Study to Evaluate the Analgesic Efficacy and Safety of Hy... | NCT02487108

Name	Class
Syneos Health	OTHER

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	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
TV-46763 5.0 mg/325 mg	Experimental	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
TV-46763 7.5 mg/325 mg	Experimental	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
TV-46763 10.0 mg/325 mg	Experimental	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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
TV-46763	Drug	TV-46763 will be administered per dose and schedule specified in the arm description.	TV-46763 10.0 mg/325 mg TV-46763 5.0 mg/325 mg TV-46763 7.5 mg/325 mg

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

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.

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
Teva Medical Expert, MD	Teva Branded Pharmaceutical Products R&D, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Teva Investigational Site 13510		Phoenix	Arizona	85023	United States
Teva Investigational Site 13173

ID	Title	Description
FG000	Placebo	Participants received placebo matched 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 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.

Arm/Group Information

ID	Title	Description
BG000	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.
BG001	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.
BG002	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.
BG003	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.
BG004	Total	Total of all reporting groups

Units	Counts
Participants	BG000142 BG001142 BG002143 BG003142 BG004569

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

The full analysis set (FAS) included all randomized participants who received at least 1 dose of study drug.

Posted

Least Squares Mean

Standard Error

units on a scale

48 hours

ID	Title	Description
OG000	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.
OG001	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.
OG002	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.
OG003	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.

Units	Counts
Participants	OG000142 OG001142 OG002141 OG003

Title

Denominators

Categories

Title	Measurements
	OG00076.5± 6.92 OG001115.4± 6.92 OG002120.5± 6.91 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Analysis was performed using ANCOVA with treatment and center as factors and the baseline pain intensity score as a covariate.	ANCOVA		<0.001		LS Mean Difference	38.9			2-Sided	95	19.931	57.855					Other
OG000 OG002	Analysis was performed using ANCOVA with treatment and center as factors and the baseline pain intensity score as a covariate.

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Least Squares Mean

Standard Error

units on a scale

0 to 6, 0 to 12, 0 to 24, and 0 to 36 hours

ID	Title	Description
OG000	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.
OG001	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.

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Least Squares Mean

Standard Error

units on a scale

0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6 hours

ID	Title	Description
OG000	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.
OG001	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.

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Median

95% Confidence Interval

hours

Within 6 hours

ID	Title	Description
OG000	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.
OG001	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.
OG002	TV-46763 7.5 mg/325 mg

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Count of Participants

Participants

2, 4, 6, 12, 24, and 48 hours

ID	Title	Description
OG000	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.
OG001	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.
OG002	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.

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Count of Participants

Participants

2, 4, 6, 12, 24, and 48 hours

ID	Title	Description
OG000	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.
OG001	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.
OG002	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.

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Median

95% Confidence Interval

hour

Day 1

ID	Title	Description
OG000	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.
OG001	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.

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Median

95% Confidence Interval

hour

Day 1

ID	Title	Description
OG000	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.
OG001	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.

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Least Squares Mean

Standard Error

tablets

6, 12, 24, and 48 hours

ID	Title	Description
OG000	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.
OG001	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.
OG002	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.

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.

The FAS included all randomized participants who received at least 1 dose of study drug.

Posted

Count of Participants

Participants

6, 12, 24, and 48 hours

ID	Title	Description
OG000	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.
OG001	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.
OG002	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.

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'.

The safety analysis set included all randomized participants who received at least 1 dose of study drug.

Posted

Count of Participants

Participants

Day 1 up to Day 13

ID	Title	Description
OG000	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.
OG001	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.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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	2	142	33	142
EG001	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	1	142	66	142
EG002	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.	141	0	141	80	141
EG003	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	0	142	98	142

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Constipation	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0002 events2 affected142 at risk EG00126 events26 affected142 at risk EG00223 events23 affected141 at risk EG00330 events30 affected142 at risk
Nausea	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG00012 events11 affected142 at risk EG00152 events37 affected142 at risk EG00263 events54 affected141 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0004 events4 affected142 at risk EG00124 events18 affected142 at risk EG00237 events27 affected141 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected142 at risk EG0019 events9 affected142 at risk EG0025 events5 affected141 at risk EG003
Dizziness	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0004 events3 affected142 at risk EG00113 events10 affected142 at risk EG00226 events24 affected141 at risk EG003
Headache	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG00022 events17 affected142 at risk EG00118 events13 affected142 at risk EG00216 events14 affected141 at risk EG003
Somnolence	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected142 at risk EG0018 events8 affected142 at risk EG0027 events7 affected141 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 18.0	Systematic Assessment	EG0002 events2 affected142 at risk EG0013 events2 affected142 at risk EG0025 events5 affected141 at risk EG003

ID	Term
D009461	Neurologic Manifestations
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D003061	Codeine
D009022	Morphine Derivatives
D009019	Morphinans
D053610	Opiate Alkaloids
D000470	Alkaloids
D006571	Heterocyclic Compounds
D006572	Heterocyclic Compounds, Bridged-Ring
D006576	Heterocyclic Compounds, 4 or More Rings
D000072471	Heterocyclic Compounds, Fused-Ring
D010616	Phenanthrenes
D011084	Polycyclic Aromatic Hydrocarbons
D011083	Polycyclic Compounds

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Drug hypersensitivity	Immune system disorders	MedDRA 18.0	Systematic Assessment	EG0000 events0 affected142 at risk EG0011 events1 affected142 at risk EG0020 events0 affected141 at risk EG0030 events0 affected142 at risk
Cellulitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected142 at risk EG0010 events0 affected142 at risk EG0020 events0 affected141 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA 18.0	Systematic Assessment	EG0001 events1 affected142 at risk EG0010 events0 affected142 at risk EG0020 events0 affected141 at risk EG003