A Single Center Randomized Open-Label Two Arm Crossover Study of Subject Productivity Improvement and Satisfaction With Migraine Treatment Using Treximet vs Usual Triptan
Phase: PHASE4
Conditions: Workplace Migraine Treatment
Sponsor: The Cleveland Clinic

 
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Jennifer Kriegler, MD 
Professor of Medicine (Neurology) 
Cleveland Clinic Lerner College of Medicine 
 
Center for Neurological Restoration 
Cleveland Clinic, Neurological Institute C21 
9500 Euclid Ave 
Cleveland, OH 44195 
Ph 216-444-8265 
Fax 216-445-1696 
krieglj@ccf.org 
 
1 
SUMMARY 
 
1.1 
TITLE 
 
A Single Center, Randomized, Open-Label, Two Arm, Crossover, Study of 
Subject Productivity Improvement and Satisfaction with Migraine Treatment 
Using Treximet™ vs Usual Triptan. “Does Treximet™ Improve Productivity and 
Patient Satisfaction Due to Sustained Response and Consistency of Response?” 
V 08-26-15  
 
1.2 
RATIONALE 
 
The finding that triptan + Nonsteroidal Anti-inflammatory (NSAID) as a 
combination in the acute treatment of migraine is superior to either of the 
medications alone suggests that there should be pharmcoeconomic 
consequences to appropriate combination treatment. In addition, patient 
satisfaction should correlate to more effective treatment. Accordingly, we have 
sought and received a grant to evaluate work productivity, patient satisfaction, 
and effectiveness of treatment in comparing sumatriptan + naproxen sodium to 
triptan monotherapy in patients in the work place.  
 
 
2 
OBJECTIVES 
 
Specific Aim 1: To compare work productivity as measured by the Work 
Productivity Assessment Instrument (WPAI) after each of the 3 attacks treated 
with usual triptan monotherapy to each of the 3 attacks treated with Treximet. 
 
Specific Aim 2: After 3 attacks treated with usual triptan monotherapy, and after 
3 attacks treated with Treximet, to compare the Completeness of Response 
Survey (CORS), which will be collected and tabulated. 
 

 
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Specific Aim 3: To compare Migraine-ACT after usual triptan monotherapy, and 
Migraine-ACT after Treximet. Migraine-ACT is a validated patient-derived 
instrument for measuring effectiveness of acute treatment, and is particularly 
suited to evaluating this hypothesis because of its items on consistency of 
response, comfort level with treatment for planning activities, and functional 
evaluation: 
 Consistency of response: Does your migraine medication work consistently, 
in the majority of your attacks? 
 Global assessment of relief: Does the headache pain disappear within 2 
hours? 
 Impact: Are you able to function normally within 2 hours? 
 Emotional response: Are you comfortable enough with your medication to be 
able to plan your daily activities? 
 
Specific Aim 4: To determine if there is an interaction between medication 
(usual triptan vs Treximet) and patient reported pain at time of dose with respect 
to workplace productivity as measured by the WPAI — is one medication more 
effective at improving workplace productivity when migraines are more severe at 
time of dose?  
 
Specific Aim 5: To compare various self-reported aspects of patient health 
acquired in the Knowledge Program (KP) after 3 treatments with usual triptan 
and 3 treatments with Treximet. 
 
3 
INVESTIGATIONAL PLAN 
 
3.1 
SUMMARY OF STUDY DESIGN 
This is a single site, randomized, open-label, two arm, crossover, study of subject 
productivity improvement and satisfaction with migraine treatment using 
Treximet™ vs usual triptan. 
This study will recruit 60 patients who are employed in a paying job, who have 
episodic migraine (<15 days/month), who are using acute care triptan 
monotherapy for their migraine (excluding combinations of any sort, such as 
acetaminophen [APAP] and non-steroidals [NSAIDs]) and who have no 
contraindications to triptan or NSAID use.  
In one arm of the study, patients will treat 3 work day migraines with their usual 
triptan and in the other arm of the study the same patients will treat 3 work day 
migraines with Treximet. The medication that they use in the first arm of the 
study is determined by randomization. They will maintain headache diaries for 
the duration of the study and fill out the WPAI after each work day migraine. After 
treating 3 work day migraines, they will also fill out CORS Part 1 and Migraine-
ACT.  

