHODD), which will be updated whenever available throughout the life of the study.  
Prior/concomitant medication use will be recorded in the eCRF beginning at Screening 
visit before the first dose of study medication and will be recorded at the subsequent visits 
as well. Any changes in prior or concomitant medications will also be recorded in the 
subject’s eCRF. 
Summary of prior and concomitant medications by treatment group and preferred term will 
be provided. All prior and concomitant medications will be presented in data listings. Prior 
and concomitant medications will be summarized for the safety set. 
7.2. Study Treatments 
 
In each treatment period, the patient will dose with either naproxen sodium 440mg (220mg 
x 2 tablets) or acetaminophen 1000mg (500mg x 2 tablets). Each treatment phase of the 
study is single-dose  
7.2.1. Exposure and Treatment Compliance 
 
The distribution of the study medication will be supervised by a member of the 
Investigator’s team. Patients will self-administer IMP at their discretion and document the 
dosing in the e-diary system. The study center will monitor used and unused IMP for 
compliance. Any discrepancies between actual and expected amount of returned study 
medication must be discussed with the patient at the time of the visit, and any explanation 
must be documented in the source records. Total exposure and percent compliance will be 
summarized for the Safety and ITT sets, and a by-patient listing will be included on the 
Safety set. A listing of patients who took rescue medication will also be included. 
 
7.2.2. Treatment Review 
 
A treatment review listing will be provided for each treatment in assigned sequence, 
including the following information: date/time of last menses, reason for not taking study 
medication, alcohol use during treatment period, caffeine use during treatment period, and 
vomiting within 30 minutes of dosing. 
 


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8. Efficacy Analysis 
 
Efficacy data will be analyzed utilizing the PP set unless noted otherwise.  Data imputation 
may occur for the following:  
 
If a patient takes rescue medication during the 12 hour assessment period, the subsequent pain 
intensity scores (NRS) following the intake of the rescue medication will be imputed by either 
the baseline score (pre-dose) or the score recorded immediately prior to taking rescue 
medication, whichever is worse. Subsequent pain relief scores following the intake of the 
rescue medication will be imputed by “none relief” (0). 
 
For those patients who are not rescued during the 12 hour assessment period, the 30 and 60 
minute assessments will be considered as missing in the event that pain intensity assessment is 
off-schedule by more than 10 minutes. Subsequent to the 1 hour reading values will be 
considered as missing in the event that the pain intensity assessment is off-schedule by more 
than 15 minutes. Any missing values during 12 hour assessment period will be imputed using 
linear interpolation (trapezoid rule) or extrapolation (last observation carried forward) 
approach depending on availability of data surrounding the missing value. If a missing value 
occurs at the 30 minute assessment, a value of “none relief” (0) will be imputed. 
 
8.1. Primary Efficacy Endpoint 
 
The primary efficacy endpoint is total pain relief scores (TOTPAR) over 12 hours. It will 
be calculated by multiplying the pain relief score at each post-dose time point by the 
duration (in hours) since the preceding time point and then summing these values. 
 
ሺ1ሻ  ܱܶܶܲܣܴ0 െ12
ൌ෍݂௜
ଵଶ
௜ୀ଴.ହ
ሺݐ௜െݐ௜ିଵሻ 
 
Where fi is the pain relief score at post-baseline time i, and (ti –ti-1) represents the duration 
in hours since the last timepoint, with t0 representing the baseline timepoint. The pain relief 
score is a categorical score from 0-4 measuring relief from starting menstrual cramp pain 
where 0=none, 1=a little, 2=some, 3= a lot, 4= complete. The patient completes this at 30 
minutes, 60 minutes, and hourly from 2-12 hours post-dose. All post-dose time point 
assessments have an allowable window of ±10 minutes for the 30 and 60 minute 
assessments, and a window of ±15 minutes for each subsequent timepoint. 
 
