Postoperative Pain
Conditions
Brief summary
A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy
Detailed description
A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy Up to 80 subjects will be randomized (32 in each active treatment group, 16 placebo). To evaluate the efficacy of combination pregabalin (PGB) and acetaminophen (APAP) administered vs. placebo for pain control in subjects undergoing bunionectomy. The placebo will be the saline solution.
Interventions
DRUGPregabalin
Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma aminobutyric acid with anticonvulsant, anxiolytic and sleep-modulating properties.
DRUGAcetaminophen
Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent.
OTHERPlacebo 1
Placebo for APAP
OTHERPlacebo 2
Placebo for combination
Sponsors
Nevakar Injectables, Inc.
Nevakar, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Up to 80 subjects will be randomized (32 in each active treatment group, 16 placebo). Eligible subjects will be randomized on Day 1 in a 2:2:1 ratio to receive either a combination of PGB and APAP administered (Group A), APAP (Group B), or placebo (Group C).
Intervention model description
Parallel Assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Provide informed consent by signing the informed consent form (ICF) approved by the Institutional Review Board (IRB); * Be male or female aged 18-65 years; * Be scheduled to undergo unilateral first metatarsal bunionectomy; * Be in good health and capable of undergoing a bunionectomy under anesthesia as described in the study surgical and anesthetic protocol; * Weigh between 50 and 100 kg (body mass index \[BMI\] \<32 kg/m2); * Have no additional planned surgeries other than bunionectomy during the course of the study; * Have negative urine drug screen for drugs indicative of illicit drug use (unless results can be explained by a current prescription or acceptable over-the-counter medication at screening as determined by the investigator) and no detectable results on the alcohol test (breath or saliva) indicative of alcohol abuse at screening, and/or prior to surgery (may be repeated if the Investigator suspects a false-positive result). Note: For those subjects who test positive for tetrahydrocannabinol (THC), if they are willing to abstain from use or consumption of THC-containing products from screening through end of the subject's participation in the study, they may be allowed to participate in the study. * Biological female subjects must be non-lactating, sterile (bilateral tubal ligation, bilateral salpingectomy, or hysterectomy), post-menopausal for at least 2 years, have a partner that is sterile, be abstinent, use a highly effective double- contraception method (hormonal protection is insufficient), or use an FDA-approved contraceptive for greater than 2 months prior to the screening visit and commit to an acceptable form of birth control for the duration of the study and for 30 days after completion of the study; * Be willing and able to complete the study procedures and pain scales and communicate meaningfully in English with study personnel.
Exclusion criteria
* Have a medical condition or history that in the Investigator's opinion could adversely impact the subject's participation or safety or the conduct of the study, or interfere with the pain assessments, including the following: 1. Serious breathing difficulties or respiratory risk factors (including use of opioid pain medicines and other drugs that depress the central nervous system), and conditions such as chronic obstructive pulmonary disease that reduce lung function. 2. Hypertension (uncontrolled), cardiovascular disease, or history of cerebrovascular events. Hypertension must be controlled without known end organ damage. 3. Concurrent painful conditions that may require analgesic treatment during the study period. 4. History of significantly reduced hepatic or renal function, angle closure glaucoma, or convulsive disorder. 5. Recent history of urinary retention. 6. Opioid tolerant, i.e., the subject is currently taking or has taken a chronic opioid at a dose greater than or equal to 20 mg morphine milligram equivalents (MME) per day (more than 30 consecutive days of daily use) for pain in the 2 months prior to surgery. 7. Active cutaneous disease, or other disease, at the surgical site. 8. Peripheral vascular disease, sickle cell disease, vascular grafts, or vasospastic disorders. 9. Known bleeding disorder or is taking agents affecting coagulation preoperatively. Deep venous thrombosis (DVT) prophylaxis of the surgeon's choice is permitted postoperatively. 10. Diabetes mellitus (uncontrolled). Diabetes mellitus must be controlled without known end organ damage. 