Study to Evaluate the Analgesic Efficacy and Safety of Hydrocodone Bitartrate/Acetaminophen Immediate-Release Tablets in Participants With Moderate to Severe Pain Following Bunionectomy

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the analgesic efficacy of hydrocodone bitartrate/acetaminophen immediate-release tablets at doses of 5.0 milligrams (mg)/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg every 4 to 6 hours compared with placebo in treating participants with moderate to severe pain following bunionectomy.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Analgesic Efficacy and Safety of Hydrocodone Bitartrate/Acetaminophen Immediate-Release Tablets (TV-46763) at Doses of 5.0 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg Every 4 to 6 Hours in Patients With Moderate to Severe Pain Following Bunionectomy

Conditions
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Pain

Intervention / Treatment
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* Drug: TV-46763
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 to 75 years, inclusive. Participants who are scheduled to undergo a primary unilateral first metatarsal Austin bunionectomy with distal osteotomy and internal fixation without any collateral procedures (ie, uncomplicated procedure). Participants who according to the American Society of Anesthesiologists Physical Status (PS) classification system are classified PS-1 (normal, healthy participant) or PS-2 (mild systemic disease). The participant is able to speak English and is willing to provide written informed consent, including a written opioid agreement, to participate in the study. The participant has a body mass index (BMI) between 18.0 and 33.0 kg/m2 (inclusive) at the time of screening. The participant is in generally good health as determined by a medical history, medical examination, ECG, serum chemistry, hematology, urinalysis, and serology. Women of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically acceptable method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after discontinuation of the study drug, unless they have exclusively same-sex partners. Acceptable methods of contraception include intrauterine device (IUD) known to have a failure rate of less than 1% per year, hormonal contraceptive (oral, implanted, transdermal, or injected), and barrier method with spermicide, abstinence, and partner vasectomy. NOTE: A woman will be considered surgically sterile if she has had a tubal ligation, hysterectomy, bilateral salpingo-oophorectomy or bilateral oophorectomy, or hysterectomy with bilateral salpingo-oophorectomy. The participant, if a man, is surgically sterile, or, if capable of producing offspring, is currently using a medically acceptable method of contraception and agrees to continue use of this method for the duration of the study (and for 90 days after taking the last dose of the study drug because of the possible effects on spermatogenesis), unless he has exclusively same-sex partners. Acceptable methods of contraception include abstinence, barrier method with spermicide, female partner's use of steroidal hormonal contraceptive (oral, implanted, transdermal, or injected) in conjunction with a barrier method, female partner's use of an IUD known to have a failure rate of less than 1% per year, or if his female partner is surgically sterile or 2 years postmenopausal. In addition, male participants may not donate sperm for the duration of the study and for 90 days after taking study drug. The participant must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study, and willing to return to the clinic for the follow-up evaluation as specified in this protocol. The participant must not participate in any other study involving an investigational agent while enrolled in the present study. The participant must report a pain intensity score of ≥4 on an 11-point NPRS-11 within 9 hours after stopping postsurgical analgesia and immediately before randomization. The participant should be free of any surgical or anesthetic complications after the surgery, which is to be performed using the intraoperative anesthetic regimen and the postoperative analgesic regimen that was followed appropriately without deviations that would confound analgesic assessments after receipt of the investigational product. Exclusion Criteria: The participant has a chronic pain condition, excluding bunion pain that requires taking opioid analgesics within 30 days prior to surgery or use of non-opioid analgesics (acetylsalicylic acid, acetaminophen, nonsteroidal anti-inflammatory drugs) within 24 hours prior to