 


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8.1.1. Primary Analysis 
 
 
The primary variable of TOTPAR0-12, as defined in (1) above, will be analyzed using a 
mixed analysis of covariance (ANCOVA) model with fixed effects for baseline 
TOTPAR0-12, sequence, treatment and period and will include a random effect for subject 
within sequence for the crossover study design.  If ‘sequence’ is not significant in the 
initial model, then a reduced model with ‘sequence’ removed from the fixed effects will be 
used.  The estimated treatment difference between the two treatment groups will be 
presented together from the reduced model with the two-sided 95% confidence interval for 
the difference and the p-value. The study will be considered positive if the p-value for the 
treatment difference is less than 0.05. However, if ‘sequence’ is significant (p-value ≤ .10) 
in the initial model, then further exploratory analyses will be conducted to investigate any 
potential bias due to carry-over effects. 
Example SAS code for the primary analysis (based on Yarandi, 2004)  
PROC MIXED DATA=DATA1;  
CLASS SEQUENCE SUBJECT PERIOD TRTA;  
MODEL TOTPAR= SEQUENCE BASELINE TRTA PERIOD; 
RANDOM SUBJECT (SEQUENCE); 
LSMEANS TREATMENT / PDIFF CL E; 
RUN; 
 
where TOTPAR is TOTPAR0-12 as defined as in the equation above, TRTA is actual 
treatment corresponding to the TOTPAR0-12, BASELINE is the baseline NRS score for 
that period, SEQUENCE is the treatment sequence a patient was randomized to (B/A or 
A/B), and PERIOD is the treatment period (either 1 or 2).  
8.1.2. Sensitivity Analysis  
 
In addition to the primary analysis, the same ANCOVA analysis will be performed on 
TOTPAR0-12 for the ITT set. The estimated treatment difference between the two 
treatment groups will be presented together with the two-sided 95% confidence interval for 
the difference and the p-value 
8.2. Secondary Efficacy Endpoints 
8.2.1. Summed Pain Intensity Difference (SPID) over the 12-hour study 
period (SPID0-12)  
 
The NRS is a numeric scale from 0-10 which measures pain at Baseline (predose), 30 
minutes, 60 minutes, and hourly from 2-12 hours post-dose. All post-dose time point 
assessments have an allowable window of ±10 minutes for the 30 and 60 minute 


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assessments, and a window of ±15 minutes for each subsequent timepoint. The baseline 
dose must be taken no more than 30 minutes before or 2 hours after the predose 
measurement. 
 
Pain intensity differences (PID) will be derived by subtracting the pain intensity (using NRS 0-
10) at the baseline time point from the post dose intensity score (baseline score – post-baseline 
score). A positive difference is indicative of improvement. Summed Pain Intensity Difference 
will be calculated as follows:  
ሺ2ሻ  ܵܲܫܦ0 െ12
ൌ෍ሺ݂଴
ଵଶ
௜ୀ଴.ହ
െ݂௜ሻሺݐ௜െݐ௜ିଵሻ 
Where fi is the NRS score at post-baseline time i, f0 represents the baseline NRS score, and 
(ti –ti-1) represents the duration in hours since the last timepoint, with t0 representing the 
baseline timepoint.  
 
The SPID0-12 as defined in equation (2) above, will be analyzed using an ANCOVA 
model similar to the primary analysis. The estimated treatment difference between the two 
treatment groups will be presented together with the two-sided 95% confidence interval for 
the difference and the p-value.  
8.2.2. SPID over 0-6 hours (SPID0-6) 
 
Summed Pain Intensity Difference from 0-6 hours will be calculated as follows:  
ሺ3ሻ  ܵܲܫܦ0 െ6
ൌ෍ሺ݂଴
଺
௜ୀ଴.ହ
െ݂௜ሻሺݐ௜െݐ௜ିଵሻ 
Where fi is the NRS score at post-baseline time i, f0 represents the baseline NRS score, 
and(ti –ti-1) represents the duration in hours since the last timepoint, with t0 representing the 
baseline timepoint.  
The SPID0-6 as defined in equation (3) above, will be analyzed using an ANCOVA model 
similar to the primary analysis. The estimated treatment difference between the two 
treatment groups will be presented together with the two-sided 95% confidence interval for 
the difference and the p-value.  
8.2.3. SPID 6-12 hours (SPID6-12) 
 
