Co-crystal E-58425 vs Tramadol and Celecoxib for Moderate to Severe Acute Pain After Bunionectomy. Phase III Clinical Trial.
Condition: Acute Post-surgical Pain
MeSH terms: Pain, Postoperative
Intervention: Co-crystal E-58425 (Tramadol/Celecoxib); Tramadol (Ultram®); Celecoxib (Celebrex®); Placebo
Intervention description: Co-crystal E-58425 (Tramadol/Celecoxib): Two immediate release oral over-encapsulated tablets of 100 mg, every 12 hours for 48 hours.; Tramadol: One immediate release oral over-encapsulated tablet of 50 mg, every 6 hours for 48 hours.; Celecoxib: One immediate release oral over-encapsulated capsule of 100 mg, every 12 hours for 48 hours.; Placebo 100 mg or 200 mg oral over-encapsulated tablets every 6 hours for 48 hours.
Intervention MeSH terms: Celecoxib; Tramadol
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 637.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Pain; Post-surgical Pain; Bunionectomy; Co-crystal; Tramadol; Celecoxib

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject must have signed consent before study entry.

          2. Subject must be at least 18 years old, scheduled to undergo primary unilateral first
             metatarsal osteotomy with internal fixation with no additional collateral procedure.

          3. 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.

          4. 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).

          5. Subject must have a body weight of 45 kg or more and a body mass index (BMI) of 40
             kg/m2 or less.

          6. 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.

          7. Subject must be in good physical health in the investigator's judgment.

          8. Subject must be sufficiently alert to understand and communicate intelligibly with the
             study observer.

        Exclusion Criteria:

          1. Subject's Baseline pain is <5 or >9 on a 0-10 NPRS.

          2. 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.

          3. 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.

          4. Subject has a history of or positive test results for human immunodeficiency virus or
             hepatitis B or C.

          5. 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).

          6. Subject is currently receiving anticoagulants (eg, heparin or warfarin) or
             antiplatelets (except aspirin ≤325 mg/day).

          7. 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).

          8. 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).

          9. 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.

         10. 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.

         11. Subject is under long-term treatment with opioid agonist-antagonists.

         12. 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.

         13. Subject is pregnant or lactating.

         14. Subject had any complication during primary bunionectomy surgery.

         15. Subject has received monoamine oxidase inhibitors, tricyclic antidepressants,
             neuroleptics, or other drugs that reduce the seizure threshold within 4 weeks of study
             entry.

         16. Subject has a history or evidence of a clinically significant (in the investigator's
             opinion) gastrointestinal (GI) event within 6 months before Screening or has any
             history of peptic or gastric ulcers or GI bleeding.

         17. Subject has clinically significant renal or hepatic disease, as indicated by clinical
             laboratory assessment (results ≥3 times the upper limit of normal for any liver
             function test, including aspartate aminotransferase, alanine aminotransferase,
             bilirubin, and lactate dehydrogenase, or creatinine ≥1.5 times the upper limit of
             normal). Laboratory tests may be repeated once at Screening to rule out laboratory
             error.

         18. Subject has any clinically significant laboratory or 12-lead electrocardiogram (ECG)
             finding at Screening that, in the opinion of the investigator, contraindicates study
             participation (eg, QTc >450 msec [male] or >470 msec [female]).

         19. Subject has a known history of allergic reaction or clinically significant intolerance
             to acetaminophen, aspirin, opioids, or any NSAIDs; history of NSAID induced
             bronchospasm (subjects with the triad of asthma, nasal polyps, and chronic rhinitis
             are at greater risk for bronchospasm and should be considered carefully) or to the
             ingredients of the study medication, or any other drugs used in the study, including
             anesthetics and antibiotics that may be required on the day of surgery.

         20. Subject has received anti-depressive medication with serotonin-norepinephrine reuptake
             inhibitors (SNRIs; milnacipran, duloxetine, venlafaxine), diet pills (including
             fenfluramine and phentermine) or methylphenidate (Ritalin®), or other similar
             medications for attention deficit hyperactivity disorder (ADHD) within 4 weeks of
             study entry. Subjects receiving selective serotonin reuptake inhibitors (SSRIs) may be
             included provided they have been on a stable dose for 60 days prior to study
             participation and plan to remain on that dose throughout the study.

         21. Subject is at risk in terms of precautions, warnings, and contraindications in the
             package insert for Ultram® (tramadol hydrochloride) or Celebrex® (celecoxib).

         22. Subject has a known coagulation disorder.

         23. Subject has history of or current medical, surgical, post-surgical, or psychiatric
             condition that would confound interpretation of safety, tolerability, or efficacy,
             (eg, uncontrolled diabetes mellitus, uncontrolled hypertension, hemodynamic
             instability, or respiratory insufficiency, cancer or palliative care).

         24. Subject received an experimental drug or used an experimental medical device within 30
             days prior to Screening or has previously participated in this trial.

         25. Subject is unable to comply with the requirements of the study or, in the
             investigator's opinion, should not participate in the study.