| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute pain after third molar tooth extraction; dental procedure must have involved extraction of at least two impacted third molars requireing bone removal. If only two impacted third molars are extracted, they must be ipsilateral and both required bone removal under local anaesthesia. |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of acute pain after third molar tooth extraction |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066714 |
| E.1.2 | Term | Acute pain |
| E.1.2 | System Organ Class | 100000004867 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the efficacy of MR308 doses in the Treatment of acute moderate to severe pain. Efficacy will be assessed by showing superiority of MR308 doses over Placebo and non-inferiority compared with Tramadol, followed by superiority over Tramadol based on teh sum of pain intesity differences over 0-4 hours (SPID4). |
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| E.2.2 | Secondary objectives of the trial |
To compare the effficacy of MR308 doses versus Tramadol and Placebo based on the secondary efficacy endpoints.
To compare the safety and tolerability of MR308 doses versus Tramadol and Placebo. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
All subjects enrolled in the study will be considered for enrolment into the pharmacogenomic sub-study sponsored by
Mundipharma Research GmbH & Co. KG.
Pharmacogenomic samples will be collected and stored at the Sponsors designated storage repository to provide a resource for future genomic analysis, which will examine why subjects may respond differently to certain drugs by analysing genetic markers. The
identification of genetic biomarkers underlying variability in drug efficacy or safety endpoints may be particularly valuable to inform drug labelling and ultimately optimise patient therapy. For example, variations in genes involved in the metabolism of drug compounds e.g. Cytochrome P450 2D6, can have an influence on the bioavailability of the compounds which could lead to an increased level of side effects or an alteration of drug
efficacy. Therefore some drugs may be more effective in certain subject groups or they may cause more side effects in certain subjects depending on their genetic make up.
Under a separate informed consent process, subjects will be invited to consent to blood sampling for pharmacogenomic testing. The collected blood samples will be anonymised, processed and DNA stored for future analysis. The consent to pharmacogenomic sampling is completely separate from the main study and subjects will be able to take part in the main study without consenting to pharmacogenomic blood sampling. Blood
sampling must take place prior to receiving any dose of IMP.
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| E.3 | Principal inclusion criteria |
Only subjects meeting all of the following inclusion criteria will be considered for study inclusion:
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.
* Randomisation within one pain group may be temporarily closed, please see section 11.4 for further details.
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| E.4 | Principal exclusion criteria |
Subjects having any of the following criteria must not be included in the study.
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. 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. 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).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the Sum of Pain Intensity Differences over 0-4 hours (SPID4). SPID4 is derived as the weighted Sum of Pain Intensity Differences (baseline pain – current pain), measured at different time points via the PI-VAS. Time between two consecutive measurements will be used for weighting. Larger values indicate larger pain relief. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
1. 50% responder at 4 hours, defined as subjects with a reduction in pain intensity (PI-VAS) from 0 hours at 4 hours of at least 50%.
2. Use of at least one dose of rescue medication during the first 4 hours.
Other secondary endpoints:
1. SPID over 0-12 hours, 0-24 hours, 0-48 hours and 0-72 hours.
2. Pain (PI-VAS) at each post-dose time point.
3. Pain Relief (PAR) at each post-dose time point.
4. Total Pain Relief (TOTPAR) over 0-4 hours, 0-12 hours, 0-24 hours, 0-48 hours and 0-72 hours, defined as the sum of respective PAR, weighted with the time between two consecutive measurements.
5. Worst pain as per PI-VAS experienced by subjects in 24 and 48 hours from first IMP intake.
6. Responder based on PI-VAS
• 50% responder, based on PI-VAS at 12, 24, 48 and 72 hours.
• 30% responder, based on PI-VAS at 4, 12, 24, 48 and 72 hours.
7. Time to 30% and time to 50% response based on PI-VAS.
8. Time to perceptible pain relief and time to meaningful pain relief.
9. Rescue medication use.
• Average dose of rescue medication per 24 hours.
• Time to first intake of rescue medication.
10. EQ-5D-5L at 4, 24, 48, and 72 hours.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 15 |
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