Maxigesic® IV Phase 3 Exposure Study

Study Overview
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Brief Summary
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The study aims to determine the tolerability of repeated doses of Maxigesic® IV over an extended period of exposure.

Detailed Description
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Combined administration of acetaminophen and ibuprofen has been shown to provide superior analgesia over administration of comparable doses of either component alone or placebo, when given as an intravenous formulation or as a solid oral tablet in the postoperative setting. The superior efficacy of the combination does not appear to come at the expense of tolerability. A previous study of Maxigesic® IV in bunionectomy patients found that there were no differences between patients treated with repeated doses of Maxigesic® IV and those treated with intravenous acetaminophen, ibuprofen or placebo in the rate of discontinuations due to adverse events (AEs), the overall incidence of treatment-emergent AEs (TEAEs) or the severity of TEAEs. The incidence of common TEAEs (affecting ≥ 10% of the study population), including gastrointestinal disorders, nervous system disorders, general disorders and administration site conditions, and skin and subcutaneous tissue disorders, was not changed due to combined administration of acetaminophen and ibuprofen in Maxigesic® IV. This study aims to determine the tolerability of repeated doses of Maxigesic® IV over an extended period of exposure (≥ 48 hours).

Official Title
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A Phase 3, Open-Label, Multiple-Dose, Single-Arm Exposure Study of Maxigesic® IV in Patients With Acute Pain Following Orthopedic, General or Plastic Surgery