Summed Pain Intensity Difference from 6-12 hours will be calculated as follows:  
ሺ4ሻ  ܵܲܫܦ6 െ12
ൌ෍ሺ݂଴
ଵଶ
௜ୀ଺
െ݂௜ሻሺݐ௜െݐ௜ିଵሻ 
Where fi is the NRS score at post-baseline time i, f0 represents the baseline NRS score, 
and(ti –ti-1) represents the duration in hours since the last timepoint, with t0 representing the 
baseline timepoint.  


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The SPID6-12 as defined in equation (3) above, will be analyzed using an ANCOVA 
model similar to the primary analysis. The estimated treatment difference between the two 
treatment groups will be presented together with the two-sided 95% confidence interval for 
the difference and the p-value.  
8.2.4. TOTPAR over 0-6 hours (TOTPAR0-6) 
 
Total Pain Relief Scores from 0-6 hours will be calculated as follows: 
ሺ5ሻ  ܱܶܶܲܣܴ0 െ6
ൌ෍݂௜
଺
௜ୀ଴.ହ
ሺݐ௜െݐ௜ିଵሻ 
 
Where fi is the pain relief score at post-baseline time i, and (ti –ti-1) represents the duration 
since the last timepoint, with t0 representing the baseline timepoint.  
The TOTPAR0-6 as defined in equation (5) above, will be analyzed using an ANCOVA 
model similar to the primary analysis.. The estimated treatment difference between the two 
treatment groups will be presented together with the two-sided 95% confidence interval for 
the difference and the p-value.  
8.2.5. TOTPAR 6-12 hours (TOTPAR6-12) 
 
Total Pain Relief Scores from 6-12 hours will be calculated as follows: 
ሺ6ሻ  ܱܶܶܲܣܴ6 െ12
ൌ෍݂௜
ଵଶ
௜ୀ଺
ሺݐ௜െݐ௜ିଵሻ 
Where fi is the pain relief score at post-baseline time i, and (ti –ti-1) represents the duration 
since the last timepoint, with t0 representing the baseline timepoint.  
The TOTPAR6-12 as defined in equation (6) above, will be analyzed using an ANCOVA 
model similar to the primary analysis. The estimated treatment difference between the two 
treatment groups will be presented together with the two-sided 95% confidence interval for 
the difference and the p-value.  
8.2.6. Time to First Intake of Rescue Medication 
 
The time to first intake of rescue medication is calculated as the number of hours between 
the time of first dose of study medication and the time of rescue medication. Patients who 
take rescue medication in the first 2 hours will be assessed for ITT analysis set only. If a 
patient does not take a rescue medication during the treatment period, she will be censored 
at the time of last assessment.  Patients who take rescue medication prior to IMP will be 
considered a “failure” at the time of IMP dose. 
 


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Kaplan-Meier (KM) estimates of rescue medication use and their 95% CIs will be 
presented at each post-dose timepoint by treatment group. The log-rank test will be used to 
test the difference in KM curves between the two treatments, with p-values presented. The 
median time to first intake of rescue medication and 95% CI for each treatment group will 
also be summarized. The plots will be based on hours to rescue medication. Pain Intensity 
Difference (PID) Scores at Each Evaluation 
 
Pain Intensity Difference (PID) scores will be evaluated at each post-dose timepoint. Pain 
Intensity Difference scores will be summarized descriptively by treatment group and plotted 
over time.  
 
8.2.7. Pain Relief Scores at Each Evaluation 
 
Pain Relief scores will also be evaluated at each post-dose timepoint. Pain Relief scores 
will be summarized numerically and categorically by treatment group; scores will also be 
plotted over time. 
 