surgery. Stable therapy of >30 days for acetylsalicylic acid (up to 81 mg/day) is allowed as cardiovascular prophylaxis. Use of glucocorticoids (except nasal corticosteroid sprays and/or topical corticosteroids) for any condition within 6 months before study drug administration. The participant uses any nonpharmacologic pain management techniques (eg, physical techniques, physiotherapy, massage therapy, acupuncture, biofeedback, and/or psychological support) and is unable or unwilling to discontinue prior to randomization (or study start). The participant has any other medical or psychiatric condition or is receiving concomitant medication/therapy that would, in the opinion of the investigator, compromise the participant's safety, compliance with the study protocol procedures, or collection of data. The participant has a clinically significant abnormality in the physical examination and/or clinical laboratory test values. The participant is a pregnant or lactating woman. (Any woman becoming pregnant during the study will be withdrawn from the study.) The participant has used an investigational drug within 1 month before the screening visit. The participant is participating any currently ongoing research study. The participant has any disorder that may interfere with gastrointestinal (GI) drug absorption (eg, gastric bypass surgery, lap band, malabsorption syndrome, and inflammatory bowel disease) or other condition that may have an effect on participant safety or efficacy aspects of participation in the opinion of the investigator. The participant is allergic to or has had a serious reaction to hydrocodone or other opioids, acetaminophen, ropivacaine, lidocaine, ketorolac, ibuprofen, propofol, or any of the drugs required by the study protocol. The participant has a recent history (within 5 years) or current evidence of alcohol or other substance abuse, with the exception of nicotine. The participant has a positive urine drug screen (UDS) for cocaine, marijuana, opioids, amphetamines, methamphetamines, benzodiazepines, barbiturates, and/or methadone, unless explained by the use of prescription medication. The participant has a history of suicidality as assessed by participant medical history and/or the C-SSRS. The participant is expected to have elective surgery during the study other than a bunionectomy. The participant has a history of malignancy within 5 years (except for treated basal cell carcinoma). The participant has a positive test result for hepatitis B surface antigen or antibodies to hepatitis C, or known or tested positive for human immunodeficiency virus. The participant has received a monoamine oxidase inhibitor (MAOI) within 14 days before the first dose of study drug. The investigator believes that the participant is not suitable for the study for any reason.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive placebo matching to TV46763 (hydrocodone bitartrate/acetaminophen) immediate release (IR) tablets for 48 hours (every 4 to 6 hours) on Days 1, 2, and 3 during the inpatient treatment period. Participants will continue to take the same treatment daily, every 4 to 6 hours after discharge on Day 3, over a 10-day (±1 day) outpatient treatment period. | Drug: Placebo<br>* Placebo matching to TV-46763 will be administered per schedule specified in the arm description.<br>|
| Experimental: TV-46763 5.0 mg/325 mg<br>Participants will receive TV46763 (hydrocodone bitartrate/acetaminophen) 5.0 mg/325 mg IR tablets for 48 hours (every 4 to 6 hours) on Days 1, 2, and 3 during the inpatient treatment period. Participants will continue to take the same treatment daily, every 4 to 6 hours after discharge on Day 3, over a 10-day (±1 day) outpatient treatment period. | Drug: TV-46763<br>* TV-46763 will be administered per dose and schedule specified in the arm description.<br>* Other names: Hydrocodone bitartrate/acetaminophen IR tablets;|
| Experimental: TV-46763 7.5 mg/325 mg<br>Participants will receive TV46763 (hydrocodone bitartrate/acetaminophen) 7.5 mg/325 mg IR tablets for 48 hours (every 4 to 6 hours) on Days 1, 2, and 3 during the inpatient treatment period. Participants will continue to take the same treatment daily, every 4 to 6 hours after discharge on Day 3, over a 10-day (±1 day) outpatient treatment period. | Drug: TV-46763<br>* TV-46763 will be administered per dose and schedule specified in the arm description.<br>* Other names: Hydrocodone bitartrate/acetaminophen IR tablets;|