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: Maxigesic® IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is male or female ≥ 18 years of age. Is classified by the anesthesiologist as P1 to P2 in the American Society of Anesthesiologists (ASA) Physical Status Classification System. Requires multiple doses of parenterally administered nonopioid analgesics over multiple days as a result of surgery (non-laparoscopic general, plastic or orthopedic surgery). Has an expected stay in facility ≥ 48 hours. Has a body weight ≥ 45 kg. If female and of childbearing potential, is nonlactating and nonpregnant. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or practicing 1 of the following medically acceptable methods of birth control: i) Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full cycle (based on the subject's usual menstrual cycle period) before study drug administration; ii) Total abstinence from sexual intercourse since the last menses before study drug administration through completion of final study visit; iii) Intrauterine device (IUD); iv) Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream). Is able to provide written informed consent to participate in the study and able to understand the procedures and study requirements. Must voluntarily sign and date an informed consent form (ICF) that is approved by an Institutional Review Board (IRB) before the conduct of any study procedure. Is willing and able to remain at the study site for at least 48 hours and to attend a follow-up visit at 7 ± 2 days after the last dose of study drug. Exclusion Criteria: Has a known history of allergic reaction or clinically significant intolerance to acetaminophen, aspirin, opioids, or any nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen); 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 sulfa (including sulfonamide) medicines, ingredients of the study drug, or any other drugs used in the study including anesthetics and antibiotics that may be required on the day of surgery. Has experienced any surgical complications or other issues that, in the opinion of the Investigator, could compromise the safety of the subject if he or she participates in the study or could confound the results of the study. Has a known or suspected history of alcoholism or drug abuse or misuse within 2 years of screening or evidence of tolerance or physical dependence before dosing with study drug. Has any clinically significant unstable cardiac, respiratory, neurological, immunological, hematological, or renal disease or any other condition that, in the opinion of the Investigator, could compromise the subject's welfare, ability to communicate with the study staff, or otherwise contraindicate study participation. Has a history or current diagnosis of a significant psychiatric disorder that, in the opinion of the Investigator, would affect the subject's ability to comply with the study requirements. Has tested positive either on the urine drug screen or on the alcohol breathalyzer test. Subjects who test positive and can produce a prescription for the medication from their physician may be considered for study enrolment at the discretion of the Investigator. Has a history of a clinically significant (Investigator opinion) gastrointestinal (GI) event within 6 months before screening or has any history of peptic or gastric ulcers or GI bleeding. Has a surgical or medical condition of the GI or renal system that might significantly alter the absorption, distribution, or excretion of any drug substance. Is considered by the Investigator, for any reason to be an unsuitable candidate to receive the study drug. Is receiving systemic chemotherapy, has an active malignancy of any type, or has been diagnosed with cancer within 5 years before Screening (excluding treated squamous or basal cell carcinoma of the skin). Is currently receiving anticoagulants (e.g. heparin or warfarin). Has received a course of systemic corticosteroids (either oral or parenteral) within 3 months before screening (inhaled nasal steroids and regional/limited area application of topical corticosteroids (Investigator discretion) are allowed). Has a history of chronic use (defined as daily use for > 2 weeks) of NSAIDs, opiates, or glucocorticoids (except inhaled nasal steroids and regional/limited topical corticosteroids), for any condition within 6 months before study drug administration. Aspirin at a daily dose of ≤ 325 mg is allowed for cardiovascular prophylaxis if the subject has been on a stable dose regimen for ≥ 30 days before screening and has not experienced any relevant medical problem. Has a significant renal or hepatic disease, as indicated by clinical laboratory assessment (results ≥ 3 times the upper limit of normal [ULN] for any liver function test, including aspartate aminotransferase [AST], alanine aminotransferase [ALT], or creatinine ≥ 1.5 times the ULN). Has any clinically significant laboratory finding at screening that, in the opinion of the Investigator, contraindicates study participation. Previously participated in another clinical study of Maxigesic® IV or received any investigational drug or device or investigational therapy within 30 days before Screening.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maxigesic® IV<br>Acetaminophen 10 mg/ml + ibuprofen 3 mg/ml in 100 ml solution for infusion. The study drug will be administered by injection into a dedicated indwelling venous cannula, infused over 15 minutes. The study drug will be administered every 6 hours (q6h) for a minimum of 48 hours up to at least 5 days, with a maximum of 4 doses within a 24 hour period. | Drug: Maxigesic® IV<br>* acetaminophen 1000 mg + ibuprofen 300 mg, 100 ml solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of TEAEs (Treatment-emergent Adverse Events) | The incidence of treatment-emergent adverse events associated with exposure Maxigesic® IV | During treatment period (≥ 48 hours - 5 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Course of TEAEs | The incidence of treatment-emergent adverse events associated with exposure Maxigesic® IV during various study time periods | After receiving the first dose of study medication until 7 days after the last dose, a total of approximately 9 days for subjects who received the treatment for 48 hours and 12 days for subjects who received the treatment for 5 days. | 
| Incidence of TRAEs (Treatment-related Adverse Events) | The incidence of treatment-related adverse events (TEAEs considered by the investigator to be probably or definitely related to the study drug) associated with exposure Maxigesic® IV | During treatment period (≥ 48 hours - 5 days) | 
| Incidence of TEAEs of Interest | The incidence of TEAEs of interest (cardiovascular, gastrointestinal, renal, hepatic, administration site conditions and bleeding-related events) | During treatment period (≥ 48 hours - 5 days) | 
| Changes in Blood Pressure | Systolic and Diastolic Blood Pressured Measured every 24 hours | From the baseline (Day 1 prior to surgery) until 7 days after the last dose | 
| Changes in Heart Rate | Measured every 24 hours | From the baseline (Day 1 prior to surgery) until 7 days after the last dose | 
| Changes in Temperature | Measured every 24 hours | From the baseline (Day 1 prior to surgery) until 7 days after the last dose | 
| Changes in Respiratory Rate | Respiratory Rate Measured every 24 hours | From the baseline (Day 1 prior to surgery) until 7 days after the last dose | 
| Changes in Hematology Values (Hemoglobin) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Hematology Values (Hematocrit) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Hematology Values (Platelet Count) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Hematology Values (Red Blood Cell Count) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Hematology Values (White Blood Cell Count) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Hematology Values (Differential Leukocyte Count) | Hematology test was Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Sodium) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Potassium) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Urea) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Creatinine) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Phosphate) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Glucose) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Albumin) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Total Protein) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Alkaline Phosphates) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Gamma-glutamyl Transferase) | Blood Biochemistry was Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Aspartate Transaminase) | Blood Chemistry (AST) was Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Alanine Transaminase) | Blood Chemistry (ALT) was Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Blood Biochemistry Values (Bilirubin) | Measured at screening visit and at the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in ECG (Electrocardiography) Status (Normal/Abnormal) | All components of the ECG will be analysed to assess safety (P wave, QRS Complex, QT interval, PR interval, T wave, ST segment, U wave, PR segment) in 5 categories of the shift from baseline to the end of treatment from: Normal to Normal Normal to Abnormal NCS (Non-clinically Significant) Abnormal NCS to Normal Abnormal NCS to Abnormal NCS Missing | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Changes in Hepatic Enzymes From Baseline to the End of the Treatment | The elevation in hepatic enzymes (ALP, ALT, AST, GGT) from baseline to the end of the treatment | Prior to surgery, on Day 1 and at discharge (Day 5) | 
| Patient's Global Evaluation of the Study Drug | Summary of the patients' ratings of the study medication (1 = Poor; 2 = Fair; 3 = Good; 4 = Very Good; 5 = Excellent) | 5 days after the first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Analgesic