 
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Between the completion of the 3rd migraine attack treatment, and the start of the 
second treatment arm, there will be a minimum of a 48 hour washout period and 
an office visit. 
In the second arm, after cross over to the other treatment, the sixty patients will 
maintain headache diaries, treat 3 attacks during any day in which they are 
scheduled to work, and fill out the WPAI after each attack. Additionally, after 3 
attacks are treated, they will fill out CORS Part 1, CORS Part 2 and Migraine-
ACT. This second arm differs from arm one in that the subjects will treat their 
migraines with the other medication from that assigned in the first arm. 
Subject participation will last approximately 3 months, depending on the days 
needed to treat migraines during the workday according to protocol. 
4. 
SUBJECT SELECTION 
 
4.1 
NUMBER OF SUBJECTS 
 
This study will enroll 60 subjects for participation. There are no other sites for this 
study. 
 
The sample size was chosen to be a sufficient number to assess the effect of 
Treximet on the WPAI using a crossover design in which patients will serve as 
their own controls. 
 
Based on previous GSK studies on Treximet utilizing the WPAI, the effect size 
between Treximet and usual triptan care is expected to be small. In those studies, 
comparisons of Treximet to placebo yielded differences of 0.4 to 1.4. For this 
study, a one-point WPAI difference between Treximet and triptan is assumed to 
be clinically meaningful. Furthermore, the GSK Treximet studies were parallel 
designs with standard deviations ranging from 2.5 to 3.5. To account for the 
correlation from patients acting as their own controls in this crossover design, a 
standard deviation of the difference equal to 2.5 is assumed. Under these 
assumptions, a total sample of 60, with 30 in each sequence, would power the 
study at 86%. 
 
4.2 
INCLUSION CRITERIA:  
A subject will be eligible to participate in this study if all of the following criteria 
apply: 
1. subject is 18 years or older at screening 
2. subject has a history of migraine greater than 1 year  
3. subject has been diagnosed with migraine before age 50 
4. subject is an employed person (is paid wages for his/her work) 

 
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5. subject has diagnosis of episodic migraine, by IHS criteria 
6. subject uses triptan monotherapy as the primary migraine abortive 
treatment 
7. subject is not pregnant or nursing 
 
4.3 
EXCLUSION CRITERIA: 
A subject will not be eligible to participate in this study if any of the following 
criteria apply: 
1. subject is less than 18 years of age at screening 
2. subject does not have history of migraine greater than 1 year 
3. subject was diagnosed with migraine after age 50 
4. subject is not currently employed 
5. subject does not have diagnosis of episodic migraine 
6. subject does not use triptan monotherapy as primary migraine abortive 
treatment 
7. subject is pregnant or nursing 
 
8. subjects with a history of stroke, myocardial infarction (including 
vasospastic coronary artery disease [CAD]or cardiovascular thrombotic 
events 
9. subjects with gastrointestinal disease history to include ulcers, bleeding or 
perforations of the stomach or intestines 
10. subjects with a history of significant renal or hepatic disease. 
11. subjects with a history of significant ischemic cardiac symptoms (to 
include angina pectoris of any type; silent myocardial ischemia: 
cerebrovascular disease ( including any type of stroke, transient ischemic 
attack), or peripheral vascular disease; such as ischemic bowel disease; 
coronary artery bypass graft surgery 
12. subjects with uncontrolled hypertension 
13. subjects with use of monoamine oxidase-A inhibitors 
14. subjects with current use of ergotamine-containing or ergot-type 
medications, like DHE 
15. subjects using 5-HT agonists 
16. subjects with diagnosis of basilar or hemiplegic migraines 
17. subjects with allergy to naproxen 
18. subjects who are allergic to aspirin or NSAIDS where such allergies 
induce syndrome of asthma, nasal polyps, urticaria and hypotension 
4.4 
RANDOMIZATION 
Quantitative Health Sciences has designed a randomization scheme which will 
be used to make the treatment assignments for the study subjects. This 
randomization plan is included in the appendix as 11.7. 

 
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5 
STUDY DOSAGE/DOSAGE REGIMEN 
 
5.1 
INITIAL TREATMENT 
Subjects will take a single dose of Treximet™ (1 tablet, which is 85mg of 
sumatriptan and 500mg of naproxen sodium) at headache onset, or Usual 
Triptan (at regular prescribed dose) to treat each of 3 migraines occurring during 
the work day.  
 