8.2.8. Global Evaluation at 12 Hours Post-Dose or Immediately Before First 
Intake of Rescue Medication 
 
The Global Evaluation is a question that rates the IMP as a pain reliever either at 12 hours 
post-dose or immediately at the first intake of rescue medication.  
 
Overall, I would rate the effectiveness of this study medication in relieving my menstrual 
cramp pain as…  
• 0 = poor  
• 1 = fair  
• 2 = good  
• 3 = very good  
• 4 = excellent 
 
Results for this variable will be summarized descriptively and analyzed using the Cochran-
Mantel-Haenszel (CMH) method with modified ridit scores. P-values will be displayed. 
Example SAS code for the this analysis  
PROC FREQ DATA=DATA1;  
TABLES TRTA*GESCORE/CMH SCORES=MODRIDIT;  
RUN; 
 
 
 
 


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9. Safety Analysis 
 
Safety parameters include monitoring of TEAEs, physical examination findings, vital sign 
measurements, and laboratory examinations. All safety summaries and analyses will be 
summarized by actual treatment group within the Safety set. 
 
9.1. Adverse Events 
All AEs that occur during the study will be recorded and classified on the basis of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology version 20.1. Treatment-
emergent AEs (TEAEs) are defined as AEs with an onset on or after the date of the first 
IMP dose. Adverse events noted prior to the first IMP administration that worsen after 
baseline will also be reported as TEAEs and included in the summaries 
All information pertaining to an AE noted during the study will be listed by subject, 
detailing verbatim term, preferred term, system organ class (SOC), onset date, resolution 
date, intensity, seriousness, action taken, outcome, drug relatedness, and relatedness to 
protocol-required procedures. The event onset will also be shown relative to IMP initiation 
(in number of days). Listings will be provided for all TEAEs. 
TEAEs will be presented on the Safety set and displayed by treatment period and group 
unless noted. 
9.1.1. Incidence of TEAEs 
Adverse events will be deemed treatment emergent if the onset date is on or after the date 
of first treatment, Day 1 in each period. Events with onset date during the screening period 
are not collected for this study. An overall summary of incidence of TEAEs (patient/event 
counts) including drug relation, serious adverse events (SAE), TEAEs leading to drug 
discontinuation and fatal AEs will be presented.  
The number and percentage of patients with at least one TEAE and the number of events 
overall will be presented by SOC and PT. 


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9.1.2. Relationship of Adverse Events to IMP 
A summary of TEAEs by relationship to IMP will be presented in a table by total number 
of TEAE and incidence of occurrence. The investigator will provide an assessment of the 
relationship of the event to the IMP as Related or Not Related. If a subject reports multiple 
occurrences of the same TEAE, only the most closely related occurrence will be presented 
in the incidence count. Treatment-emergent AEs that are missing a relationship will be 
presented in the summary table as “Related” but will be presented in the data listing with a 
missing relationship. Percentages will be calculated based on the number of patients in the 
safety set. 
The TEAE data will be categorized and presented by SOC, PT, and relationship in a 
manner similar to that described in Section 9.1.1. 
9.1.3. Intensity of Adverse Event 
A summary of TEAEs by intensity will be presented in a table by total number of TEAE 
and incidence of occurrence. The intensity that will be presented represents the most 
extreme intensity captured on the eCRF page. The possible intensities are “Mild,” 
“Moderate,” and “Severe.” In the TEAE intensity table, if a subject reported multiple 
occurrences of the same TEAE, only the most severe will be presented in the incidence 
count. Treatment-emergent AEs that are missing intensity will be presented in tables as 
“Severe” but will be presented in the data listing with a missing intensity. Percentages will 
be calculated based on the number of patients in the safety set.  
The TEAE data will be categorized and presented by SOC, PT, and intensity in a manner 
similar to that described in Section 9.1.1. 
9.1.4. Serious Adverse Events 
The treatment-emergent SAE data will be categorized and presented by SOC and PT in a 
manner similar to that described in Section 9.1.1. At each level of subject summarization, a 
subject is counted once for the incidence if the subject reported one or more events. 