11. History of malignancy in the past 2 years with the exception of squamous cell carcinoma or basal cell carcinoma. 12. Prior bunionectomy on the index foot or other foot surgery on the index foot that could impact the surgery or data collection endpoints. * Use of disallowed medications including the following: 1. Pain medication (opioids, NSAIDs, cyclooxygenase (COX)-2 inhibitors, tramadol, ketamine, clonidine, gabapentin, pregabalin, or cannabinoids) within 2 days prior to Day 1. 2. Central nervous system (CNS) active drugs such as benzodiazepines, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors (SNRIs), or selective serotonin reuptake inhibitors (SSRIs) for pain within seven days prior to Day 1. These drugs are permitted for non-pain indications if the dose has been stable for at least 30 days prior to Day 1 and is planned to remain stable throughout the study. The use of lorazepam and other sleep medications, except those containing analgesic properties, is permitted. 3. Use of parenteral or oral corticosteroid(s) within 14 days prior to Day 1. 4. Antihypertensive agent or diabetic regimen at a dose that has not been stable for at least 30 days, or which is not expected to remain stable throughout the study. 5. Digoxin, warfarin (see exception below), lithium, theophylline preparations, aminoglycosides, and all antiarrhythmics except beta-blockers, and use of anticonvulsants except benzodiazepines within 7 days prior to Day 1 and throughout the study. * Use of warfarin is allowed, at the investigator's discretion, for DVT prophylaxis after the surgery. * Significant history of allergic reactions or known intolerance to pregabalin or any gabapentinoid, to APAP, to any rescue medication used in the study, or any medication used in the surgical and anesthetic protocol. * Female subjects (biological females only) who are pregnant or lactating, who plan to get pregnant, or who have a positive serum pregnancy test at Screening or a positive urine pregnancy test at either Day -1 or Day 1 prior to surgery. * Participated in another clinical trial within 30 days, or previously participated in a clinical study with a similar investigational product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity (SPI) Between Group A and Group C | 0 to 48 hours | Pain Intensity using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with a score between 0-10 (0= no pain; 10 = worst imaginable pain). Summed Pain Intensity (SPI0-48) was calculated using the trapezoidal method as the area under the curve (AUC) of pain intensity as measured using the NRS through various time intervals up to 48 hours. For SPI0-48 calculation, all available NRS pain intensity scores (scheduled pain intensity, unscheduled pain intensity and pre-rescue pain intensity) from 0 to 48 hours, including any imputed values, was used in the calculation. Hour 0 was defined as the time of the end of surgery. SPI0-48 was calculated using the formula: Sum (1/2 (SPIi + SPIi+1)\*Δt), where Δt was the time difference between Time i and Time (i+1). The represented values are sum of pain intensity scores at various time points. This outcome was compared between a combination of PGB and APAP (Group A) and placebo (Group C) from Hour 0 to Hour 48 (SPI0-48) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | 0, 12, 24, 48 hours | Pain Intensity was determined using a pain rating of 0-10 on the NRS, with a score between 0-10 (0= no pain; 10 = worst imaginable pain). SPI were calculated using the trapezoidal method as the AUC of pain intensity as measured using the NRS through various time intervals at 0-12, 12-24 and 24-48 hours. For specific time interval SPI calculation, all available NRS pain intensity scores (scheduled pain intensity, unscheduled pain intensity and pre-rescue pain intensity) in the respective time interval, including any imputed values, were used in the calculation. Hour 0 was defined as the time of the end of surgery. SPI at various time intervals were calculated using the formula: SUM (1/2 (SPIi + SPIi+1)\*Δt), where Δt was the time difference between Time i and Time (i+1). The represented values are sum of pain intensity scores at respective time interval (0-12, 12-24 and 24-48 hours). This outcome was compared between a combination of PGB and APAP, APAP alone, and placebo. |
| Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | 0, 1, 2, 4, 6, 8, 10 ,12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, and 48 hours | Pain Intensity was determined using a pain rating of 0-10 on the NRS, with a score between 0-10 (0= no pain; 10 = worst imaginable pain). SPI were calculated using the trapezoidal method as the AUC of pain intensity as measured using the NRS through various time intervals from 0 hour till each time point at 1, 2, 4, 6, 8, 10 ,12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, and 48 hours. For specific time interval SPI calculation, all available NRS pain intensity scores (scheduled pain intensity, unscheduled pain intensity and pre-rescue pain intensity) in the respective time interval, including any imputed values, were used in the calculation. Hour 0 was defined as the time of the end of surgery. SPI at various time intervals were calculated using the formula: SUM (1/2 (SPIi + SPIi+1)\*Δt), where Δt was the time difference between Time i and Time (i+1). The represented values are sum of pain intensity scores at respective time intervals. |
| Number of Participants With Treatment-Related Adverse Events (TRAE) | 7 days | A TRAE is defined as a treatment-emergent adverse event (TEAE) that was classified by the investigator as related to study drug. The number of participants with TRAE were reported |
| Percentage of Participants Who Were Opioid Free Over Time | 12 to 48 hours | Percentages of participants who did not take opioid (rescue medication) over time. |
| Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours | 24 hours and 48 hours | The total consumption of opioid rescue analgesia through 24 hours and through 48 hours was reported |
| Summed Pain Intensity (SPI) Compared Between Group A and Group B | 0 to 48 hours | Pain Intensity using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with a score between 0-10 (0= no pain; 10 = worst imaginable pain). Summed Pain Intensity (SPI0-48) -was calculated using the trapezoidal method as the area under the curve (AUC) of pain intensity as measured using the NRS through various time intervals up to 48 hours. For SPI0-48 calculation, all available NRS pain intensity scores (scheduled pain intensity, unscheduled pain intensity and pre-rescue pain intensity) from 0 to 48 hours, including any imputed values, were used in the calculation. Hour 0 was defined as the time of the end of surgery. SPI0-48 was calculated using the formula: SUM (1/2 (SPIi + SPIi+1)\*Δt), where Δt was the time difference between Time i and Time (i+1). The represented values are sum of pain intensity scores at various time points. This outcome was compared between a combination of PGB and APAP (Group A) and APAP alone (Group B) from Hour 0 to Hour 48 (SPI0-48) |
| Time to First Use of Rescue Medication From Hour 0 | 7 days | Time to first use of rescue medication from Hour 0 was reported. Hour 0 was defined as the end of surgery (i.e., completion of the last suture). |
| Percentage of Participants Who Used Rescue Medication | 7 days | Percentage of participants who used rescue medication is reported |
| Patient Global Assessment of Pain | 48 hours | Patient Global Assessment (PGA) of pain control at 48 hours was reported. Patient global evaluation will be self-reported over 24 hours, using a 0-4 categorical rating scale of: (0) poor, (1) fair, (2) good, (3) very good, and (4) excellent |
| Maximum Observed Concentration for PGB and APAP | Pre-infusion (at least 3.0 minutes before the start of the first infusion) and at 0.5, 1.5, 6.0, 8.0, 12.0, 16.0, 18.0, 24.0, 30.0, 32.0, 36.0, 40.0, 42.0, and 48 hours post-infusion | The Plasma Concentration (Cmax) is defined as the maximum observed concentration. Multiple blood samples were drawn at pre-decided time points. Timing for blood draws was within 3 minutes of the end of every infusion. Three minutes was the maximum allowance as every effort was made to take the sample as close as possible to 1.0 minute after infusion. |
| Minimum Observed Concentration for PGB and APAP | Pre-infusion (at least 3.0 minutes before the start of the first infusion) and at 0.5, 1.5, 6.0, 8.0, 12.0, 16.0, 18.0, 24.0, 30.0, 32.0, 36.0, 40.0, 42.0, and 48 hours post-infusion | The Plasma Concentration (Cmin) is defined as the minimum observed concentration. Multiple blood samples were drawn at pre-decided time points. Timing for blood draws was within 3 minutes of the end of every infusion. Three minutes was the maximum allowance as every effort was made to take the sample as close as possible to 1.0 minute after infusion. |
| Total Consumption of Rescue Medication | 7 days | The total consumption of rescue analgesia was reported. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from 28 July 2020 till 26 Oct 2020 across the sites.
Pre-assignment details
Subjects underwent a Screening Visit (Day -42 to Day -2) and were required to sign an informed consent form (ICF) before undertaking any study-specific procedures or assessments. Pre-operative assessments were conducted within 24 hours prior to surgery (on either Day -1 or Day 1 prior to surgery.