5.2 
RESCUE TREATMENT 
At 2 hours post-dose, if the subject has headache pain such that additional 
treatment is desired, subjects treating with their Usual Triptan will be permitted to 
take a second dose of their Usual Triptan, or their usual care rescue medication 
( however, no NSAIDS or other triptans would be permitted as a rescue 
treatment). For subjects treating with Treximet™, who have headache pain such 
that additional treatment is desired at 2 hours post dose, subjects may treat with 
a second Treximet™tablet or their usual care rescue medication (however, no 
NDAIDS or other triptans would be permitted as a rescue treatment). Subjects in 
both treatment arms may, at 24 hours post initial dose, take a second dose tablet, 
(if a second dose [usual triptan or Treximet™tablet] has not already been 
taken),when headache pain continues to require treatment. No more than 2 
Treximet™ tablets are permitted to treat one migraine. 
 
5.3 
STUDY DRUG SUPPLY 
 
For the treatment period when the subjects are taking Treximet™, they will be 
dispensed a study drug bottle containing 3 Treximet™ tablets for initial dosing (1 
tablet dose) of 3 migraines during the work day. 
 
5.3.1 Treatment Assignment will be made according to the randomization 
schedule created by Quantitative Health Sciences at Cleveland Clinic. 
 
5.3.2 Treatment will be open label. 
 
5.3.3 For study product accountability, subjects will have documented 
dispensation of study product and will return study drug containers at the office 
visit following the Treximet™ treatment arm completion.  
 
5.3.4 Subjects will record treatment use in study diaries for the treated migraine 
attacks. 
 
6 
STUDY ASSESSMENTS 
 
The Study Flowsheet (time and events table) provided below lists the study 
activities throughout the protocol.  
 
STUDY FLOW CHART 
 
 
 
Washo
 
 

 
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Screen 
(Office 
Visit) 
First Arm 
(Treximet™ or Usual 
Triptan) 
- Treat 3 Migraines 
ut 
Windo
w 
(at 
least 
48h 
post V4 
tx) 
(Office 
Visit) 
Second Arm 
(Treximet™ or Usual 
Triptan) 
- Treat 3 Migraines 
 
 
 
EOS 
(Office 
Visit) 
Procedure 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 9 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusio
n 
X 
 
 
 
 
 
 
 
 
Office Visit (PE, 
Vitals Neuro 
Exam) 
 
X 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy 
Test (if female and 
childbearing 
potential) 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Conmeds 
X 
 
 
 
X 
 
 
 
X 
AE/SAE collect 
 
 
 
 
X 
 
 
 
X 
Migraine History & 
update 
X 
 
 
 
X 
 
 
 
 
Medical History- & 
update 
X 
 
 
 
X 
 
 
 
X 
Educ/Disp/Revu 
Diary 
X 
X 
X 
X 
Collect 
x 
x 
x 
Collect 
 
Randomization 
 
X 
 
 
 
Switch 
TX Arm 
 
 
 
 
Disp/Take/Collect 
Study Drug 
 
X 
 
X 
 
X 
 
X 
 
Collect 
 
X 
 
X 
 
X 
 
Collect 
WPAI 
 
X 
X 
X 
Collect 
X 
X 
X 
Collect 
CORS 1 
 
 
 
X 
Collect 
 
 
X 
Collect 
CORS 2 
 
 
 
 
 
 
 
X 
Collect 
MigraineAct 
X 
 
 
X 
Collect 
 
 
X 
Collect 
KP Data 
X 
 
 
 
X 
 
 
 
X 
 
6.1 
EFFICACY 
 
Efficacy comparisons of Treximet™ vs Usual Triptan treatment will be collected 
using the CORS 1, CORS 2, WPAI and Migraine-Act assessment tools. Pain 
level at time of dose is captured as part of the Study Diary. 
 
6.2 
SAFETY 
 
Adverse events will be collected via subject report on study diaries and at office 
visits during the physician assessments and noted in the electronic medical 
record. Adverse events will be noted from the date of the first study visit until the 
end of study visit has been completed. 

 
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Serious Adverse Events will be reported to the Cleveland Clinic Office of the IRB, 
to Pernix Therapeutics and the FDA, in accordance with IRB policy. Medical 
details of these Serious Adverse Events will be noted in the electronic medical 
record. 
 
