Pharmacokinetics & Safety of Cambia® in Migraine With or Without Aura in 12-17 Year Olds

Study Overview
=================
Brief Summary
-----------------
Study Objectives: The primary objective is to characterize the pharmacokinetics of a single oral administration of 50 mg Cambia in pediatric subjects, ages 12-17 years with a diagnosis of episodic migraine with or without aura. The secondary objectives are to determine: The safety and tolerability of Cambia from a single dose Three-month safety evaluation of Cambia in outpatient usage in this population

Official Title
-----------------
A Phase 4, Open-Label Study of the Pharmacokinetics and Safety of Cambia® (Diclofenac Potassium for Oral Solution) for the Acute Treatment of Migraine Attacks With or Without Aura in Pediatric Subjects (Ages 12-17 Years)

Conditions
-----------------
Migraine

Intervention / Treatment
-----------------
* Drug: Diclofenac Potassium for Oral Solution


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is ≥12 and ≤17 years of age at screening. Subject diagnosed with episodic migraine with or without aura for at least 3 months (migraine defined based on the International classification of headache disorders-II 1.2.1 or 1.1). Subject has 14 or fewer headache days per month. Subject receiving prophylactic treatment for migraine may be included. If female, is not of childbearing potential (defined as premenarchal) or if of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Study Day 1, if the Screening visit and Day 1 are not on the same day, and must use medically acceptable methods of birth control as listed below and agrees to continue its use throughout the study:1) hormonal methods (e.g., oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full menstrual cycle before study drug administration), 2) Total abstinence from sexual intercourse since the last menses before study drug administration, 3) intrauterine device, 4) double-barrier method (e.g., condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream). Subject's legally authorized representative (e.g., parent, guardian) must voluntarily sign and date an informed consent form (ICF) that is approved by an Institutional Review Board (IRB), and the subject must sign an assent (if appropriate), before the commencement of any study assessment. Subject's legally authorized representative (e.g., parent, guardian) and subject (if appropriate), is able to read and understand the study procedures and requirements and adhere to the protocol requirements and procedures. Exclusion Criteria: Subject has a known history of allergic reaction, hypersensitivity, or clinically significant intolerance to diclofenac, aspirin, or any nonsteroidal anti inflammatory drugs (NSAIDs); history of NSAID induced bronchospasm (subjects with the triad of asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and should be considered carefully); or hypersensitivity, allergy, or significant reaction to the non-active ingredients of the study medication. Subject is pregnant or lactating or considered at risk of pregnancy. Subject has been under an inconsistent dosing regimen of prophylactic treatment for migraine. Subject has headache symptoms likely due to, or aggravated by, traumatic injury to the head or neck region, such as whiplash, within the last six months; Subject has or is suspected of having a secondary headache. Subject has significant abnormal findings during the neurological exam at screening. Subject has a history of any GI event (e.g., perforation, obstruction, bleed) before Screening that, in the opinion of the investigator, would make the subject unsuitable for study participation. Subject is receiving any medication that, in the opinion of the investigator, may cause a clinically significant condition when used concomitantly with diclofenac (e.g., aspirin, anticoagulants, ACE inhibitors, methotrexate, cyclosporine, furosemide, lithium). Subject is and has been receiving a medication that is known to strongly inhibit and/or induce cytochrome P450 2C9 such that it might unpredictably affect the pharmacokinetics of diclofenac (e.g., fluconazole, amiodarone, oxandrolone, sulfipyrazone as inhibitors and rifampin as an inducer). Subject has any condition or any laboratory abnormality that would, in the opinion of the investigator, contraindicate study participation. Subject has impaired liver function (e.g., alanine aminotransferase [ALT] ≥ 3 times the upper limit of normal [ULN] or bilirubin ≥ 3 times ULN), known active hepatic disease (e.g., hepatitis), or evidence of clinically significant liver disease or other condition affecting the liver that may suggest the potential for an increased susceptibility to hepatic toxicity with oral diclofenac exposure. Subject has any history of renal disease that, in the opinion of the investigator, would contraindicate study participation; or subject has significantly impaired renal function as evidenced by an estimated GFR of ≤60 ml/min/1.73m2. Subject is considered by the investigator, for any reason (including, but not limited to the risks described as precautions, warnings, and contraindications in the Prescribing Information for Cambia), to be an unsuitable candidate to receive the study medication. Subject has a history of laboratory test results obtained within 6 months before the Screening visit that show the presence of HIV, hepatitis B surface antigen, hepatitis C antibody, or active hepatitis A immunoglobulin M. Subject is currently receiving any medication that is contraindicated for use concomitantly with diclofenac (refer to the products' professional labeling) or the subject has not undergone a washout period of at least 5-6 half-lives of PK or PD, whichever is longer, for these medications. Subject has a known or suspected history of alcohol use and or drug/ substance abuse or misuse within 2 years before Screening; or evidence of tolerance or physical dependence before study medication administration. Subject has a documented history of a medical condition that, in the opinion of the investigator, would compromise the subject's ability to absorb, metabolize, or excrete diclofenac, including (but not limited to) intractable nausea and/or vomiting and/or severe GI narrowing (pathologic or iatrogenic). Subject has received any investigational product or device within 30 days before the Screening, or is scheduled to receive an investigational device or another investigational drug (other than Cambia) during the course of this study. Subject is a relative of a member of the study site staff or Sponsor directly involved in this study.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diclofenac Potassium<br>Diclofenac Potassium for Oral Solution 50 mg | Drug: Diclofenac Potassium for Oral Solution<br>* NSAID<br>* Other names: Cambia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics Outcome (1 of 6) | • Cmax: maximum concentration (ng/mL) | 6 hours (pre-dose, 5, 10, 15, 20, 30, 40, and 60 min, and 2, 4, and 6 hrs post-dose) | 