Participants by arm
| Arm | Count |
|---|---|
| PGB and APAP (Group A) Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery. | 35 |
| APAP (Group B) Group B receives placebo 2 prior to surgery and APAP post-surgery. | 35 |
| Placebo (Group C). Group C receives placebo 1 prior to surgery and placebo 2 post-surgery. | 17 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other | 1 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | PGB and APAP (Group A) | APAP (Group B) | Placebo (Group C). | Total |
|---|---|---|---|---|
| Age, Continuous | 43.7 years STANDARD_DEVIATION 13.33 | 42.1 years STANDARD_DEVIATION 11.68 | 43.3 years STANDARD_DEVIATION 11.98 | 43.0 years STANDARD_DEVIATION 12.31 |
| Body Mass Index | 26.03 kg/m^2 STANDARD_DEVIATION 3.213 | 26.55 kg/m^2 STANDARD_DEVIATION 3.471 | 26.05 kg/m^2 STANDARD_DEVIATION 3.406 | 26.24 kg/m^2 STANDARD_DEVIATION 3.326 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 12 Participants | 7 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 23 Participants | 10 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 7 Participants | 4 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 26 Participants | 12 Participants | 62 Participants |
| Sex: Female, Male Female | 25 Participants | 31 Participants | 17 Participants | 73 Participants |
| Sex: Female, Male Male | 10 Participants | 4 Participants | 0 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 | 0 / 17 |
| other Total, other adverse events | 27 / 35 | 15 / 35 | 9 / 17 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 | 0 / 17 |
Outcome results
Primary
Summed Pain Intensity (SPI) Between Group A and Group C
Pain Intensity using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with a score between 0-10 (0= no pain; 10 = worst imaginable pain). Summed Pain Intensity (SPI0-48) was calculated using the trapezoidal method as the area under the curve (AUC) of pain intensity as measured using the NRS through various time intervals up to 48 hours. For SPI0-48 calculation, all available NRS pain intensity scores (scheduled pain intensity, unscheduled pain intensity and pre-rescue pain intensity) from 0 to 48 hours, including any imputed values, was used in the calculation. Hour 0 was defined as the time of the end of surgery. SPI0-48 was calculated using the formula: Sum (1/2 (SPIi + SPIi+1)\*Δt), where Δt was the time difference between Time i and Time (i+1). The represented values are sum of pain intensity scores at various time points. This outcome was compared between a combination of PGB and APAP (Group A) and placebo (Group C) from Hour 0 to Hour 48 (SPI0-48)
Time frame: 0 to 48 hours
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Between Group A and Group C | 153.08 score on a scale | Standard Error 15.238 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Between Group A and Group C | 267.51 score on a scale | Standard Error 21.864 |
p-value: <0.001ANOVA
Secondary
Maximum Observed Concentration for PGB and APAP
The Plasma Concentration (Cmax) is defined as the maximum observed concentration. Multiple blood samples were drawn at pre-decided time points. Timing for blood draws was within 3 minutes of the end of every infusion. Three minutes was the maximum allowance as every effort was made to take the sample as close as possible to 1.0 minute after infusion.
Time frame: Pre-infusion (at least 3.0 minutes before the start of the first infusion) and at 0.5, 1.5, 6.0, 8.0, 12.0, 16.0, 18.0, 24.0, 30.0, 32.0, 36.0, 40.0, 42.0, and 48 hours post-infusion
Population: The PK Analysis Set included all randomized subjects who received any amount of study drug, had no protocol deviations affecting the pharmacokinetic (PK) variables, and had sufficient data collected to allow evaluation of least one PK parameter (minimum plasma concentration of the drug \[Cmin\], Cmax, or both). Subjects were analyzed according to treatment received. All PK analyses were performed using the PK Analysis Set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| PGB and APAP (Group A) | Maximum Observed Concentration for PGB and APAP | Mean Cmax Values of Pregabalin- First Dose | 10068 nanogram per milliliter (ng/ml) | Geometric Coefficient of Variation 36 |
| PGB and APAP (Group A) | Maximum Observed Concentration for PGB and APAP | Mean Cmax Values of Pregabalin- Last Dose | 12960 nanogram per milliliter (ng/ml) | Geometric Coefficient of Variation 27 |
| PGB and APAP (Group A) | Maximum Observed Concentration for PGB and APAP | Mean Cmax Values of Acetaminophen-First Dose | 28700 nanogram per milliliter (ng/ml) | Geometric Coefficient of Variation 34 |
| Placebo (Group C). | Maximum Observed Concentration for PGB and APAP | Mean Cmax Values of Acetaminophen-First Dose | 16847 nanogram per milliliter (ng/ml) | Geometric Coefficient of Variation 39 |
Secondary
Minimum Observed Concentration for PGB and APAP
The Plasma Concentration (Cmin) is defined as the minimum observed concentration. Multiple blood samples were drawn at pre-decided time points. Timing for blood draws was within 3 minutes of the end of every infusion. Three minutes was the maximum allowance as every effort was made to take the sample as close as possible to 1.0 minute after infusion.
