Pain
Conditions
Brief summary
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.
Interventions
DRUGTV-46763
TV-46763 will be administered per dose and schedule specified in the arm description.
DRUGPlacebo
Placebo matching to TV-46763 will be administered per schedule specified in the arm description.
Sponsors
Syneos Health
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women aged 18 to 75 years, inclusive. 2. 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). 3. 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). 4. 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. 5. The participant has a body mass index (BMI) between 18.0 and 33.0 kg/m2 (inclusive) at the time of screening. 6. The participant is in generally good health as determined by a medical history, medical examination, ECG, serum chemistry, hematology, urinalysis, and serology. 7. 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. 8. 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. 9. 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. 10. The participant must not participate in any other study involving an investigational agent while enrolled in the present study. 11. 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. 12. 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
1. 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. 2. Use of glucocorticoids (except nasal corticosteroid sprays and/or topical corticosteroids) for any condition within 6 months before study drug administration. 3. 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). 4. 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. 5. The participant has a clinically significant abnormality in the physical examination and/or clinical laboratory test values. 6. The participant is a pregnant or lactating woman. (Any woman becoming pregnant during the study will be withdrawn from the study.) 7. The participant has used an investigational drug within 1 month before the screening visit. 8. The participant is participating any currently ongoing research study. 9. 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. 10. 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. 11. The participant has a recent history (within 5 years) or current evidence of alcohol or other substance abuse, with the exception of nicotine. 12. 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. 13. The participant has a history of suicidality as assessed by participant medical history and/or the C-SSRS. 14. The participant is expected to have elective surgery during the study other than a bunionectomy. 15. The participant has a history of malignancy within 5 years (except for treated basal cell carcinoma). 16. 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. 17. The participant has received a monoamine oxidase inhibitor (MAOI) within 14 days before the first dose of study drug. 18. The investigator believes that the participant is not suitable for the study for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 48 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Intensity Difference (PID) Scores | 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6 hours | 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. |
| Time to Peak PID | Within 6 hours | 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. |
| Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2, 4, 6, 12, 24, and 48 hours | 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. |
| Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2, 4, 6, 12, 24, and 48 hours | 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. |
| SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | 0 to 6, 0 to 12, 0 to 24, and 0 to 36 hours | 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. |
| Time to Onset of Meaningful Pain Relief (MPR) | Day 1 | 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. |
| Total Rescue Medication Use (Number of Tablets Used) | 6, 12, 24, and 48 hours | 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. |
| Number of Participants Taking Rescue Medication | 6, 12, 24, and 48 hours | 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. |
| Number of Participants With Adverse Events (AEs) | Day 1 up to Day 13 | 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'. |
| Time to Onset of Perceptible Pain Relief (PPR) | Day 1 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to TV46763 (hydrocodone bitartrate/acetaminophen) IR tablets for 48 hours (every 4 to 6 hours) on Days 1, 2, and 3 during the inpatient treatment period. Participants continued 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. | 142 |
| TV-46763 5.0 mg/325 mg Participants received 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 continued 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. | 142 |
| TV-46763 7.5 mg/325 mg Participants received 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 continued 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. | 143 |
| TV-46763 10.0 mg/325 mg Participants received 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 continued 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. | 142 |
| Total | 569 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 6 | 12 | 6 |
| Overall Study | Non-compliance to study medication | 3 | 2 | 5 | 4 |
| Overall Study | Non-compliance to study procedures | 0 | 0 | 0 | 1 |
| Overall Study | Other than specified | 3 | 2 | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 1 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 5 | 5 | 0 |
Baseline characteristics
| Characteristic | Placebo | TV-46763 5.0 mg/325 mg | TV-46763 7.5 mg/325 mg | TV-46763 10.0 mg/325 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 47.5 years STANDARD_DEVIATION 14.39 | 45.8 years STANDARD_DEVIATION 14.45 | 44.9 years STANDARD_DEVIATION 13.87 | 46.2 years STANDARD_DEVIATION 13.94 | 46.1 years STANDARD_DEVIATION 14.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 35 Participants | 49 Participants | 47 Participants | 171 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 102 Participants | 107 Participants | 94 Participants | 94 Participants | 397 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 8 Participants | 7 Participants | 5 Participants | 24 Participants |
| Race/Ethnicity, Customized Black | 24 Participants | 30 Participants | 29 Participants | 26 Participants | 109 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 111 Participants | 102 Participants | 104 Participants | 107 Participants | 424 Participants |
| Sex: Female, Male Female | 119 Participants | 124 Participants | 125 Participants | 113 Participants | 481 Participants |
| Sex: Female, Male Male | 23 Participants | 18 Participants | 18 Participants | 29 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 142 | 0 / 142 | 0 / 141 | 0 / 142 |
| other Total, other adverse events | 33 / 142 | 66 / 142 | 80 / 141 | 98 / 142 |
| serious Total, serious adverse events | 2 / 142 | 1 / 142 | 0 / 141 | 0 / 142 |
Outcome results
Primary
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.