7 
DATA MANAGEMENT 
 
Study data points will be collected on the questionnaires and diaries completed 
by the subjects. These data will be provided to QHS for statistical analysis and to 
Pernix Therapeutics for their review and analysis. 
 
8 
DATA ANALYSIS 
 
8.1 
HYPOTHESIS 
 
Treximet™, because of its multiple mechanisms of action and resultant synergy 
of effects, should be more effective than usual care in improving productivity, 
reducing migraine impact, and providing patients with optimal treatment upon 
which they can rely, the latter specifically because of Treximet™’s consistency of 
response and high pain free and sustained relief efficacy. 
 
8.2 
DESIGN AND DATA ANALYSIS CONSIDERATIONS 
For the crossover design, there is a special need to identify if a carryover effect 
exists. For the primary outcome, WPAI score after last attack, the mean 
sequence sums will be compared with a 2-sample t-test (see Toutenburg in 
references pp. 344-346). If no significance is found, then the assumption will be 
that there is no carryover effect and treatment differences will be evaluated 
through a mixed model analysis. The model will include trial period, sequence 
(usual triptan f/b Treximet or Treximet f/b usual triptan) and treatment as fixed 
effects. If carryover does exist, then only the first trial period results will be used 
and a 2-sample t-test will be conducted to look for treatment differences. A 
sensitivity analysis will be performed in which WPAI scores from all 3 attacks will 
be included in the model.A second model will be created with the inclusion of an 
interaction term between treatment and pain level at time of dose.   
Lost Workplace Productivity and Non-Work Activity Time - WPAI analysis 
 
Subjects are to record the number of hours they miss from work due to migraine 
symptoms (WM), the number of hours they miss from routine activities outside of 
paid work due to migraine symptoms (RAM), the number of hours they continue 
to work while having migraine symptoms (WS), the number of hours they 
continue routine activities while having migraine symptoms (RAS), and how 
effective they are while continuing routine activities while having migraine 
symptoms (RAE). Lost workplace productivity (LWP) and lost activity time (LAT) 

 
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will be calculated as follows. The overall lost workplace productivity and activity 
time for the attack will be the sum of the two measures (LWP + LAT) where 
 
 
 
LWP = WM + (WS x [(100% - WE/100%]) 
 
 
 
LAT = (RAM + (RAS x [(100% - RAE)/100%])) 
 
If the subject has indicated that work was not scheduled on a given diary, the 
LWP for that diary day will be 0 regardless of what information may have been 
filled out on the diary regarding WM, WS, or WE. 
For the secondary outcome Migraine-ACT, a binary outcome will be calculated 
(e.g. 0=if Migraine-ACT is not favorable, 1=if Migraine-ACT is favorable) and 
used to identify carryover. [Note: A favorable response in Migraine-ACT is a 
value of 3 or 4.] The odds of a favorable triptan f/b Treximet sequence will be 
compared to the odds of a favorable Treximet f/b triptan sequence through an 
odds ratio, which will be evaluated with a chi-square test (see Toutenburg1 p. 
369). If no significance is found, then the assumption will be that there is no 
carryover effect. That assumption will be applied when analyzing both the binary 
and ordinal (levels > 2) values of Migraine-ACT. Treatment differences will be 
evaluated through a generalized estimating equation with a logit link function (or 
cumulative logit link function). The models will include trial period, sequence, and 
treatment as fixed effects. If carryover does exist, then only first trial period 
results will be used. In that case, treatment differences will be evaluated through 
a chi-squared test for binary outcomes and through a Mann-Whitney U-test for 
ordinal outcomes (levels > 2).  
All tests for significance will be conducted at the 95% confidence level (i.e. α 
= .05). Analysis will be conducted in SAS® v9.2. 
CORS data will be tabulated as follows: For CORS part 1, a frequency count and 
percent by question answer will be provided. This will be reported by treatment 
(Treximet™ vs triptan) within period and in total. For CORS part 2, a frequency 
count and percent will be provided by answer for each question. In addition, a de-
identified data set containing CORS information will be provided to Pernix 
Therapeutics for additional psychometric analysis. 
9 
STUDY CONDUCT CONSIDERATIONS 
 
The clinical research will be performed according to current Cleveland Clinic IRB 
Policy regarding Good Clinical Practices. The study principal investigator will 
oversee the performance of this study and is up to date and certified with CITI. 
 
