Ibuprofen Liquid Capsules 2 x 200 mg Efficacy and PK/PD Study in Surgical Removal of Impacted Third Molars

A Randomised, Double-blind, Double-dummy, Parallel-group, Single Dose, Active and Placebo-controlled Efficacy and Pharmacokinetics/Pharmacodynamics Study of 2 x 200 mg Ibuprofen Liquid Capsules for the Treatment of Pain After Surgical Removal of Impacted Third Molars.

This is a single centre, three-arm randomised, double-blind, double-dummy, parallel group, single-dose, active and placebo-controlled efficacy and pharmacokinetics/ pharmacodynamics study to evaluate the efficacy and safety of 2 x 200 mg Ibuprofen Liquid Capsules in subjects with post-operative 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.

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 a single dose of 2×200 mg Ibuprofen Liquid Capsules, 2×200 mg ibuprofen tablets, or placebo. The randomisation will be stratified by baseline pain category (moderate or severe) using a categorical scale based on the NRS score 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, 10, 20, 30 and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 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 and satisfaction with pain relied assessment 12 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 hours after Time 0, immediately before the first dose of rescue medication(if required) and at the follow-up visit. 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 12 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).

Other restrictions include the following: alcohol use is prohibited from 24 hours before surgery until discharge on Day 2; Food will be restricted from midnight before surgery until 4 hour after surgery; during this time, water may be permitted up to 2 hours prior to surgery and a single drink of 8 fluid ounces of water with their treatment, water will not be permitted until 1 hour post dose. Vaccinations should not have been administered 7 days prior to surgery, subjects should avoid strenuous physical activity from 72 hours prior to dosing, and will not be permitted to smoke or use nicotine containing products for the duration of their involvement in the study.

A subset of 70 subjects will be randomly selected from the study population to take part in a Pharmacokinetic sub study. Blood samples will be collected at 10, 15, 20, 30 and 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post dose.

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:

• Subject has provided written informed consent (for subjects who are below the age of legal consent, parent(s) or legally authorized representative(s) provides written informed consent and the subject provides written assent).
• Subject is male or female and aged ≥16 and ≤55 years of age at screening.
• 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.
• Experiences moderate to severe pain intensity within 6 hours after surgery, as measured by a NRS score of ≥ 5 on a 0-10 scale.
• Has a body weight ≥ 45 kg and a BMI ≥17 kg/m2 and ≤ 30 kg/m2.
• Female subjects or the female partners of male subjects of childbearing potential must be using a highly effective method of contraception for at least one month prior to screening, throughout the study and for one menstrual cycle after last drug administration. [A highly effective method of contraception is defined as a method that can achieve a low failure rate of less than 1% per year when used consistently and correctly. Such methods include combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, injectable & implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomised partner (who has received medical assessment of the surgical success), or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments and must be the preferred and usual lifestyle of the subject)].
• Free of clinically significant abnormal findings as determined by medical history, physical examination, vital signs, laboratory tests and ECG.
• Is willing and able to comply with study requirements (including diet and smoking restrictions), complete the pain evaluations, remain at the study site overnight (if necessary) and return for follow-up 7 (± 2) days after surgery, (Day 8 ± 2 days).

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.
• In the opinion of the investigator, any subject with a clinically relevant history of peptic ulceration, gastrointestinal bleeding or perforation, heart failure, renal or hepatic failure, uncontrolled hypertension, nasal polyps, or chronic rhinitis.
• In the opinion of the investigator, the participant has a clinically significant history of asthma or a documented intolerance to NSAIDs resulting in exacerbation of symptoms.
• 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 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) or positive alcohol breathalyser test during the study.
• 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.
• Is a current smoker (including any nicotine products e.g., e-cigarettes or chewing tobacco) or ex-smoker who has smoked or used nicotine replacement products within 1 year of screening
• 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.
• Those taking medicinal products prone to drug-drug interactions described in the investigator's brochure [IB]. These include Acetyl Salicylic Acid, other NSAIDs including cyclo-oxygenase-2 selective inhibitors, anticoagulants, antihypertensives (ACE inhibitors and Angiotensin II receptor antagonists) and diuretics, corticosteroids, anti-platelet agents and Selective Serotonin Re-uptake Inhibitors (SSRIs), cardiac glycosides, lithium, methotrexate, ciclosporin, mifepristone, tacrolimus, zidovudine and quinolone antibiotics.
• 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 200 mg ibuprofen liquid capsules), 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, including topical), opiates, or corticosteroids (except inhaled nasal steroids), for any condition within 3 months before dosing with study drug.
• Has significant difficulties swallowing capsules or tablets or is unable to tolerate oral medication.
• Subject has received an investigational product or participated in another trial involving a marketed or investigational drug in the 90 days (or for investigational agents with a long half-life, a washout of 5 half-lives) prior to first drug administration (washout period between studies is defined as the period of time elapsed between the last dose of the previous study and first dose for this study). Or if the investigator believes that any previous participation in an investigational study would be to the detriment of the safety of the participant or the conduct of the study.
• 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.