Long-Term Safety of Treximet (Sumatriptan/Naproxen Sodium) for Migraine in Adolescents

Study Overview
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Brief Summary
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This study was designed to determine long-term safety of TREXIMET (sumatriptan/naproxen sodium) in adolescents for the acute treatment of migraine.

Detailed Description
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This study was designed to determine long-term safety of TREXIMET (sumatriptan/naproxen sodium) in adolescents (aged 12 to 17 years) for the acute treatment of migraine.

Official Title
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Study TXA107977, a Long-Term Safety Study of a Combination Product Containing Sumatriptan Succinate and Naproxen Sodium for the Treatment of Migraine in Adolescents

Conditions
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Migraine Disorders

Intervention / Treatment
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* Drug: Combination Tablet of Treximet (sumatriptan/naproxen sodium)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is between 12 and 17 years old at the Screening visit. If subject is female, she must have a negative urine pregnancy test at screening, does not plan to become pregnant during the course of the study and agrees to use an acceptable method of birth control (i.e., a method with a failure rate <1% or abstinence) if she is/becomes sexually active. Subject has migraine with or without aura (2004 ICHD-II criteria). Subject has history suggestive of typical migraine attacks with duration of about 2 or more hours (untreated, or unsuccessfully treated). Subject has at least 2, but not more than 8, migraine attacks per month in each of the 2 months prior to the Screening visit. Subject has at least a 6-month history of moderate to severe migraine attacks, sufficient to establish a definitive diagnosis of migraine. Subject is able to distinguish migraine from other headaches (e.g., tension-type headaches). Subject and subject's parent or legal guardian are willing and able to provide informed consent prior to entry into this treatment phase of the study. Subject and subject's parent or legal guardian are able to read and write English or Spanish. Subject is able to understand and complete the electronic device to report treatment information. Exclusion Criteria: Subject is < 75 pounds (33.3kg). Subject has ≥15 headache days per month in total, retinal (ICHD-II 1.4), basilar (ICHD-II 1.26) or hemiplegic migraine (ICHD-II 1.25), or secondary headaches. Subject, in the investigator's opinion, is likely to have unrecognized cardiovascular or cerebrovascular disease (See Appendix 1, section 11.1). Subject has uncontrolled hypertension (See Appendix 2, section 11.2) or is taking any angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker. Subject has a history of congenital heart disease, cardiac arrhythmias requiring medication, or a history of a clinically significant electrocardiogram abnormality that, in the investigator's opinion, contraindicates participation in this study. Subject has evidence or history of any ischemic vascular diseases including: ischemic heart disease, ischemic abdominal syndromes, peripheral vascular disease or Raynaud's Syndrome, or signs/symptoms consistent with any of the above. Subject has evidence or history of central nervous system pathology including stroke and/or transient ischemic attacks (TIAs), epilepsy or structural brain lesions which lower the convulsive threshold; or has been treated with an antiepileptic drug for seizure control within 5 years prior to screening. Subject has a history of impaired hepatic or renal function that, in the investigator's opinion, contraindicates participation in this study. Subject has hypersensitivity, allergy, intolerance, or contraindication to the use of any triptan, NSAID or aspirin (including all sumatriptan and naproxen preparations) or has nasal polyps and asthma. Subject is currently taking, or has taken in the previous three months, a migraine prophylactic medication containing methysergide or dihydroergotamine; or is taking a medication that is not stabilized (i.e., change of dose within the past 2 months) for either chronic or intermittent migraine prophylaxis or for a co-morbid condition that is not stabilized. Subject has a recent history of regular use of opioids or barbiturates for treatment of his/her migraine headache and/or other non-migraine pain. Regular use is defined