Time frame: 48 hours
Population: The full analysis set (FAS) included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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) | 76.5 units on a scale | Standard Error 6.92 |
| TV-46763 5.0 mg/325 mg | 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) | 115.4 units on a scale | Standard Error 6.92 |
| TV-46763 7.5 mg/325 mg | 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) | 120.5 units on a scale | Standard Error 6.91 |
| TV-46763 10.0 mg/325 mg | 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) | 129.9 units on a scale | Standard Error 6.88 |
Comparison: Analysis was performed using ANCOVA with treatment and center as factors and the baseline pain intensity score as a covariate.p-value: <0.00195% CI: [19.931, 57.855]ANCOVA
Comparison: Analysis was performed using ANCOVA with treatment and center as factors and the baseline pain intensity score as a covariate.p-value: <0.00195% CI: [25.122, 62.881]ANCOVA
Comparison: Analysis was performed using ANCOVA with treatment and center as factors and the baseline pain intensity score as a covariate.p-value: <0.00195% CI: [34.589, 72.282]ANCOVA
Secondary
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.
Time frame: 6, 12, 24, and 48 hours
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Taking Rescue Medication | Rescue medication use over 6 hours | 101 Participants |
| Placebo | Number of Participants Taking Rescue Medication | Rescue medication use over 12 hours | 124 Participants |
| Placebo | Number of Participants Taking Rescue Medication | Rescue medication use over 24 hours | 132 Participants |
| Placebo | Number of Participants Taking Rescue Medication | Rescue medication use over 48 hours | 132 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 12 hours | 96 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 24 hours | 101 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 48 hours | 106 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 6 hours | 76 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 24 hours | 107 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 12 hours | 98 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 48 hours | 110 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 6 hours | 74 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 48 hours | 99 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 12 hours | 84 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 6 hours | 62 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants Taking Rescue Medication | Rescue medication use over 24 hours | 93 Participants |
Secondary
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.
Time frame: 2, 4, 6, 12, 24, and 48 hours
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2 hours | 41 Participants |
| Placebo | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 4 hours | 39 Participants |
| Placebo | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 6 hours | 32 Participants |
| Placebo | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 12 hours | 38 Participants |
| Placebo | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 24 hours | 67 Participants |
| Placebo | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 48 hours | 86 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 48 hours | 96 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 12 hours | 55 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2 hours | 71 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 6 hours | 56 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 4 hours | 44 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 24 hours | 83 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 4 hours | 41 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 6 hours | 51 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 12 hours | 54 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 48 hours | 92 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 24 hours | 80 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2 hours | 76 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 24 hours | 91 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 48 hours | 100 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 4 hours | 60 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 12 hours | 76 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2 hours | 83 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 30% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 6 hours | 66 Participants |
Secondary
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.
Time frame: 2, 4, 6, 12, 24, and 48 hours
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 6 hours | 18 Participants |
| Placebo | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2 hours | 27 Participants |
| Placebo | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 4 hours | 20 Participants |
| Placebo | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 12 hours | 22 Participants |
| Placebo | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 24 hours | 46 Participants |
| Placebo | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 48 hours | 73 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 24 hours | 66 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2 hours | 52 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 4 hours | 29 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 48 hours | 75 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 12 hours | 33 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 6 hours | 40 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 24 hours | 63 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 6 hours | 39 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 48 hours | 79 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2 hours | 63 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 4 hours | 28 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 12 hours | 31 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 48 hours | 90 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 4 hours | 40 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 6 hours | 45 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 12 hours | 52 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 24 hours | 75 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With a 50% Reduction in Pain Intensity Measured Using NPRS-11 Scores | 2 hours | 63 Participants |
Secondary
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'.
