Co-crystal E-58425 vs Tramadol and Celecoxib for Moderate to Severe Acute Pain After Bunionectomy. Phase III Clinical Trial.

NCT03108482 | Completed Phase 3 Results FDA Drug

• 1 other identifier: ESTEVE-SUSA-301
• Study Type: interventional
• Target: 637
• Locations: 1 country
• Sites: 5

Brief Summary

This is a Phase 3, randomized, double-blind, controlled, parallel-group, multicenter clinical trial with co-crystal E-58425 compared to tramadol, to celecoxib, and to placebo. The primary objective of the trial is to establish the analgesic efficacy of co-crystal E-58425 by demonstrating a superior effect compared to tramadol and to celecoxib for the management of moderate to severe acute post-operative pain for 48 hours after bunionectomy.

Conditions

Acute Post-surgical Pain

Keywords

Acute Pain; Post-surgical Pain; Bunionectomy; Co-crystal; Tramadol; Celecoxib

Outcome Measures

Primary Outcomes (1)

• Sum of Pain Intensity Differences (SPID)

  The primary efficacy variable was the Pain Intensity (PI) measured by the Numerical Pain Rating Scale (NPRS); a scale from zero to 10 on which subjects circled a single number to indicate current pain level, with zero representing "No Pain" and 10 representing "Worst Possible Pain". The primary analysis endpoint was the Sum of Pain Intensity Differences (SPID) from 0 to 48 hours. Pain Intensity Differences (PID) was the difference between current PI at assessment minus baseline PI (prior to the first dose). Baseline PI ranged from 5 to 9. SPID was calculated as a time-weighted Sum of PID scores over 48 hours. Negative differences correspond to an amelioration of pain, while positive differences correspond to recrudescence of pain. The total scale ranged from -480 (best) to +480 (worst). A higher negative value of SPID indicates greater pain relief.

  Assessments was recorded from time 0 to 48 hours.

Study Arms (4)

Co-crystal E-58425 (Tramadol/Celecoxib)

EXPERIMENTAL

Co-crystal E-58425 (Tramadol/Celecoxib): Two tablets of 100 mg every 12 hours. The total daily dose will be 400 mg of Co-crystal E-58425.

Drug: Co-crystal E-58425 (Tramadol/Celecoxib)

Tramadol (Ultram®)

ACTIVE COMPARATOR

Tramadol: One tablet of 50 mg every 6 hours. The total daily dose will be 200 mg of tramadol.

Drug: Tramadol (Ultram®)

Celecoxib (Celebrex®)

ACTIVE COMPARATOR

Celecoxib: One capsule of 100 mg every 12 hours. The total daily dose will be 200 mg of celecoxib.

Drug: Celecoxib (Celebrex®)

Placebo

PLACEBO COMPARATOR

Placebo: One or two tablets of 100 mg every 6 hours.

Drug: Placebo

Interventions

Co-crystal E-58425 (Tramadol/Celecoxib) DRUG

Co-crystal E-58425 (Tramadol/Celecoxib): Two immediate release oral over-encapsulated tablets of 100 mg, every 12 hours for 48 hours.

Co-crystal E-58425 (Tramadol/Celecoxib)

Tramadol (Ultram®) DRUG

Tramadol: One immediate release oral over-encapsulated tablet of 50 mg, every 6 hours for 48 hours.

Tramadol (Ultram®)

Celecoxib (Celebrex®) DRUG

Celecoxib: One immediate release oral over-encapsulated capsule of 100 mg, every 12 hours for 48 hours.

Celecoxib (Celebrex®)

Placebo DRUG

Placebo 100 mg or 200 mg oral over-encapsulated tablets every 6 hours for 48 hours.

Placebo

Eligibility Criteria

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

You may qualify if:

• Subject must have signed consent before study entry.
• Subject must be at least 18 years old, scheduled to undergo primary unilateral first metatarsal osteotomy with internal fixation with no additional collateral procedure.
• Male and female subjects are eligible. If female, subject must be either not of childbearing potential (defined as postmenopausal for at least 1 year or surgically sterile \[bilateral tubal ligation, bilateral oophorectomy, or hysterectomy\]) or practicing 1 of the following effective methods of birth control:
• Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal contraceptives.
• Total abstinence from sexual intercourse since the last menses before study medication administration.
• Intrauterine device
• Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or cream).
• Women must use effective methods of birth control from 6 weeks before administration of study medication until 4 weeks after the last administration.
• If female and of childbearing potential, subject must be non-lactating and non pregnant (has negative serum pregnancy test results at Screening and negative urine test on the day of surgery prior to surgery).
• Subject must have a body weight of 45 kg or more and a body mass index (BMI) of 40 kg/m2 or less.
• Subject must have a qualifying pain score of ≥5 and \<9 on the 0-10 NPRS at rest as a result of turning off the popliteal sciatic block for bunionectomy to be eligible for randomization.
• Subject must be in good physical health in the investigator's judgment.
• Subject must be sufficiently alert to understand and communicate intelligibly with the study observer.