as an average of 4 days per month over the last 6 months. Subject has taken, or plans to take, a monoamine oxidase inhibitor (MAOI), including herbal preparations containing St. John's Wort (Hypericum perforatum), anytime within the 2 weeks prior to screening through 2 weeks post final study treatment. Subject history of any bleeding disorder or is currently taking any anti-coagulant or any antiplatelet agent. Subject has evidence or history of any gastrointestinal surgery or GI ulceration or perforation in the past six months, gastrointestinal bleeding in the past year; or evidence or history of inflammatory bowel disease. Subject tests positive for illicit substances on toxicology screen, or has evidence of alcohol or substance abuse within the last year, or any concurrent medical or psychiatric condition which, in the investigator's judgment, will likely interfere with the study conduct, subject cooperation, or evaluation and interpretation of the study results, or which otherwise contraindicates participation in this clinical trial. Subject has participated in an investigational drug trial within the previous 4 weeks or plans to participate in another study at any time during this study.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Active Drug<br>Combination Tablet of Treximet (sumatriptan/naproxen sodium) | Drug: Combination Tablet of Treximet (sumatriptan/naproxen sodium)<br>* Combination Tablet of Treximet(sumatriptan/naproxen sodium)<br>* Other names: Combination Product (sumatriptan succinate / naproxen sodium);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Drug-related Adverse Events | The number of participants with a drug-related adverse event (AE). Frequency threshold for reporting a drug-related AE: >=2% participants recorded as having at least one occurrence of a reported drug-related AE. | Baseline through End of Study (up to Month 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event Categorized by Severity | The number of participants with at least one mild (an event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities), moderate (an event that is sufficiently discomforting to interfere with normal everyday activities), or severe adverse event (an event that prevents normal everyday activities) was recorded. | Baseline through End of Study (up to Month 12) | 
| Number of Participants With Any Adverse Event Categorized Over Time | The number of participants with an adverse event occurring in either the first six months of the study (months 0-6; <=194 days) or the second six months of the study (months 6-12; =>194 days until end of study) was recorded. | Baseline through End of Study (up to Month 12) | 
| Number of Participants With Any Adverse Event Categorized by Participant Age | The number of participants with any adverse event by age group (12-14 and 15-17 years) is recorded. | Baseline through End of Study (up to Month 12) | 
| Number of Participants With Any Adverse Event Categorized by Participant Race | The number of participants with any adverse event was categorized by race. The category Other captures : American Indian or Alaskan Native; Asian, Native Hawaiian, or Other Pacific Islander; African American/African Heritage and Asian; African American/African Heritage and White; and American Indian or Alaskan Native and White. | Baseline through End of Study (up to Month 12) | 
| Number of Participants With Any Adverse Event Categorized by Participant Gender | The number of participants with adverse events by gender is recorded. | Baseline through End of Study (up to Month 12) | 
| Number of Participants With Any Adverse Event That Occurred Within 3 or 5 Days of the First Dose of the Combination Tablet | The number of participants with adverse events that occurred within 3 or 5 days of their first dose of the Combination Tablet was recorded. | Baseline through End of Study (up to Month 12) | 
| Number of Tablets Taken, After Which at Least One Adverse Event Occurred Within 3 or 5 Days of Dosing With That Combination Tablet | The number of events that occurred within 3 or 5 days of dosing with the combination tablet on a per tablet basis. A total of 8413, 5876, and 9989 tablets were taken by the 6 Month Completer, 12 Month Completer, and the Safety Populations, respectively. | Baseline through End of Study (up to Month 12) | 