10 
STUDY REFERENCES 
 

 
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Brandes JL, Kudrow D, Stark SR, O'Carroll CP, Adelman JU, O'Donnell FJ, 
Alexander WJ, Spruill SE, Barrett PS, Lener SE. Sumatriptan-naproxen for acute 
treatment of migraine: a randomized trial. JAMA. 2007 Apr 4;297(13):1443-54. 
 
Cleves C, Tepper SJ. Sumatriptan/naproxen sodium combination for the 
treatment of migraine. Expert Rev Neurother. 2008 Sep;8(9):1289-97. 
Dowson AJ, et al. Identifying patients who require a change in their current acute 
migraine treatment: the Migraine Assessment of Current Therapy (Migraine-ACT) 
questionnaire. Current Medical Research and Opinion 2004;20:1125-35. 
Dowson AJ, et al. Identifying patients who require a change in their current acute 
migraine treatment: the Migraine Assessment of Current Therapy (Migraine-ACT) 
Questionnaire. Headache Care 2005;2:5-10. 
Mathew NT, Landy S, Stark S, Tietjen GE, Derosier FJ, White J, Lener SE, 
Bukenya D. Fixed-dose sumatriptan and naproxen in poor responders to triptans 
with a short half-life. Headache. 2009 Jul;49(7):971-82.  
Tepper SJ, et al. The Migraine Assessment of Current Therapy (Migraine-ACT) 
Questionnaire: Further Investigation of Study Results. Headache Care 
2005;2:27-31. 
Toutenberg, Helge (2002). Statistical Analysis of Designed Experiments, 2nd 
edition, NY:Springer. 
 
 

 
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11 
APPENDICES 
 
11.1 WPAI 
11.2 CORS 1 
11.3 CORS 2 
11.4 MIGRAINE-ACT 
11.5 Study Diary 
11.6 Treximet™ Package Insert 
11.7  Randomization Table 
 

 
 
 
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11
APPENDIX II.I 
 
PRODUCTIVITY QUESTIONNAIRE  
 
Study ID # 
 
__________  
Date Completed 
___/___/___ 
 
 
Answer the following questions at bedtime of the day you treated your migraine 
attack with study medication. 
 
Were you scheduled to do paid work during this migraine attack?     [Y] □ Yes     [N] □ No 
 
If Yes, record the number of hours (to the nearest one-half hour) you  
were scheduled to do paid work during this migraine attack:         □□ . □  Hours 
 
Record details of how this migraine attack affected your work and non-work related activities 
in the table below: 
 
 
 
 
 
 
 
 
Activity 
 
 
Number of 
hours 
missed from 
doing 
activity due 
to migraine 
symptoms 
 
 
Zero = 00.0 
 
 
Number of 
hours 
continued to 
do activity 
with migraine 
symptoms 
 
 
 
Nine hours = 
9.0 
Estimate how effective 
you were, compared to 
your usual performance, 
while you continued to do 
activity with migraine 
symptoms  
 
If number of hours doing 
activity is 00.0, DO NOT 
COMPLETE. 
 
100% = effective as usual 
 
(%) 
1. Paid work activities. 
  Complete this row only if you  
  were scheduled to do paid 
work   
  during this attack. 
 
 
 
 
2. Activities outside your paid 
work. 
  (eg, leisure activities, 
household  
  chores/tasks, family/social  
  activities, etc.) 
 
 
 
 

 
 
 
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12
APPENDIX II.2 
 
CORS 1 
 

 
 
 
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13
APPENDIX II.3 
 
CORS 2 

 
 
 
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14
APPENDIX II.4 
 
MIGRAINE-ACT 
 
 
Migraine-ACT 
Question 
Yes 
No 
 
When you take your treatment: 
 
Does your migraine medication work consistently, in the 
majority of your attacks? 
 
 
 
 
When you take your treatment: 
 
Does the headache pain disappear within two hours? 
 
 
 
 
When you take your treatment: 
 
Are you able to function normally within two hours? 
 
 
 
 
When you take your treatment: 
 
Are you comfortable enough with your medication to be 
able to plan your daily activities? 
 