Time frame: Day 1 up to Day 13
Population: The safety analysis set included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) | 56 Participants |
| TV-46763 5.0 mg/325 mg | Number of Participants With Adverse Events (AEs) | 79 Participants |
| TV-46763 7.5 mg/325 mg | Number of Participants With Adverse Events (AEs) | 87 Participants |
| TV-46763 10.0 mg/325 mg | Number of Participants With Adverse Events (AEs) | 106 Participants |
Secondary
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.
Time frame: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6 hours
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Pain Intensity Difference (PID) Scores | 5 hours | 0.6 units on a scale | Standard Error 0.19 |
| Placebo | Pain Intensity Difference (PID) Scores | 2 hours | 0.8 units on a scale | Standard Error 0.2 |
| Placebo | Pain Intensity Difference (PID) Scores | 3 hours | 1.0 units on a scale | Standard Error 0.2 |
| Placebo | Pain Intensity Difference (PID) Scores | 0.5 hour | 0.5 units on a scale | Standard Error 0.15 |
| Placebo | Pain Intensity Difference (PID) Scores | 0.25 hour | 0.1 units on a scale | Standard Error 0.11 |
| Placebo | Pain Intensity Difference (PID) Scores | 6 hours | 0.4 units on a scale | Standard Error 0.19 |
| Placebo | Pain Intensity Difference (PID) Scores | 0.75 hour | 0.6 units on a scale | Standard Error 0.17 |
| Placebo | Pain Intensity Difference (PID) Scores | 1 hour | 0.7 units on a scale | Standard Error 0.19 |
| Placebo | Pain Intensity Difference (PID) Scores | 4 hours | 0.7 units on a scale | Standard Error 0.19 |
| Placebo | Pain Intensity Difference (PID) Scores | 1.5 hours | 0.8 units on a scale | Standard Error 0.21 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 5 hours | 1.4 units on a scale | Standard Error 0.19 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 3 hours | 1.8 units on a scale | Standard Error 0.2 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.75 hour | 0.9 units on a scale | Standard Error 0.17 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 2 hours | 1.9 units on a scale | Standard Error 0.2 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 6 hours | 1.3 units on a scale | Standard Error 0.19 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.25 hour | 0.2 units on a scale | Standard Error 0.11 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 4 hours | 1.3 units on a scale | Standard Error 0.19 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.5 hour | 0.5 units on a scale | Standard Error 0.15 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 1.5 hours | 1.6 units on a scale | Standard Error 0.21 |
| TV-46763 5.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 1 hour | 1.4 units on a scale | Standard Error 0.19 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 1.5 hours | 2.2 units on a scale | Standard Error 0.21 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.25 hour | 0.1 units on a scale | Standard Error 0.11 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.5 hour | 0.8 units on a scale | Standard Error 0.15 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.75 hour | 1.4 units on a scale | Standard Error 0.17 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 1 hour | 1.8 units on a scale | Standard Error 0.19 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 2 hours | 2.2 units on a scale | Standard Error 0.2 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 3 hours | 1.7 units on a scale | Standard Error 0.2 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 4 hours | 1.0 units on a scale | Standard Error 0.19 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 5 hours | 1.2 units on a scale | Standard Error 0.19 |
| TV-46763 7.5 mg/325 mg | Pain Intensity Difference (PID) Scores | 6 hours | 1.3 units on a scale | Standard Error 0.19 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 1 hour | 1.5 units on a scale | Standard Error 0.19 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.75 hour | 1.1 units on a scale | Standard Error 0.17 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.25 hour | 0.0 units on a scale | Standard Error 0.11 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 4 hours | 1.3 units on a scale | Standard Error 0.19 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 6 hours | 1.7 units on a scale | Standard Error 0.19 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 5 hours | 1.6 units on a scale | Standard Error 0.19 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 2 hours | 2.1 units on a scale | Standard Error 0.2 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 1.5 hours | 2.0 units on a scale | Standard Error 0.21 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 0.5 hour | 0.5 units on a scale | Standard Error 0.15 |
| TV-46763 10.0 mg/325 mg | Pain Intensity Difference (PID) Scores | 3 hours | 1.7 units on a scale | Standard Error 0.2 |
Secondary
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.