| Experimental: TV-46763 10.0 mg/325 mg<br>Participants will receive TV46763 (hydrocodone bitartrate/acetaminophen) 10.0 mg/325 mg IR tablets for 48 hours (every 4 to 6 hours) on Days 1, 2, and 3 during the inpatient treatment period. Participants will continue to take the same treatment daily, every 4 to 6 hours after discharge on Day 3, over a 10-day (±1 day) outpatient treatment period. | Drug: TV-46763<br>* TV-46763 will be administered per dose and schedule specified in the arm description.<br>* Other names: Hydrocodone bitartrate/acetaminophen IR tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed Pain Intensity Difference (SPID) Score Calculated Over the First 48 Hours (SPID48) After the First Dose of Study Drug on an 11-Point Numerical Pain Rating Scale (NPRS-11) | The SPID48 was calculated as the time-weighted sum of pain intensity difference (PID) at each time point over 48 hours. The SPID48 was based on the NPRS-11, which is an 11-point Likert-type scale in which 0 means no pain and 10 means the most intense pain imaginable. Least square (LS) mean was calculated using an analysis of covariance (ANCOVA) with treatment and center as factors and the baseline pain intensity score as a covariate. Multiple imputation method was used to handle missing data. | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | The SPID was calculated as the time-weighted sum of PID at each time point over the intervals during the first 36 hours. The SPID was based on the NPRS-11, which is an 11-point Likert-type scale in which 0 means no pain and 10 means the most intense pain imaginable. LS mean was calculated using ANCOVA with treatment and center as factors and the baseline pain intensity score as a covariate. Multiple imputation method was used to handle missing data. | 0 to 6, 0 to 12, 0 to 24, and 0 to 36 hours | 
| Pain Intensity Difference (PID) Scores | The PID was based on the NPRS-11, which is an 11-point Likert-type scale in which 0 means no pain and 10 means the most intense pain imaginable. PID was calculated at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6 hours after the first dose of study drug. LS mean was calculated using ANCOVA with treatment and center as factors and the baseline pain intensity score as a covariate. Multiple imputation method was used to handle missing data. | 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6 hours | 
| Time to Peak PID | Time to peak PID after the first dose of study drug but before the second dose of study drug was calculated. Kaplan-Meier method was used to calculate the data. Multiple imputation method was used to handle missing pain intensity scores at scheduled time points. | Within 6 hours | 
| Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | Number of participants with a 30% reduction in NPRS-11 scores was reported at 6, 12, 24, and 48 hours after the first dose of study drug. | 2, 4, 6, 12, 24, and 48 hours | 
| Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | Number of participants with a 50% reduction in NPRS-11 scores was reported at 6, 12, 24, and 48 hours after the first dose of study drug. | 2, 4, 6, 12, 24, and 48 hours | 
| Time to Onset of Perceptible Pain Relief (PPR) | Time to perceptible pain relief (PPR) (i.e., onset of pain relief) after the first dose of study drug was calculated using the stopwatch technique. The PPR stopwatch was started immediately after administration of the first dose of study drug (time zero [T0]) and it was given to the participant with the instructions to stop the stopwatch when he or she first perceived pain relief (time to perceptible relief). Kaplan-Meier method was used to calculate the data. | Day 1 | 
| Time to Onset of Meaningful Pain Relief (MPR) | Time to meaningful pain relief (MPR) after the first dose of study drug was calculated using the stopwatch technique. The MPR stopwatch was started immediately after administration of the first dose of study drug (time zero [T0]). The stopwatch was given to the participant with the instructions to stop the stopwatch when he or she first experienced meaningful pain relief (time to meaningful relief). Kaplan-Meier method was used to calculate the data. | Day 1 | 
| Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication (oral nonprescription ibuprofen) use (number of tablets used) over 6, 12, 24, and 48 hours after the first dose of study drug was calculated. | 6, 12, 24, and 48 hours | 
| Number of Participants Taking Rescue Medication | Number of participants taking rescue medication (oral nonprescription ibuprofen) over 6, 12, 24, and 48 hours after the first dose of study drug were calculated. | 6, 12, 24, and 48 hours | 
| Number of Participants With Adverse Events (AEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | Day 1 up to Day 13 |