Efficacy and Safety in a Randomised Acute Pain Study of MR308 (Tramadol/Celecoxib).

A Randomized, Double-Blind, Multicenter, Placebo- and Active Comparator-Controlled Study to Evaluate Efficacy and Safety of MR308 in the Treatment of Acute Pain After Third Molar Tooth Extraction (STARDOM1).

The MR308-3501 study is a multicenter, randomised, double-blind, parallel-group study in male and female adult subjects to demonstrate the efficacy of MR308 in the treatment of acute moderate to severe pain after the extraction of at least two third molars requiring bone removal.

This is a multicenter double-blind, randomised, phase III study in male and female subjects with acute pain after third molar tooth extraction. The dental procedure must have involved extraction of at least two impacted third molars requiring bone removal. If only two impacted third molars are extracted, they must be ipsilateral and both require bone removal under local anaesthesia.

The Screening Visit (Visit 1) can take place up to 28 days before the planned third molar extractions. The randomisation visit (Visit 2) consists of three different sections, a part before the surgery, the part with the surgery and before randomisation, and a part with the randomisation and post-randomisation assessments. The visits 3 and 4, one respectively two days after the randomisation can be performed by telephone if the subject does not participate in the pharmacokinetic sampling.

The last dose of IMP should be taken by the subject about 72h after the initial dose and before the Completion/Discontinuation Visit (Visit 5) is performed.

The Adverse Event (AE) Follow-up Visit (Visit 6) is the last study visit and should not be done earlier than seven days after the subject's last dose of IMP. It can be performed by telephone.

Inclusion Criteria:

1. Male/female subjects ≥ 18 years on the day of consent.
2. Willing and able to provide written informed consent for this study.
3. Subjects must have a planned elective dental procedure i.e. extraction of at least two impacted third molars (one of them must be mandibular) requiring bone removal, within 28 days after the Screening Visit. If only two impacted third molars are extracted, they must be ipsilateral and require bone removal.
4. If a female is of child-bearing potential, she must be using highly effective methods of contraception throughout the study, not breastfeeding, and have negative pregnancy tests prior to receiving IMP. 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 sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasectomised partner).
5. Good general health as judged by Investigators on the basis of medical history and physical examination.
6. Willingness to comply with the study procedures and requirements.

Additional Inclusion Criteria after Surgery:

1. Third molar extractions completed without any immediate complication.
2. Tolerating oral fluids, no uncontrolled nausea/vomiting and ready to take oral analgesia.
3. The subject is alert and calm, spontaneously pays attention to caregiver, e.g. RASS = 0 (Sessler et al., 2002 & Ely et al., 2003).
4. Subjects with moderate or severe pain (qualifying PI-VAS score ≥ 45mm and < 70mm or ≥ 70mm) as a result of an oral surgical procedure under local anaesthesia and/or sedation*. This must be measured within a maximum of 6 hours after the end of the surgical procedure.

Exclusion Criteria:

1. Any abnormal laboratory value that is clinically significant in the opinion of Investigator that would compromise the safety of the subject in the study.
2. Any recent history of frequent nausea or vomiting, dizziness within the last 3 months regardless of etiology.
3. Subjects having any medical condition or treatment that is either a warning or contraindication as per the SmPC of tramadol (e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, MAO inhibitors (within 14 days before taking IMP), antipsychotics, anticonvulsant and other seizure threshold-lowering medicinal products), celecoxib (e.g. increased risk of post-operative bleeding, active peptic ulceration, GI bleeding or inflammatory bowel disease) or paracetamol.
4. Known sensitivity and/or contraindication to tramadol, celecoxib, paracetamol, sulfonamides, opioids, NSAIDS, COX-2 inhibitors, or related compounds or formulation excipients as well as severe hypersensitivity reactions (e.g. anaphylactic shock, bronchospasm, angioedema) to any drugs.
5. Subjects who are known to have had inadequate pain relief from paracetamol, tramadol or celecoxib.
6. Subjects requiring any medication which is prohibited as per section prohibited medication.
7. Subjects who are in the Investigators opinion considered at increased risk of post-operative complications e.g. major dental infection/abscess.
8. Any history of drug or alcohol abuse, misuse, physical or psychological dependence, mood changes, sleep disturbance and functional capacity which have an impact on pain perception.
9. Significant neurological or psychiatric disorders including mental instability (unrelated to the pain) that could interfere with pain assessment; other pain that might impair the assessment of the nociceptive pain.
10. Any medical history of significant and/or inadequately controlled cardiovascular (uncontrolled high blood pressure, high risk of cardiovascular events, severe heart failure), pulmonary, hematologic, (including coagulopathy/bleeding disorders), neurological (e.g. subjects with epilepsy or those susceptible to seizures), liver disease (e.g. severe hepatic impairment), kidney disease (e.g. serum creatinine level greater than 1.5 times the upper limit of normal, impaired renal function in subjects taking diuretics, ACE-inhibitors, or angiotensin II antagonists), endocrine, immunologic, dermatologic painful conditions or any other conditions that may compromise the ability of the subject to participate in the study or might interfere with drug absorption, distribution, metabolism or excretion.
11. Previous randomisation in this study.
12. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study entry (defined as the start of the Screening Period).
13. Subjects who were treated regularly with opioid analgesic or NSAIDs within 30 days prior to screening or who have received a long-acting NSAID within three days prior to the start of the surgery.
14. Subjects who have received any analgesic medication (e.g. NSAIDs, oral opioid preparations etc.) other than short-acting preoperative or intraoperative local anaesthetic agents within 12 hours before the start of the surgery or peri operatively until randomisation.
15. Subjects who are incapable of complying with the protocol.

Additional Exclusion Criteria after Surgery:

1. Serious complication during surgery and up to randomisation, including:

   • Post-operative primary and secondary bleed that cannot be controlled.
   • Subjects who did not had the third molar extraction completed as planned.

2. Post-operative medications or treatments that can have an analgesic effect or cause sedation or have amnesic effect are not permitted as these may interfere with the study assessments. These include use of ice packs, corticosteroids, nitrous oxide, benzodiazepines, alcohol, hypnotics, analgesics, opioids, other psychotropic medicinal products and any other analgesia except the provided study treatments

3. If in the Investigators opinion there are any factors that may confound the analysis of the study regarding efficacy and safety (e.g. a PI-VAS score greater than 90).