You may not qualify if:

• Subject's Baseline pain is \<5 or \>9 on a 0-10 NPRS.
• Subject received any analgesic medication other than short-acting pre-operative or intra-operative anesthetic agents before the end of bunionectomy surgical procedure. Subjects who received any analgesic medication immediately after the bunionectomy surgical procedure was completed and before study medication is administered will also be excluded, with the exception of ketorolac 30 mg intravenously supplemental analgesia during the continuous infusion period and up until 1:00 A.M.
• Subject has a history of seizures or alcohol abuse (eg, drinks \>4 units of alcohol per day, a unit being equal to 8 oz. beer, 3 oz. wine, 1 oz. spirits) within the past 5 years, has a history of prescription/illicit drug abuse within 6 months before dosing with study medication, or has positive results on the urine drug screen or alcohol breath test indicative of illicit drug or alcohol abuse.
• Subject has a history of or positive test results for human immunodeficiency virus or hepatitis B or C.
• Subject has an active malignancy of any type, or has been diagnosed with cancer within 5 years before Screening (excluding successfully treated squamous or basal cell carcinoma of the skin).
• Subject is currently receiving anticoagulants (eg, heparin or warfarin) or antiplatelets (except aspirin ≤325 mg/day).
• Subject has received a course of systemic (either oral or parenteral) or intra-articular corticosteroids within 3 months before Screening (inhaled nasal steroids and topical corticosteroids are allowed).
• Subject has any ongoing condition, other than one associated with the current primary, unilateral, first metatarsal bunionectomy, that, in the investigator's opinion, could generate levels of pain sufficient to confound assessments of post-operative pain (eg, severe osteoarthritis of the target joint or extremity, fibromyalgia, rheumatoid arthritis, moderate to severe headache, diabetic foot pain or neuropathy).
• Subject has been receiving or has received chronic (defined as daily use for \>2 weeks) opioid (oral codeine, dextromoramide, dihydrocodeine, oxycodone, or morphine-like anti-tussive) therapy defined as \>15 morphine equivalents units per day for more than 3 out of 7 days per week over a 1-month period within 12 months of surgery, or has been treated chronically with opioid analgesic (buprenorphine, nalbuphine, or pentazocine) or NSAIDs within 30 days before Screening.
• Subject received a long-acting Non-Steroidal Anti-Inflammatory Drug (NSAID) within 4 days before initiation of study medication (except aspirin ≤325 mg/day), or a short-acting NSAID within 1 day.
• Subject is under long-term treatment with opioid agonist-antagonists.
• Subject has used drugs with enzyme-inducing properties, such as rifampicin and St. John's Wort, or any drug known to be a strong inhibitor or inducer of CYP3A4, CYP2C9, or CYP2D6 within 3 weeks before surgery.
• Subject is pregnant or lactating.
• Subject had any complication during primary bunionectomy surgery.
• Subject has received monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or other drugs that reduce the seizure threshold within 4 weeks of study entry.

Sponsors & Collaborators

• Esteve Pharmaceuticals, S.A.: lead
• Premier Research: collaborator

Study Sites (5)

Arizona Research Center

Phoenix, Arizona, 85023, United States

Location

Anaheim Clinical Trials, LLC

Anaheim, California, 92801, United States

Location

Chesapeake Research Group, LLC

Pasadena, Maryland, 21122, United States

Location

Optimal Research, LLC

Austin, Texas, 78705, United States

Location

Jean Brown Research

Salt Lake City, Utah, 84124, United States

Location

Related Publications (2)

• Morte A, Sust M, Vaque A, Cebrecos J, Gimenez-Arnau JM. Adverse Reactions Following First-Dose Administration of Co-Crystal of Tramadol-Celecoxib Versus Tramadol Alone for Moderate-To-Severe Acute Pain. Pain Ther. 2025 Jun;14(3):1147-1154. doi: 10.1007/s40122-025-00730-w. Epub 2025 May 2.

  PMID: 40314885 DERIVED

• 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

MeSH Terms

Conditions

Acute Pain; Pain, Postoperative

Interventions

Tramadol; Celecoxib

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Postoperative Complications; Pathologic Processes

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

Results Point of Contact

• Title: Dr. Neus Gascon
• Organization: Esteve Pharmaceuticals, S.A.

ngascon@esteve.com

+34934446000

Study Officials

• Jesus Cebrecos, MD, MBA

  Esteve Pharmaceuticals, S.A.

  STUDY DIRECTOR

• Michael Kuss

  Premier Research

  STUDY CHAIR

• Ira J Gottlieb, DPM

  Chesapeake Research Group, LLC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

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: March 30, 2017
• First Posted: April 11, 2017
• Study Start: March 14, 2017
• Primary Completion: November 9, 2017
• Study Completion: November 28, 2017
• Last Updated: January 24, 2019
• Results First Posted: January 9, 2019

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)