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9.1.5. Deaths, Adverse Events Leading to Treatment Discontinuation/Study 
Discontinuation 
A listing of all Serious TEAEs (including deaths) and/or AEs leading to treatment or study 
discontinuation will be presented. Additionally, a separate listing of any deaths will be 
presented. Deaths and discontinuations will be assessed based on data recorded in the AE 
eCRF page. Subject deaths will be identified as AEs where the outcome is “Fatal”. 
Adverse events leading to treatment discontinuation will be identified as AEs where the 
action taken with IMP is “Drug Withdrawn”. Adverse events leading to study 
discontinuation will be identified as AEs where the caused study discontinuation field is 
marked as “Yes”. 
9.2. Clinical Laboratory Evaluations 
9.2.1. Urine Drug Screen 
 
A screen for drugs of abuse will be performed at Screening (Visit 1) and Visit 2. A by-
patient list of urine drug screen will be presented. Patients will be tested for the following 
drugs: Methamphetamines, Amphetamines, cannabinoids, cocaine, opiates, 
benzodiazepines, barbiturates, Methylenedioxymethamphetamine, methadone, Oxycodone, 
Adulterants. 
 
9.2.2. Urine Pregnancy Test 
 
At screening, and prior to dosing all patients must perform a urine pregnancy test and verify 
that the results are negative (not pregnant). Any patient who has a positive pregnancy test or is 
not sure of the results must contact the study center immediately. Patients with a verified 
positive pregnancy test will be withdrawn from the study. Pregnancy test results will be listed 
by patient. 
 


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9.3. Vital Sign Measurements 
 
The vital sign summary and analysis will be based on the recordings of the variables blood 
pressure (systolic and diastolic [mm Hg]), oral body temperature (F), heart rate 
(beats/min), and respiratory rate (breaths/min). Notable abnormal values will be flagged in 
the data listings. The conversion between conventional unit to SI unit for temperature and 
weight and definitions for notable abnormal values are listed in the appendix (Section 
12.1Error! Reference source not found., Table 1). Observed values at Screening and 
Visits 1 and 2 and change from Baseline values to Visits 1 and 2 for vital sign 
measurements will be summarized descriptively by treatment group. 
 
All summaries will be done for the Safety set and all vital sign data will be listed. 
 
9.4. Physical Examination 
 
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician at the study site covering at least the organs of the cardiovascular, respiratory, 
and abdominal system.  
 
Abnormal physical examination findings are recorded either as medical history or as adverse 
events. Physical examination results will be listed. 
 
10. Interim Analysis 
 
There is no interim analysis scheduled for this study.  
 
11. References 
 
Kenward MG, Roger JH. The use of baseline covariates in crossover studies. Biostatistics, 
Jan 2010; 1-17. 
 
Choi K, Hong T, Lee J. On comparison of SAS Codes with GLM and MIXED for the 
crossover studies with QT interval data. Transl Clin Pharamcol, 2014; 78-82. 
 
Yarandi, HN. Paper SD04 – Crossover Designs and Proc Mixed in SAS. 
http://analytics.ncsu.edu/sesug/2004/SD04-Yarandi.pdf


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12. Appendices 
12.1. Notable Abnormal Vital Signs  
Table 1 
Notable Abnormal Vital Signs 
Parameter 
Actual Value 
Change from Baseline 
Pulse 
< 40 bpm 
> 120 bpm 
>= 15 bpm increase from baseline 
>= 15 bpm decrease from baseline 
Systolic blood 
pressure 
< 80 mmHg 
> 180 mmHg 
>= 20 mmHg increase from baseline 
>= 20 mmHg decrease from baseline 
Diastolic blood 
pressure 
< 50 mmHg 
> 105 mmHg 
>= 15 mmHg increase from baseline 
>= 15 mmHg decrease from baseline 
Temperature 
NA 
>= 2 F increase from baseline 
>= 2 F decrease from baseline 
12.2. Table of Contents: Summary Tables, Listings and Figures 
 