 
 
 
Migraine-ACT Score 
 
 
 
 

 
 
 
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15
APPENDIX II.5 
 
STUDY DIARY 
 
WEEK 1 
WEEK 2 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale of 0 
to 10  
(with 0 being absence of pain and 10 being worst 
possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale 
of 0 to 10  
(with 0 being absence of pain and 10 being 
worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale of 0 
to 10  
(with 0 being absence of pain and 10 being worst 
possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale 
of 0 to 10  
(with 0 being absence of pain and 10 being 
worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale of 0 
to 10  
(with 0 being absence of pain and 10 being worst 
possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale 
of 0 to 10  
(with 0 being absence of pain and 10 being 
worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale of 0 
to 10  
(with 0 being absence of pain and 10 being worst 
possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale 
of 0 to 10  
(with 0 being absence of pain and 10 being 
worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale of 0 
to 10  
(with 0 being absence of pain and 10 being worst 
possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale 
of 0 to 10  
(with 0 being absence of pain and 10 being 
worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 

 
 
 
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16
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale of 0 
to 10  
(with 0 being absence of pain and 10 being worst 
possible pain) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale 
of 0 to 10  
(with 0 being absence of pain and 10 being 
worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale of 0 
to 10  
(with 0 being absence of pain and 10 being worst 
possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle one) 
Headache today Y or N (please circle one) 
If YES: 
Time Headache Started: ________ AM/PM 
Time Headache Stopped: ________ AM/PM 
Pain Level at Dose Time = _________ Scale 
of 0 to 10  
(with 0 being absence of pain and 10 being 
worst possible pain) 
 

 
 
 
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17
 
WEEK 3 
WEEK 4 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
Date: ___/___/___   
Day M T W TH F S SU (please circle 

 
 
 
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18 
18
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 

 
 
 
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19
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
 

 
 
 
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20
 
WEEK 5 
WEEK 6 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
Date: ___/___/___   
Day M T W TH F S SU (please circle 

 
 
 
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21 
21
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 

 
 
 
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22
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
 

 
 
 
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23
 
 
WEEK 7 
WEEK 8 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Date: ___/___/___   

 
 
 
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24
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 
Date: ___/___/___   
Day M T W TH F S SU (please circle 
one) 
Headache today Y or N (please circle 
one) 

 
 
 
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25
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = _________ 
Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 
If YES: 
Time Headache Started: ________ 
AM/PM 
Time Headache Stopped: ________ 
AM/PM 
Pain Level at Dose Time = 
_________ Scale of 0 to 10  
(with 0 being absence of pain and 10 
being worst possible pain) 

 
 
 
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26
APPENDIX 11.6 
 
TREXIMET™ PACKAGE INSERT 

 
 
 
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27 
27

 
 
 
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28 
28

 
 
 
Version 04-28-16   
29 
29

 
 
 
Version 04-28-16   
30 
30

 
 
 
Version 04-28-16   
31 
31

 
 
 
Version 04-28-16   
32 
32

 
 
 
Version 04-28-16   
33 
33

 
 
 
Version 04-28-16   
34 
34

 
 
 
Version 04-28-16   
35 
35

 
 
 
Version 04-28-16   
36 
36

 
 
 
Version 04-28-16   
37 
37

 
 
 
Version 04-28-16   
38 
38

 
 
 
Version 04-28-16   
39 
39

 
 
 
Version 04-28-16   
40 
40

 
 
 
Version 04-28-16   
41 
41

 
 
 
Version 04-28-16   
42 
42

 
 
 
Version 04-28-16   
43 
43

 
 
 
Version 04-28-16   
44 
44

 
 
 
Version 04-28-16   
45 
45

 
 
 
Version 04-28-16   
46 
46

 
 
 
Version 04-28-16   
47 
47

 
 
 
Version 04-28-16   
48 
48

 
 
 
Version 04-28-16   
49 
49

 
 
 
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50 
50

 
 
 
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51 
51

 
 
 
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52 
52
 

 
 
