A Study to Assess Menstrual Cramp Pain Associated With Primary Dysmenorrhea

Study Overview
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Brief Summary
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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.

Official Title
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A Double-Blind, Randomized, Crossover Study to Assess Menstrual Cramp Pain Associated With Primary Dysmenorrhea

Conditions
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Dysmenorrhea

Intervention / Treatment
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* Drug: Naproxen Sodium, (Aleve, BAY117031)
* Drug: Acetaminophen (Tylenol Extra Strength)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulatory healthy female patients between 15 and 35 years of age; Patient has a history of Over-the-Counter (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, 0-3) 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 an 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; 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; Patient is willing and able to participate in all scheduled visits, treatment plan, laboratory tests and other study procedures according to the clinical protocol. Exclusion Criteria: 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; 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 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.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naproxen Sodium : Acetaminophen<br>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 | Drug: Naproxen Sodium, (Aleve, BAY117031)<br>* 220 mg *2 tablets, orally, single dose<br>Drug: Acetaminophen (Tylenol Extra Strength)<br>* 500 mg *2 caplets, orally, single dose<br>|
| Experimental: Acetaminophen : Naproxen Sodium<br>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 | Drug: Naproxen Sodium, (Aleve, BAY117031)<br>* 220 mg *2 tablets, orally, single dose<br>Drug: Acetaminophen (Tylenol Extra Strength)<br>* 500 mg *2 caplets, orally, single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of Total Pain Relief (TOTPAR) Over 0-12 Hours | Pain relief was measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, 4 = complete relief). Total pain relief scores (TOTPARs) were calculated by multiplying the pain relief score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values. The minimum value is 0, and the maximum value is 46. Higher scores was indicative of more pain relief. | Up to 12 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed Pain Intensity Difference (SPID) Over 0-12 Hours | Pain intensity was measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). For each postdose time point, pain intensity differences (PIDs) were derived by subtracting the pain intensity at the postdose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference was indicative of improvement. Time-weighted summed pain intensity differences (SPIDs) were calculated by multiplying the PID score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values. The minimum value could be -115, and the maximum value could be 115. | Up to 12 hours post-dose | 
| SPID Over 0-6 Hours | Pain intensity was measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). For each postdose time point, pain intensity differences (PIDs) were derived by subtracting the pain intensity at the postdose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference was indicative of improvement. Time-weighted summed pain intensity differences (SPIDs) were calculated by multiplying the PID score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values. The minimum value could be -55, and the maximum value could be 55. | Up to 6 hours post-dose | 
| SPID Over 6-12 Hours | Pain intensity was measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). For each postdose time point, pain intensity differences (PIDs) were derived by subtracting the pain intensity at the postdose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference was indicative of improvement. Time-weighted summed pain intensity differences (SPIDs) were calculated by multiplying the PID score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values. The minimum value could be -60, and the maximum value could be 60. | From 6 hours to 12 hours post-dose | 
| TOTPAR Over 0-6 Hours | Pain relief was measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, 4 = complete relief). Total pain relief scores (TOTPARs) were calculated by multiplying the pain relief score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values. The minimum value is 0, and the maximum value is 22. Higher scores was indicative of more pain relief. | Up to 6 hours post-dose | 
| TOTPAR 6-12 Hours | Pain relief was measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, 4 = complete relief). Total pain relief scores (TOTPARs) were calculated by multiplying the pain relief score at each postdose time point by the duration (in hours) since the preceding time point and then summing these values. The minimum value is 0, and the maximum value is 24. Higher scores was indicative of more pain relief. | From 6 hours to 12 hours post-dose | 
| Time to First Intake of Rescue Medication | Time to first intake of rescue medication was defined as the number of hours elapsed between time of dose and time of rescue medication in each treatment period. Participants would be censored at time of last pain assessment. | Up to 12 hours post-dose | 
| Pain Intensity Difference (PID) Scores at Each Evaluation | Pain intensity was measured using Numerical Rating Scale (from 0 to 10: 0 = no pain, 10 = worst possible pain). For each postdose time point, pain intensity differences (PIDs) were derived by subtracting the pain intensity at the postdose time point from the baseline intensity score (baseline score - post-baseline score). A positive difference was indicative of improvement. | Up to 12 hours post-dose | 
| Number of Participants by Global Evaluation Scores | Global evaluation was performed either at 12 hours post-dose or immediately prior to the first intake of rescue medication. Global Evaluation Score was based on the question 'Overall, I would rate the effectiveness of the study medication in relieving my menstrual pain as: 0=Poor, 1=Fair, 2=Good, 3=Very Good, 4=Excellent.' | Up to 12 hours post-dose | 
| Pain Relief Scores at Each Evaluation | Pain relief was measured using Categorical Pain Relief Rating Scale (0 = No relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, 4 = complete relief). | Up to 12 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary dysmenorrhea of at least moderate severity