Time frame: Pre-infusion (at least 3.0 minutes before the start of the first infusion) and at 0.5, 1.5, 6.0, 8.0, 12.0, 16.0, 18.0, 24.0, 30.0, 32.0, 36.0, 40.0, 42.0, and 48 hours post-infusion
Population: The PK Analysis Set included all randomized subjects who received any amount of study drug, had no protocol deviations affecting the PK variables, and had sufficient data collected to allow evaluation of least one PK parameter (minimum plasma concentration of the drug \[Cmin\], Cmax, or both). Subjects were analyzed according to treatment received. All PK analyses were performed using the PK Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| PGB and APAP (Group A) | Minimum Observed Concentration for PGB and APAP | NA nanogram per milliliter (ng/ml) |
| Placebo (Group C). | Minimum Observed Concentration for PGB and APAP | NA nanogram per milliliter (ng/ml) |
Secondary
Number of Participants With Treatment-Related Adverse Events (TRAE)
A TRAE is defined as a treatment-emergent adverse event (TEAE) that was classified by the investigator as related to study drug. The number of participants with TRAE were reported
Time frame: 7 days
Population: The Safety Analysis Set included all subjects who received any amount of study drug (APAP + PGB, APAP, or placebo), whether or not they were prematurely withdrawn from the study. The Safety Analysis Set was used for the summaries and listings of all safety assessments. Subjects were analyzed according to treatment received
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PGB and APAP (Group A) | Number of Participants With Treatment-Related Adverse Events (TRAE) | 22 participants |
| Placebo (Group C). | Number of Participants With Treatment-Related Adverse Events (TRAE) | 9 participants |
| Placebo (Group C). | Number of Participants With Treatment-Related Adverse Events (TRAE) | 7 participants |
Secondary
Patient Global Assessment of Pain
Patient Global Assessment (PGA) of pain control at 48 hours was reported. Patient global evaluation will be self-reported over 24 hours, using a 0-4 categorical rating scale of: (0) poor, (1) fair, (2) good, (3) very good, and (4) excellent
Time frame: 48 hours
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PGB and APAP (Group A) | Patient Global Assessment of Pain | (3) Very good | 10 Participants |
| PGB and APAP (Group A) | Patient Global Assessment of Pain | (2) Good | 6 Participants |
| PGB and APAP (Group A) | Patient Global Assessment of Pain | (0) Poor | 1 Participants |
| PGB and APAP (Group A) | Patient Global Assessment of Pain | (1) Fair | 4 Participants |
| PGB and APAP (Group A) | Patient Global Assessment of Pain | (4) Excellent | 14 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (2) Good | 7 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (0) Poor | 1 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (1) Fair | 7 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (3) Very good | 10 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (4) Excellent | 9 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (4) Excellent | 1 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (3) Very good | 3 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (0) Poor | 1 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (2) Good | 3 Participants |
| Placebo (Group C). | Patient Global Assessment of Pain | (1) Fair | 7 Participants |
Secondary
Percentage of Participants Who Used Rescue Medication
Percentage of participants who used rescue medication is reported
Time frame: 7 days
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PGB and APAP (Group A) | Percentage of Participants Who Used Rescue Medication | 57.1 percentage of participants |
| Placebo (Group C). | Percentage of Participants Who Used Rescue Medication | 80.0 percentage of participants |
| Placebo (Group C). | Percentage of Participants Who Used Rescue Medication | 82.4 percentage of participants |
Secondary
Percentage of Participants Who Were Opioid Free Over Time
Percentages of participants who did not take opioid (rescue medication) over time.