| Pharmacokinetics Outcome (2 of 6) | • tmax: time to maximum concentration (min) | 6 hours (pre-dose, 5, 10, 15, 20, 30, 40, and 60 min, and 2, 4, and 6 hrs post-dose) | 
| Pharmacokinetics Outcome (3 of 6) | • λz: elimination rate constant associated with the terminal (log linear) portion of the curve (1/min) | 6 hours (pre-dose, 5, 10, 15, 20, 30, 40, and 60 min, and 2, 4, and 6 hrs post-dose) | 
| Pharmacokinetics Outcome (4 of 6) | • t1/2: terminal elimination half-life (min) | 6 hours (pre-dose, 5, 10, 15, 20, 30, 40, and 60 min, and 2, 4, and 6 hrs post-dose) | 
| Pharmacokinetics Outcome (5 of 6) | • AUC 0-t: area under the concentration-time curve from time 0 to last time point (t) where diclofenac could be measured (min*ng/mL) | 6 hours (pre-dose, 5, 10, 15, 20, 30, 40, and 60 min, and 2, 4, and 6 hrs post-dose) | 
| Pharmacokinetics Outcome (6 of 6) | • AUC 0-∞: area under the concentration-time curve from time 0 to infinity (∞) (min*ng/mL) | 6 hours (pre-dose, 5, 10, 15, 20, 30, 40, and 60 min, and 2, 4, and 6 hrs post-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Outcome (1 of 7) | • Treatment emergent AEs (TEAEs) | 3 months (time of first dose of study medication taken to 30 days after the last dose of study medication taken) | 
| Safety Outcome (2 of 7) | • Serious adverse events (SAEs) | 3 months (signed informed consent/assent to 30 days post Day 90 or last dose of study medication taken) | 
| Safety Outcome (3 of 7) | • Withdrawals due to AEs | 3 months (signed informed consent/assent to 30 days after the last dose of study medication taken) | 
| Safety Outcome (4 of 7) | • Deaths | 3 months (signed informed consent/assent to 30 days post Day 90 or last dose of study medication taken) | 
| Safety Outcome (5.1 of 7) | • Changes in vital sign measurements: Temperature (degrees C). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (5.2 of 7) | • Changes in vital sign measurements: Heart Rate (beats/min). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (5.3 of 7) | • Changes in vital sign measurements: Respiratory Rate (breaths/min). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (5.4 of 7) | • Changes in vital sign measurements: Systolic Blood Pressure (mmHg). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (5.5 of 7) | • Changes in vital sign measurements: Diastolic Blood Pressure (mmHg). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.1 of 7) | • Changes in clinical laboratory results: Hematology - Hematocrit (L/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.2 of 7) | • Changes in clinical laboratory results: Hematology - Hemoglobin (g/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.3 of 7) | • Changes in clinical laboratory results: Hematology - Platelet Count (Cells * 10^9/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.4 of 7) | • Changes in clinical laboratory results: Hematology - White Blood Cells (Cells * 10^9/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.5 of 7) | • Changes in clinical laboratory results: Hematology - Basophils (%). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.6 of 7) | • Changes in clinical laboratory results: Hematology - Eosinophils (%). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.7 of 7) | • Changes in clinical laboratory results: Hematology - Neutrophils (%). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.8 of 7) | • Changes in clinical laboratory results: Hematology - Lymphocytes (%). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.9 of 7) | • Changes in clinical laboratory results: Hematology - Monocytes (%). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.10 of 7) | • Changes in clinical laboratory results: Chemistry - Albumin (g/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.11 of 7) | • Changes in clinical laboratory results: Chemistry - Alkaline Phosphatase (U/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.12 of 7) | • Changes in clinical laboratory results: Chemistry - ALT (SGPT) (U/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.13 of 7) | • Changes in clinical laboratory results: Chemistry - AST (SGOT) (U/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.14 of 7) | • Changes in clinical laboratory results: Chemistry - Bicarbonate (CO2) (mmol/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.15 of 7) | • Changes in clinical laboratory results: Chemistry - Bilirubin Total (umol/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.16 of 7) | • Changes in clinical laboratory results: Chemistry - BUN (Urea) (mmol/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.17 of 7) | • Changes in clinical laboratory results: Chemistry - Chloride (mmol/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.18 of 7) | • Changes in clinical laboratory results: Chemistry - Creatinine (umol/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.19 of 7) | • Changes in clinical laboratory results: Chemistry - Glucose (mmol/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.20 of 7) | • Changes in clinical laboratory results: Chemistry - LDH (U/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.21 of 7) | • Changes in clinical laboratory results: Chemistry - Potassium (mmol/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.22 of 7) | • Changes in clinical laboratory results: Chemistry - Sodium (mmol/L). | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.23 of 7) | • Changes in clinical laboratory results: Urinalysis - pH. | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (6.24 of 7) | • Changes in clinical laboratory results: Urinalysis - Specific Gravity. | 3 months (signed informed consent/assent to the final visit) | 
| Safety Outcome (7 of 7) | • Physical examination findings including abnormal clinically significant findings | 3 months (signed informed consent/assent to the final visit) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Migraine with and without aura