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

NCT02982161 | Completed Phase 3

• 1 other identifier: MR308-3501
• Study Type: interventional
• Target: 818
• Locations: 6 countries
• Sites: 7

Brief Summary

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.

Conditions

Acute Pain

Keywords

Third Molar Tooth Extraction

Outcome Measures

Primary Outcomes (1)

• Efficacy of MR308 doses in the treatment of moderate to severe acute pain, based on the Sum of Pain Intensity Differences (SPID).

  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.

  0-4 hours

Study Arms (5)

MR308 100 mg bid

ACTIVE COMPARATOR

Tramadol/Celecoxib 100 mg

Drug: MR308

MR308 150 mg bid

ACTIVE COMPARATOR

Tramadol/Celecoxib 150 mg

Drug: MR308

MR308 200 mg bid

ACTIVE COMPARATOR

Tramadol/Celecoxib 200 mg

Drug: MR308

Tramadol 100 mg qid

ACTIVE COMPARATOR

Tramadol IR 100 mg

Drug: Tramadol

Placebo

PLACEBO COMPARATOR

Placebo to match MR308 and Tramadol IR

Drug: Placebo

Interventions

MR308 DRUG

Over-encapsulated tablet, Dosing frequency: two times daily, Mode of administration: oral

Also known as: Tramadol/Celecoxib

MR308 100 mg bid; MR308 150 mg bid; MR308 200 mg bid

Tramadol DRUG

Over-encapsulated capsule, Dosing frequency: four times daily, Mode of administration: oral

Also known as: Tramadol immediate release

Tramadol 100 mg qid

Placebo DRUG

Capsule, Dosing frequency: four times daily, Mode of administration: oral

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male/female subjects ≥ 18 years on the day of consent.
• Willing and able to provide written informed consent for this study.
• 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.
• 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).
• Good general health as judged by Investigators on the basis of medical history and physical examination.
• Willingness to comply with the study procedures and requirements.
• Third molar extractions completed without any immediate complication.
• Tolerating oral fluids, no uncontrolled nausea/vomiting and ready to take oral analgesia.
• The subject is alert and calm, spontaneously pays attention to caregiver, e.g. RASS = 0 (Sessler et al., 2002 \& Ely et al., 2003).
• 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.

You may not qualify if:

• Any abnormal laboratory value that is clinically significant in the opinion of Investigator that would compromise the safety of the subject in the study.
• Any recent history of frequent nausea or vomiting, dizziness within the last 3 months regardless of etiology.
• 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.
• 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.
• Subjects who are known to have had inadequate pain relief from paracetamol, tramadol or celecoxib.
• Subjects requiring any medication which is prohibited as per section prohibited medication.
• Subjects who are in the Investigators opinion considered at increased risk of post-operative complications e.g. major dental infection/abscess.
• 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.
• 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.
• 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.
• Previous randomisation in this study.
• 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).
• 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.
• 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.
• Subjects who are incapable of complying with the protocol.

Sponsors & Collaborators

• Mundipharma Research GmbH & Co KG: lead

Study Sites (7)

Medical Arts Health Research Group

Penticton, Canada

Location

Mount Sinai Hospital

Toronto, Canada

Location

University Hospital Greifswald

Greifswald, Germany

Location

Semmelweis Egyetem Fogorvostudomnyi Kar

Budapest, Hungary

Location

Policlinico G.B. Rossi

Verona, Italy

Location

POLIMEDICA Centrum Badań, Profilaktyki i Leczenia Sp. z o.o. Sp. k.

Zgierz, Poland

Location

Facultad de Odontología, Universitat de Barcelona

Barcelona, Spain

Location

Related Publications (2)

• Viscusi ER, Langford R, Morte A, Vaque A, Cebrecos J, Sust M, Gimenez-Arnau JM, de Leon-Casasola O. Safety of Co-Crystal of Tramadol-Celecoxib (CTC) in Patients with Acute Moderate-to-Severe Pain: Pooled Analysis of Three Phase 3 Randomized Trials. Pain Ther. 2024 Dec;13(6):1617-1631. doi: 10.1007/s40122-024-00655-w. Epub 2024 Sep 24.

  PMID: 39316284 DERIVED

• Langford R, Pogatzki-Zahn EM, Morte A, Sust M, Cebrecos J, Vaque A, Ortiz E, Fettiplace J, Adeyemi S, Lopez-Cedrun JL, Bescos S, Gascon N, Plata-Salaman C. Co-crystal of Tramadol-Celecoxib Versus Tramadol or Placebo for Acute Moderate-to-Severe Pain After Oral Surgery: Randomized, Double-Blind, Phase 3 Trial (STARDOM1). Adv Ther. 2024 Mar;41(3):1025-1045. doi: 10.1007/s12325-023-02744-2. Epub 2024 Jan 6.

  PMID: 38183526 DERIVED

MeSH Terms

Conditions

Acute Pain

Interventions

Tramadol; Celecoxib

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Organic Chemicals; Dimethylamines; Methylamines; Amines; Lipids; Benzenesulfonamides; Sulfonamides; Amides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2016
• First Posted: December 5, 2016
• Study Start: December 28, 2016
• Primary Completion: January 4, 2018
• Study Completion: January 4, 2018
• Last Updated: May 29, 2018

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1); DE (1); ES (1); PL (1); HU (1); CA (2)