Maxigesic IV Phase 3 Bunionectomy Study

The purpose of the study is to determine the clinical efficacy and safety of Maxigesic IV, acetaminophen IV, Ibuprofen IV versus placebo IV for the treatment of acute postoperative pain after bunionectomy

AFT Pharmaceuticals Ltd. has been developing a fixed-dose combination of acetaminophen 1000mg and ibuprofen 300mg/100mL solution for infusion (Maxigesic IV) for the temporary relief of postoperative pain, when administration by intravenous route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration not possible.

A phase 3 efficacy study (AFT-MXIV-07) is proposed to determine the analgesic effects of the fixed dose combination product Maxigesic IV versus its individual components (acetaminophen IV and ibuprofen IV) and placebo in participants with acute post-operative pain after bunionectomy.

The primary efficacy objective is to determine the efficacy of Maxigesic IV, acetaminophen IV, Ibuprofen IV versus placebo IV as measured by the summed pain intensity difference (SPID) (calculated as a time-weighted average) over 0-48 hours (SPID-48) after time 0.

Other secondary efficacy endpoints are:

VAS Pain intensity difference (PID) at each scheduled assessment time point after Time 0 VAS Pain intensity score at each scheduled assessment time point VAS SPID over 0 to 6 hours (SPID-6), over 0 to 12 hours (SPID-12), and over 0 to 24 hours (SPID-24) after Time 0

Summed pain relief (TOTPAR) (calculated as a time-weighted average) over 0 to 6 hours (TOTPAR-6), over 0 to 12 hours (TOTPAR-12), over 0 to 24 hours (TOTPAR-24) after Time 0, and over 0 to 48 hours (TOTPAR-48) after Time 0

Time to onset of analgesia (measured as time to perceptible pain relief confirmed by meaningful pain relief) using the two-stopwatch method Pain relief score on a 5-point categorical scale at each scheduled time point after Time 0

Peak pain relief

Time to peak pain relief

Time to first perceptible pain relief

Time to meaningful pain relief

Proportion of subjects using rescue medication

Time to first use of rescue medication (duration of analgesia)

Total use of rescue analgesia over 0 to 24 hours and over 0 to 48 hours Patient's global evaluation of study drug

Eligibility Criteria:
Inclusion Criteria:

1. Is male or female ≥ 18 and ≤ 65 years of age.
2. Is classified by the anesthesiologist as P1 to P2 in the American Society of Anesthesiologists (ASA) Physical Status Classification System.
3. Has undergone primary, unilateral, distal, first metatarsal bunionectomy (osteotomy and internal fixation) with no additional collateral procedures.
4. Experiences a pain intensity rating of ≥ 40 mm on a 100-mm Visual Analogue Scale (VAS) during the 9-hour period after discontinuation of the anesthetic block.
5. Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 40 kg/m2.
6. If female and of childbearing potential, is nonlactating and nonpregnant (has negative pregnancy test results at Screening \[urine\] and on the day of surgery prior to surgery \[urine\]).
7. 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:

   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.

   Total abstinence from sexual intercourse since the last menses before study drug administration through completion of final study visit.

   Intrauterine device (IUD). Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream).
8. Is able to provide written informed consent to participate in the study and able to understand the procedures and study requirements.
9. 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.
10. Is willing and able to comply with study requirements (including diet, alcohol, and smoking restrictions), complete the pain evaluations, remain at the study site for approximately 72 hours, and return for follow-up 7 ± 2 days after surgery.

Exclusion Criteria:

1. 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.
2. 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 continues into randomized treatment period or could confound the results of the study.
3. Has 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.
4. 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.
5. Has any ongoing condition, other than a condition associated with the current primary, unilateral, first metatarsal bunionectomy that could generate levels of pain sufficient to confound the results of the study (eg, gout, severe osteoarthritis of the target joint or extremity).
6. 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.
7. Has tested positive either on the urine drug screen or on the alcohol breathalyzer test. Subjects who test positive at Screening only and can produce a prescription for the medication from their physician may be considered for study enrolment at the discretion of the investigator.
8. 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.
9. 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.
10. Is considered by the investigator, for any reason (including, but not limited to, the risks described as precautions, warnings, and contraindications in the current version of the Investigator's Brochure for IV Maxigesic®), to be an unsuitable candidate to receive the study drug.
11. 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).
12. Is currently receiving anticoagulants (eg, heparin or warfarin).
13. 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).
14. Has received or will require any analgesic medication within 5 half-lives (or, if half-life is unknown, within 48 hours) before surgery.
15. 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.
16. Has been treated with agents that could affect the analgesic response (such as central alpha agents \[clonidine and tizanidine\], neuroleptic agents, and other antipsychotic agents) within 2 weeks before dosing with study drug.
17. 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 \[ALT\], and lactate dehydrogenase, or creatinine ≥ 1.5 times the ULN).
18. Has any clinically significant laboratory finding at Screening that, in the opinion of the investigator, contraindicates study participation.
19. Has significant difficulties swallowing capsules or is unable to tolerate oral medication.
20. Previously participated in another clinical study of Maxigesic® IV or received any investigational drug or device or investigational therapy within 30 days before Screening.