| Number of Participants With Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatinine, Potassium, and Blood Urea Nitrogen (BUN) Values of Interest That Shifted From Normal at Baseline to Abnormal at the End of Study Visit | A shift from normal to low, for example, indicates that a value was normal at baseline but low at the end of study visit. The value ranges were determined by the central laboratory. Reference ranges: ALT, 12 years old (y): 0-45 Units/liter (U/L), >13 y: 0-48 U/L; AST, 12 y: 0-42 U/L, >13 y 0-42 U/L; creatinine, 12 y: 27-88 micromoles/liter (UMOL/L), >13 y: 44-124 UMOL/L; potassium, 12 y: 3.5-5.5 millimoles/liter (MMOL/L), >13 y: 3.5-5.3 MMOL/L; BUN, 12-17 y: 24-101 milligrams (mg)/deciliter (dL). | Baseline through End of Study (up to Month 12) | 
| Number of Participants With Hematocrit and Hemoglobin Values of Interest That Shifted From Normal at Baseline to Abnormal at the End of Study Visit | A shift from normal to low, for example, indicates that a value was normal at baseline but low at the end of study visit. The value ranges were determined by the central laboratory. Reference ranges: hemoglobin, 12-17 years old (y): 120-160 grams (g)/L; hematocrit (expressed as the percentage of blood occupied by red blood cells), 12-17 y: 0.360-0.490. | Baseline through End of Study (up to Month 12) | 
| Mean Height for All Study Participants at the Indicated Time Points |  | Screening and Months 3, 6, 9, and 12 | 
| Mean Weight for All Study Participants at the Indicated Time Points |  | Screening and Months 3, 6, 9, and 12 | 
| Mean Body Mass Index (BMI) for All Study Participants at the Indicated Time Points | BMI = (Weight in kilograms)/(height in centimeters/100)^2 | Screening and Months 3, 6, 9, and 12 | 
| Mean Blood Pressure for All Study Participants at the Indicated Time Points | At each visit, a participant's blood pressure was taken three times. The average of the three readings was then calculated for each participant at each visit (mean blood pressure). The outcome measure represents the average of the mean blood pressure of all of the study participants. SBP, systolic blood pressure; DBP, diastolic blood pressure. | Screening and Months 3, 6, 9, and 12 | 
| Mean Heart Rate for All Study Participants at the Indicated Time Points | A sitting heart rate was measured once for each participant at each visit. | Screening and Months 3, 6, 9, and 12 | 
| Number of Participants With Abnormal Electrocardiogram Findings at Screening and at the Final Visit as Assessed by the Investigator | The number of participants with an electrocardiogram (ECG) status of normal, abnormal, clinically significant (CS), or not clinically significant (NCS), as determined by the Investigator, was reported. Specific definitions of ECG categorizations were not provided; investigators were expected to apply reasonable standards of clinical judgment. Normal, all ECG parameters within accepted normal ranges; abnormal, ECG finding(s) outside of normal ranges; CS, ECG with a CS abnormality that meets exclusion criteria; NCS, ECG with an abnormality not CS or meeting exclusion criteria per investigator. | Screening and Final Visit (up to Month 12) | 
| Number of Treated Migraine Attacks | The number of migraine attacks eligible for evaluation, not associated with rescue medication use, or prohibited medications, was summarized. Rescue medication was additional medication taken within 24 hours of Combination Tablet. Prohibited medications: ergot, opioid, barbiturate, 5-HT1 agonist, long-acting non-steroidal anti-inflammatory drug (NSAID), short-acting NSAID-containing compound, analgesic, anti-emetic, monoamine oxidase inhibitors, St. John's Wort, angiotensin-converting enzyme inhibitor, Angiotensin II receptor blockers, anti-coagulant, anti-platelet. | Baseline through End of Study (up to Month 12) | 
| Number of Treated Attacks Classified as Migraine Pain-Free (MPF) Within 24 Hours of Dosing With the Combination Tablet | The number of migraine attacks eligible for evaluation, not associated with rescue medication use, and not associated with either rescue medication use or prohibited medications were counted. Migraine Pain Free was defined as the migraine attack ending <= 24 hours after the participant was dosed with the Combination Tablet. | Baseline through End of Study (up to Month 12) | 
| Number of Treated Attacks Classified as Migraine Pain-Free (MPF) Within 4 Hours of Dosing With a Combination Tablet | The number of migraine attacks eligible for evaluation, not associated with rescue medication use, and not associated with either rescue medication use or prohibited medications were counted. Migraine Pain Free was defined as the migraine attack ending <= 4 hours after the participant was dosed with the Combination Tablet. | Baseline through End of Study (up to Month 12) | 
