Efficacy of 300mg Ibuprofen Prolonged-Release Tablets for the Treatment of Pain After Surgical Removal of Impacted Third Molars

This is a single centre, randomised, double blind, double-dummy, parallel group ,
multiple-dose, active and placebo controlled efficacy study to evaluate the efficacy and
safety of ibuprofen 2×300 mg ibuprofen PR tablets in subjects with postoperative dental pain.

Eligible subjects will complete all screening procedures within 28 days before the surgery
and randomisation.

At Screening, subjects will provide written informed consent to participate in the study
before any protocol specified procedures or assessments are completed. On Day 1, subjects who
continue to be eligible for study participation after completing screening procedures and
assessments will undergo extraction of 2 or more third molars. At least 1 of the third molars
must be a fully or partially bone impacted mandibular molar. If only 2 molars are removed,
then they must be ipsilateral.

All subjects will receive local anaesthesia (2% lidocaine with 1:100,000 epinephrine).
Nitrous oxide will be allowed at the discretion of the investigator. Subjects who experience
moderate to severe pain intensity (a score of ≥ 5 on a numeric rating scale [NRS] from 0-10
where 0 = no pain, 10 = worst pain ever) within 6 hours after surgery and who continue to
meet all study entry criteria will be randomised in a 3:3:1 ratio to receive 2×300 mg
ibuprofen PR tablets every 12 hours (Q12h), 2×200 mg ibuprofen IR tablets every 8 hours
(Q8h), or placebo. The randomisation will be stratified by baseline pain category (moderate
or severe) using a categorical scale that includes the categories of none (0), mild (1-4),
moderate (5-7), and severe (8-10).

Subjects will re-assess their baseline pain intensity using the NRS immediately before
receiving study drug (pre-dose, Time 0) and their pain intensity (NRS) and pain relief (5
point categorical scale) at the following time points (pre-dose, if at one of the dosing
timepoints of 0, 8, 12 and/or 16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6,
7, 8, 10, 12, 16, and 24 hours after Time 0; and immediately before each dose of rescue
medication, if any. For assessments less than 1 hour apart a window of +/-2 min is allowable
whilst for assessments at least 1 hour apart a +/-5 min window is allowable.

The double stopwatch method will be used to record the time to perceptible pain relief and
time to meaningful pain relief during the 8 hours following the first dose or until subject
takes rescue medication. Subjects will complete a global evaluation of study drug 24 hours
(+/- 5 minutes) after Time 0 or immediately before the first dose of rescue medication
(whichever occurs first). Vital signs will be recorded after the subject has been in a
sitting position for 3 minutes at the following times: before surgery, within 30 minutes
before Time 0, 12 and 24 hours after Time 0, and/or immediately before the first dose of
rescue medication. Adverse events (AEs) will be monitored and recorded from the time of
signing of the informed consent form (ICF) until the Follow up Visit (or Early Termination
Visit). During the 24 hours following Time 0, subjects will complete efficacy and safety
assessments. Subjects will remain at the study site overnight and will be discharged on Day
2.

Paracetamol / acetaminophen (1000 mg) will be permitted as the initial rescue medication.
Subjects will be encouraged to wait at least 60 minutes after receiving study drug before
taking rescue medication. If acetaminophen rescue medication is not effective in relieving
the subject's pain, 5 mg oxycodone rescue medication may be administered at the discretion of
the investigator.

Subjects are not permitted to take any concomitant medications that might confound
assessments of pain relief, such as psychotropic drugs, antidepressants, sedative-hypnotics
(other than those permitted for conscious sedation), or other analgesics taken within five
times of their elimination half-lives (other than those used at the surgery). Selective
serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors
(SNRIs) are permitted if the subject has been on a stable dose for at least four weeks prior
to Visit 1 (screening).

Other restrictions include the following: alcohol use is prohibited from 24 hours before
surgery until discharge on Day 2; nothing by mouth from midnight before surgery until 1 hour
after surgery; clear liquids only are allowed starting 1 hour after surgery until 1 hour
after dosing; 1 hour after dosing, the subject's diet may be advanced according to standard
practice.

Upon discharge from the study site, subjects may be prescribed pain medication for use at
home according to the standard practice of the study site. On Day 8 (± 2 days), subjects will
return to the study site for an abbreviated confirmatory physical assessment and AE
assessments.

Inclusion Criteria:

- Is male or female ≥ 18 and ≤ 50 years of age.