Time frame: 0 to 6, 0 to 12, 0 to 24, and 0 to 36 hours
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-6 | 3.7 units on a scale | Standard Error 0.87 |
| Placebo | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-12 | 6.4 units on a scale | Standard Error 1.78 |
| Placebo | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-24 | 21.1 units on a scale | Standard Error 3.55 |
| Placebo | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-36 | 44.2 units on a scale | Standard Error 5.26 |
| TV-46763 5.0 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-12 | 15.8 units on a scale | Standard Error 1.77 |
| TV-46763 5.0 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-24 | 43.9 units on a scale | Standard Error 3.53 |
| TV-46763 5.0 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-36 | 78.2 units on a scale | Standard Error 5.26 |
| TV-46763 5.0 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-6 | 8.3 units on a scale | Standard Error 0.87 |
| TV-46763 7.5 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-24 | 44.5 units on a scale | Standard Error 3.53 |
| TV-46763 7.5 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-12 | 16.5 units on a scale | Standard Error 1.76 |
| TV-46763 7.5 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-36 | 81.1 units on a scale | Standard Error 5.22 |
| TV-46763 7.5 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-6 | 8.3 units on a scale | Standard Error 0.87 |
| TV-46763 10.0 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-36 | 88.2 units on a scale | Standard Error 5.22 |
| TV-46763 10.0 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-12 | 19.1 units on a scale | Standard Error 1.78 |
| TV-46763 10.0 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-6 | 9.1 units on a scale | Standard Error 0.88 |
| TV-46763 10.0 mg/325 mg | SPID Scores Over the Intervals During the First 36 Hours Following the First Dose of Study Drug | SPID 0-24 | 50.9 units on a scale | Standard Error 3.53 |
Secondary
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.
Time frame: Day 1
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset of Meaningful Pain Relief (MPR) | NA hour |
| TV-46763 5.0 mg/325 mg | Time to Onset of Meaningful Pain Relief (MPR) | 1.9 hour |
| TV-46763 7.5 mg/325 mg | Time to Onset of Meaningful Pain Relief (MPR) | 1.3 hour |
| TV-46763 10.0 mg/325 mg | Time to Onset of Meaningful Pain Relief (MPR) | 1.8 hour |
Secondary
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.
Time frame: Day 1
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset of Perceptible Pain Relief (PPR) | 0.8 hour |
| TV-46763 5.0 mg/325 mg | Time to Onset of Perceptible Pain Relief (PPR) | 0.5 hour |
| TV-46763 7.5 mg/325 mg | Time to Onset of Perceptible Pain Relief (PPR) | 0.5 hour |
| TV-46763 10.0 mg/325 mg | Time to Onset of Perceptible Pain Relief (PPR) | 0.6 hour |
Secondary
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.
Time frame: Within 6 hours
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Peak PID | 3.0 hours |
| TV-46763 5.0 mg/325 mg | Time to Peak PID | 2.0 hours |
| TV-46763 7.5 mg/325 mg | Time to Peak PID | 1.53 hours |
| TV-46763 10.0 mg/325 mg | Time to Peak PID | 2.0 hours |
Secondary
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.
Time frame: 6, 12, 24, and 48 hours
Population: The FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 6 hours | 1.2 tablets | Standard Error 0.07 |
| Placebo | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 12 hours | 2.0 tablets | Standard Error 0.1 |
| Placebo | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 24 hours | 3.0 tablets | Standard Error 0.13 |
| Placebo | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 48 hours | 4.4 tablets | Standard Error 0.22 |
| TV-46763 5.0 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 12 hours | 1.4 tablets | Standard Error 0.1 |
| TV-46763 5.0 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 24 hours | 2.1 tablets | Standard Error 0.13 |
| TV-46763 5.0 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 48 hours | 2.9 tablets | Standard Error 0.21 |
| TV-46763 5.0 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 6 hours | 0.8 tablets | Standard Error 0.07 |
| TV-46763 7.5 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 24 hours | 1.9 tablets | Standard Error 0.13 |
| TV-46763 7.5 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 12 hours | 1.4 tablets | Standard Error 0.1 |
| TV-46763 7.5 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 48 hours | 2.6 tablets | Standard Error 0.21 |
| TV-46763 7.5 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 6 hours | 0.7 tablets | Standard Error 0.07 |
| TV-46763 10.0 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 48 hours | 2.1 tablets | Standard Error 0.22 |
| TV-46763 10.0 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 12 hours | 1.1 tablets | Standard Error 0.1 |
| TV-46763 10.0 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 6 hours | 0.6 tablets | Standard Error 0.07 |
| TV-46763 10.0 mg/325 mg | Total Rescue Medication Use (Number of Tablets Used) | Total rescue medication use over 24 hours | 1.6 tablets | Standard Error 0.13 |