| Number of Treated Attacks Classified as Migraine Pain-Free Within 4 Hours That Were Also Pain Free Within 2 Hours of Dosing With the Combination Tablet | The number of migraine attacks eligible for evaluation, not associated with rescue medication use, and not associated with either rescue medication use or prohibited medications were counted. Migraine Pain Free was defined as the migraine attack ending <= 4 hours after the participant was dosed with the Combination Tablet. | Baseline through End of Study (up to Month 12) | 
| Average Number of Headaches, Migraine Attacks, and Treated Migraine Attacks Per Month | The average number of headaches (non-migraine and migraine attacks), migraine attacks, and treated migraine attacks per month was calculated for each participant, based on their time in the study. The outcome measure represents the average of the mean number of the headaches, migraine headaches, and treated migraines per month of the study participants in the 6 Month, 12 Month, and ITT Populations. A treated attack is defined as a migraine treated with the Combination Tablet. | Baseline through End of Study (up to Month 12) | 
| Number of Total Migraines Headaches and Migraines Treated With the Combination Tablet | The total number of migraine headaches and the number of migraine headaches treated with the Combination Tablet during the study were summarized. | Baseline through End of Study (up to Month 12) | 
| Number of Migraine Attacks Rated With the Indicated Pain Severity | The number of migraine attacks treated at the mild, moderate, or severe intensity were counted. Pain severity was assessed by participants based on a scale of 0-3: 0=no pain, 1=mild, 2= moderate, 3=severe. | Baseline through End of Study (up to Month 12) | 
| Number of Treated Migraine Attacks With Photophobia, Phonophobia, Nausea, Neck Pain, Sinus Pain, and Vomiting | The number of treated migraine attacks with the reported migraine-associated symptoms of photophobia, phonophobia, nausea, neck pain, sinus pain, and vomiting were counted. Photophobia: sensitivity to light; phonophobia: sensitivity to sound. | Baseline through End of Study (up to Month 12) | 
| Mean Change From Baseline in the Migraine Specific Quality of Life (QOL) Questionnaire for Adolescents (MSQ-A) Score at Months 3, 6, 9, and 12 | The MSQ-A consists of 14 items measuring how migraines affect QOL: Role Function (RF)-Restrictive (items 1-7) and RF-Preventative (items 8-11), examining the degree to which performance of daily activities is limited or interrupted, respectively, by migraine; RF-Emotional (items 12-14, examining frustration/helplessness due to migraine). Dimensions (dim.) are scored independently. The 14 items are reverse coded onto a 1-6 scale; dim. are then created by summing specific item scores and transforming raw total score onto a 0-100 scale. For each dim., higher scores indicate better health status. | Baseline and Months 3, 6, 9, and 12 | 
| Number of Participants Categorized by Response to Each of the 3 Global Satisfaction Questions From the Patient Perception Migraine Questionnaire-Revised (PPMQ-R) at the Screening Visit | The PPMQ-R is a fully validated 32-item questionnaire assessing participant satisfaction with acute migraine medication and includes 3 questions that assess satisfaction with respect to efficacy, side effects, and overall satisfaction (i.e., How effective the medication is overall, side effects of the medication, overall satisfaction with the medication). Each item is rated on a 7-point scale ranging from very satisfied (1) to very dissatisfied (7). | Screening | 
| Number of Participants Categorized by Response to Each of the 3 Global Satisfaction Questions From the Patient Perception Migraine Questionaire-Revised (PPMQ-R) at Month 12 | The PPMQ-R is a fully validated 32-item questionnaire assessing participant satisfaction with acute migraine medication and includes 3 questions that assess satisfaction with respect to efficacy, side effects, and overall satisfaction (i.e., How effective the medication is overall, side effects of the medication, overall satisfaction with the medication). Each item is rated on a 7-point scale ranging from very satisfied (1) to very dissatisfied (7). | End of Study/Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Long-term Safety, Migraine, Adolescent Migraine Headache, sumatriptan succinate, naproxen sodium