Type 
 Table 
Number 
TLF Title 
Table 
14.1-1 
Summary of Patient Disposition All Patients 
Table 
14.1-2 
Summary of Analysis Sets All Randomized Patients 
Table 
14.1-3 
Summary of Exclusions from Per-Protocol Set All Randomized Patients 
Table 
14.1-4.1 
Summary of Demographics and Baseline Characteristics Intent-to-Treat 
Table 
14.1-4.2 
Summary of Demographics and Baseline Characteristics Per-Protocol 
Table 
14.1-4.3 
Summary of Demographics and Baseline Characteristics Safety Set 
Table 
14.1-5 
Summary of Medical History Safety Set 
Table 
14.1-6 
Summary of History of Substance Use  Safety Set 
Table 
14.1-7 
Summary of Prior Medications  Safety Set 
Table 
14.2-1.1 
Summary of Analysis of Sum of Total Pain Relief over 0-12 hours (TOTPAR0-12) Per-
Protocol 


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Table 
14.2-1.2 
Summary of Analysis of Sum of Total Pain Relief over 0-12 hours (TOTPAR0-12) 
Intent-to-Treat 
Table 
14.2-2.1 
Summary of Analysis of Summed Pain Intensity Difference over the 12-hour study 
period (SPID0-12) Per-Protocol 
Table 
14.2-2.2 
Summary of Analysis of Summed Pain Intensity Difference over the 12-hour study 
period (SPID0-12) Intent-to-Treat 
Table 
14.2-3.1 
Summary of Analysis of Summed Pain Intensity Difference over 0-6 hours (SPID0-6) 
Per-Protocol  
Table 
14.2-3.2 
Summary of Analysis of Summed Pain Intensity Difference over 0-6 hours (SPID0-6) 
Intent-to-Treat 
Table 
14.2-4.1 
Summary of Analysis of Summed Pain Intensity Difference over 6-12 hours (SPID6-12) 
Per-Protocol  
Table 
14.2-4.2 
Summary of Analysis of Summed Pain Intensity Difference over 6-12 hours(SPID6-12)  
Intent-to-Treat 
Table 
14.2-5.1 
Summary of Analysis of Sum of Total Pain Relief over 0-6 hours (TOTPAR0-6) Per-
Protocol 
Table 
14.2-5.2 
Summary of Analysis of Sum of Total Pain Relief over 0-6 hours (TOTPAR0-6) Intent-
to-Treat 
Table 
14.2-6.1 
Summary of Analysis of Sum of Total Pain Relief over 6-12 hours (TOTPAR6-12) Per-
Protocol 
Table 
14.2-6.2 
Summary of Analysis of Sum of Total Pain Relief over 6-12 hours (TOTPAR6-12) 
Intent-to-Treat 
Table 
14.2-7.1 
Summary of Analysis of Time (Hours) to First Intake of Rescue Medication Per-
Protocol 
Table 
14.2-7.2 
Summary of Analysis of Time (Hours) to First Intake of Rescue Medication Intent-to-
Treat 
Table 
14.2-8.1 
Summary of Pain Intensity Difference Scores by Evaluation Timepoint Per-Protocol 
Table 
14.2-8.2 
Summary of Pain Intensity Difference Scores by Evaluation Timepoint Intent-to-Treat 
Table 
14.2-9.1 
Summary of Pain Relief Scores by Evaluation Timepoint Per-Protocol 
Table 
14.2-9.2 
Summary of Pain Relief Scores by Evaluation Timepoint Intent-to-Treat 
Table 
14.2-10.1 
Summary of Global Evaluation Scores Per-Protocol 