- Requires extraction of 2 or more third molars. At least 1 of the third molars must be
a fully or partially bone impacted mandibular molar. If only 2 molars are removed,
then they must be ipsilateral.

- Experiences moderate to severe pain intensity within 6 hours after surgery, as
measured by a numeric rating scale (NRS) score of ≥ 5 on a 0-10 scale.

- Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 35 kg/m2.

- Female subjects of child-bearing potential must be willing to use a highly effective
method of contraception throughout the study. A highly effective method of birth
control is defined as one which results in a low failure rate (i.e. less than 1% per
year) when used consistently and correctly, such as the following:

1. surgical sterilisation

2. contraceptive implants or injectables

3. combined oral contraceptives

4. some intrauterine devices (IUDs)

5. true sexual abstinence, when this is in line with the preferred and usual
lifestyle of the subject (periodic abstinence such as calendar, ovulation,
symptothermal, or post-ovulation methods; declaration of abstinence for the
duration of the trial; or withdrawal are not acceptable methods of
contraception), or

6. vasectomised partner. To be considered not of child-bearing potential, females
must be surgically sterile (defined as bilateral tubal ligation, bilateral
oophorectomy, or hysterectomy) or post-menopausal (defined as no menses for 12
months in women not using hormonal contraception or hormone replacement therapy,
confirmed by a follicle stimulating hormone (FSH) level in the postmenopausal
range at Screening).

- Free of clinically significant abnormal findings as determined by medical history,
physical examination, vital signs, laboratory tests and ECG.

- Is able to provide written informed consent.

- Is willing and able to comply with study requirements (including diet and smoking
restrictions), complete the pain evaluations, remain at the study site overnight, and
return for followup 7 (± 2) days after surgery.

Exclusion Criteria:

- Known hypersensitivity reactions or allergy (e.g., asthma, rhinitis, angioedema or
urticaria) in response to nonsteroidal anti-inflammatory drugs (NSAIDs, including
ibuprofen), acetylsalicylic acid (aspirin), ingredients of the study drug, or any
other drugs used in the study, including anaesthetics and antibiotics that may be
required on the day of surgery.

- A history of active or previous peptic ulceration/ haemorrhage, gastrointestinal
bleeding or perforation, heart failure, renal or hepatic failure, uncontrolled
hypertension, asthma, nasal polyps, or chronic rhinitis.

- Has complications from the tooth extraction or any other clinically significant
medical history that, in the opinion of the investigator, would affect the subject's
ability to comply or otherwise contraindicate study participation, including but not
limited to the following: cardiac, respiratory, gastroenterological, neurological,
psychological, immunological, haematological, oncological, or renal disease.

- Has undergone another dental surgery within 60 days prior to the day of surgery.

- A positive urine drugs of abuse screen or alcohol breathalyser test at screening and
during the study (with the exception of a positive drugs of abuse screen that is a
consequence of permitted prescription medicines).

- If female, has a positive pregnancy test at screening (serum) or on the day of surgery
prior to surgery (urine), or is lactating.

- Has known or suspected, (in the opinion of the investigator), history of alcoholism or
drug abuse within 2 years of screening or evidence of tolerance or physical dependence
before dosing with study drug.

- Taking any concomitant medications that might confound assessments of pain relief,
such as psychotropic drugs, antidepressants, sedative-hypnotics (other than those
permitted for conscious sedation), or other analgesics taken within five times of
their elimination half-lives. Selective serotonin reuptake inhibitors (SSRIs) and
serotonin and noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject
has been on a stable dose for at least four weeks prior to Visit 1 (screening).

- 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 (IB) for 300 mg ibuprofen PR tablets), to be an
unsuitable candidate to receive the study drug.

- Has a history of chronic use (defined as daily use for > 2 weeks) of nonsteroidal
anti-inflammatory (NSAIDs), opiates, or glucocorticoids (except inhaled nasal steroids
and topical corticosteroids), for any condition within 6 months before dosing with
study drug.

- Has significant difficulties swallowing capsules or tablets or is unable to tolerate
oral medication.

- Previously participated in another clinical study of 300 mg ibuprofen PR tablets, or
received any investigational drug, device, or therapy within 90 days before screening.

- Enrolment of the Investigator, his / her family members, employees and other dependent
persons.

- Failure to satisfy the investigator of fitness to participate for any other reason.