Maxigesic IV Phase 3 Bunionectomy Study

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

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.