 
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53 
53
APPENDIX 11.7 
 
Randomization Table 
 
SubjectOrderEnt
ry 
Sequence 
First Period 
Treatment 
Second Period 
Treatment 
1 Treximet f/b 
Triptan 
Treximet 
Triptan 
2 Treximet f/b 
Triptan 
Treximet 
Triptan 
3 Triptan f/b 
Treximet 
Triptan 
Treximet 
4 Treximet f/b 
Triptan 
Treximet 
Triptan 
5 Triptan f/b 
Treximet 
Triptan 
Treximet 
6 Treximet f/b 
Triptan 
Treximet 
Triptan 
7 Triptan f/b 
Treximet 
Triptan 
Treximet 
8 Triptan f/b 
Treximet 
Triptan 
Treximet 
9 Treximet f/b 
Triptan 
Treximet 
Triptan 
10 Triptan f/b 
Treximet 
Triptan 
Treximet 
11 Triptan f/b 
Treximet 
Triptan 
Treximet 
12 Treximet f/b 
Triptan 
Treximet 
Triptan 
13 Triptan f/b 
Treximet 
Triptan 
Treximet 
14 Treximet f/b 
Triptan 
Treximet 
Triptan 
15 Treximet f/b 
Triptan 
Treximet 
Triptan 
16 Triptan f/b 
Treximet 
Triptan 
Treximet 
17 Triptan f/b 
Treximet 
Triptan 
Treximet 
18 Treximet f/b 
Triptan 
Treximet 
Triptan 
19 Treximet f/b 
Triptan 
Treximet 
Triptan 
20 Triptan f/b 
Treximet 
Triptan 
Treximet 
21 Triptan f/b 
Triptan 
Treximet 

 
 
 
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54
Treximet 
22 Triptan f/b 
Treximet 
Triptan 
Treximet 
23 Triptan f/b 
Treximet 
Triptan 
Treximet 
24 Triptan f/b 
Treximet 
Triptan 
Treximet 
25 Treximet f/b 
Triptan 
Treximet 
Triptan 
26 Triptan f/b 
Treximet 
Triptan 
Treximet 
27 Treximet f/b 
Triptan 
Treximet 
Triptan 
28 Treximet f/b 
Triptan 
Treximet 
Triptan 
29 Triptan f/b 
Treximet 
Triptan 
Treximet 
30 Treximet f/b 
Triptan 
Treximet 
Triptan 
31 Treximet f/b 
Triptan 
Treximet 
Triptan 
32 Triptan f/b 
Treximet 
Triptan 
Treximet 
33 Triptan f/b 
Treximet 
Triptan 
Treximet 
34 Treximet f/b 
Triptan 
Treximet 
Triptan 
35 Triptan f/b 
Treximet 
Triptan 
Treximet 
36 Treximet f/b 
Triptan 
Treximet 
Triptan 
37 Treximet f/b 
Triptan 
Treximet 
Triptan 
38 Treximet f/b 
Triptan 
Treximet 
Triptan 
39 Triptan f/b 
Treximet 
Triptan 
Treximet 
40 Triptan f/b 
Treximet 
Triptan 
Treximet 
41 Triptan f/b 
Treximet 
Triptan 
Treximet 
42 Treximet f/b 
Triptan 
Treximet 
Triptan 
43 Treximet f/b 
Triptan 
Treximet 
Triptan 

 
 
 
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55 
55
44 Treximet f/b 
Triptan 
Treximet 
Triptan 
45 Triptan f/b 
Treximet 
Triptan 
Treximet 
46 Triptan f/b 
Treximet 
Triptan 
Treximet 
47 Triptan f/b 
Treximet 
Triptan 
Treximet 
48 Treximet f/b 
Triptan 
Treximet 
Triptan 
49 Triptan f/b 
Treximet 
Triptan 
Treximet 
50 Triptan f/b 
Treximet 
Triptan 
Treximet 
51 Treximet f/b 
Triptan 
Treximet 
Triptan 
52 Triptan f/b 
Treximet 
Triptan 
Treximet 
53 Treximet f/b 
Triptan 
Treximet 
Triptan 
54 Treximet f/b 
Triptan 
Treximet 
Triptan 
55 Triptan f/b 
Treximet 
Triptan 
Treximet 
56 Treximet f/b 
Triptan 
Treximet 
Triptan 
57 Treximet f/b 
Triptan 
Treximet 
Triptan 
58 Triptan f/b 
Treximet 
Triptan 
Treximet 
59 Treximet f/b 
Triptan 
Treximet 
Triptan 
60 Treximet f/b 
Triptan 
Treximet 
Triptan