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Table 
14.2-10.2 
Summary of Global Evaluation Scores Intent-to-Treat 
Table 
14.3-1 
Summary of Treatment Exposure and Compliance Safety Set 
Table 
14.3-2 
Summary of Treatment Exposure and Compliance Intent-to-Treat 
Table 
14.3-3 
Summary of Concomitant Medications Safety Set 
Table 
14.3-4 
Summary of Change from Baseline in Vital Signs Safety Set 
Table 
14.3.1-1 
Overall Summary of Treatment Emergent Adverse Events Safety Set 
Table 
14.3.1-2 
Summary of Frequent Treatment Emergent Adverse Events with 2% or Greater 
Incidence Safety Set 
Table 
14.3.1-3 
Summary of Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term Safety Set 
Table 
14.3.1-4 
Summary of Treatment Emergent Adverse Events by Intensity, System Organ Class and 
Preferred Term Safety Set 
Table 
14.3.1-5 
Summary of Treatment Emergent Adverse Events by Relationship to IMP, System Organ 
Class and Preferred Term Safety Set 
Table 
14.3.1-6 
Summary of Serious Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term Safety Set 
Listing 
16.1-7 
Listing of Randomized Allocation to Treatment All Randomized Patients 
Listing 
16.2-1.1 
Listing of Study Completion All Patients 
Listing 
16.2-2.1 
Listing of Protocol Deviations All Randomized Patients 
Listing 
16.2-2.2 
Listing of Patient Populations and Reasons Excluded from Analysis Sets All Randomized 
Patients 
Listing 
16.2-4.1 
Listing of Demographics and Baseline Characteristics Safety Set 
Listing 
16.2-4.2 
Listing of Inclusion and Exclusion Criteria All Patients 
Listing 
16.2-4.3 
Listing of Prior and Concomitant Medications Safety Set 
Listing 
16.2-4.4 
Listing of Medical History Safety Set 
Listing 
16.2-5.1 
Listing of IMP Administration Patient Diary  Safety Set 
Listing 
16.2-5.2 
Listing of Rescue Medication Administration  Safety Set 
Listing 
16.2-5.3 
Listing of Treatment Review  Safety Set 
Listing 
16.2-7.1 
Listing of Treatment-Emergent Adverse Events Safety Set 
Listing 
16.2-7.2 
Listing of Serious Adverse Events Safety Set 
Listing 
16.2-7.3 
Listing of Adverse Events Leading to Treatment or Study Discontinuation Safety Set 


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Listing 
16.2-7.4 
Listing of Deaths Safety Set 
Listing 
16.2-8.1 
Listing of Laboratory Results - Urine Drug Screen Safety Set 
Listing 
16.2-8.2 
Listing of Laboratory Results - Pregnancy Testing Results Safety Set 
Listing 
16.2-8.3 
Listing of Physical Exam Results at Screening Safety Set 
Listing 
16.2-9.1 
Listing of Vital Sign Results Safety Set 
Listing 
16.2-10.1 
Listing of Time to Rescue Medication Safety Set 
Listing 
16.2-10.2 
Listing of NRS and PID Scores Safety Set 
Listing 
16.2-10.3 
Listing of Pain Relief Scores Safety Set 
Listing 
16.2-10.4 
Listing of Global Evaluation Scores Safety Set 
Figure 
14.2-1.1 
Kaplan-Meier Plot of Time to Rescue Medication by Treatment Per-Protocol 
Figure 
14.2-1.2 
Kaplan-Meier Plot of Time to Rescue Medication by Treatment Intent-to-Treat 
Figure 
14.2-2.1 
Line Graph of Average Pain Relief Scores over Time by Treatment Per-Protocol 
Figure 
14.2-2.2 
Line Graph of Average Pain Relief Scores over Time by Treatment Intent-to-Treat 
Figure 
14.2-3.1 
Line Graph of Average NRS Scores over Time by Treatment Per-Protocol 
Figure 
14.2-3.2 
Line Graph of Average NRS Scores over Time by Treatment Intent-to-Treat 
Figure 
14.2-4.1 
Line Graph of Average Pain Intensity Difference Scores over Time by Treatment Per-
Protocol 
Figure 
14.2-4.2 
Line Graph of Average Pain Intensity Difference Scores over Time by Treatment Intent-
to-Treat 
 
 
 
 


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12.3. 
Schedule of Study Procedures