Time frame: 12 to 48 hours
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PGB and APAP (Group A) | Percentage of Participants Who Were Opioid Free Over Time | During 12-24 Hours | 65.7 percentage of participants |
| PGB and APAP (Group A) | Percentage of Participants Who Were Opioid Free Over Time | During 12-48 Hours | 48.6 percentage of participants |
| Placebo (Group C). | Percentage of Participants Who Were Opioid Free Over Time | During 12-24 Hours | 45.7 percentage of participants |
| Placebo (Group C). | Percentage of Participants Who Were Opioid Free Over Time | During 12-48 Hours | 28.6 percentage of participants |
| Placebo (Group C). | Percentage of Participants Who Were Opioid Free Over Time | During 12-24 Hours | 35.3 percentage of participants |
| Placebo (Group C). | Percentage of Participants Who Were Opioid Free Over Time | During 12-48 Hours | 29.4 percentage of participants |
Secondary
Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48).
Pain Intensity was determined using a pain rating of 0-10 on the NRS, with a score between 0-10 (0= no pain; 10 = worst imaginable pain). SPI were calculated using the trapezoidal method as the AUC of pain intensity as measured using the NRS through various time intervals at 0-12, 12-24 and 24-48 hours. For specific time interval SPI calculation, all available NRS pain intensity scores (scheduled pain intensity, unscheduled pain intensity and pre-rescue pain intensity) in the respective time interval, including any imputed values, were used in the calculation. Hour 0 was defined as the time of the end of surgery. SPI at various time intervals were calculated using the formula: SUM (1/2 (SPIi + SPIi+1)\*Δt), where Δt was the time difference between Time i and Time (i+1). The represented values are sum of pain intensity scores at respective time interval (0-12, 12-24 and 24-48 hours). This outcome was compared between a combination of PGB and APAP, APAP alone, and placebo.
Time frame: 0, 12, 24, 48 hours
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 12-24 | 50.92 score on a scale | Standard Error 5.082 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 0-12 | 33.09 score on a scale | Standard Error 3.728 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 24-48 | 126.83 score on a scale | Standard Error 13.128 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 12-24 | 69.35 score on a scale | Standard Error 5.082 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 0-12 | 49.09 score on a scale | Standard Error 3.728 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 24-48 | 184.33 score on a scale | Standard Error 13.128 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 0-12 | 58.89 score on a scale | Standard Error 5.349 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 24-48 | 221.58 score on a scale | Standard Error 18.837 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale From Hour 0 to Hour 12 (SPI0-12), Hour 12 to Hour 24 (SPI12-24), and Hour 24 to Hour 48 (SPI24-48). | SPI 12-24 | 88.95 score on a scale | Standard Error 7.292 |
Secondary
Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time
Pain Intensity was determined using a pain rating of 0-10 on the NRS, with a score between 0-10 (0= no pain; 10 = worst imaginable pain). SPI were calculated using the trapezoidal method as the AUC of pain intensity as measured using the NRS through various time intervals from 0 hour till each time point at 1, 2, 4, 6, 8, 10 ,12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, and 48 hours. For specific time interval SPI calculation, all available NRS pain intensity scores (scheduled pain intensity, unscheduled pain intensity and pre-rescue pain intensity) in the respective time interval, including any imputed values, were used in the calculation. Hour 0 was defined as the time of the end of surgery. SPI at various time intervals were calculated using the formula: SUM (1/2 (SPIi + SPIi+1)\*Δt), where Δt was the time difference between Time i and Time (i+1). The represented values are sum of pain intensity scores at respective time intervals.
Time frame: 0, 1, 2, 4, 6, 8, 10 ,12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, and 48 hours
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-8 | 20.00 score on a scale | Standard Deviation 14.211 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-2 | 1.26 score on a scale | Standard Deviation 1.591 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-4 | 5.63 score on a scale | Standard Deviation 5.12 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-6 | 12.68 score on a scale | Standard Deviation 9.65 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-1 | 0.26 score on a scale | Standard Deviation 0.509 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-10 | 26.25 score on a scale | Standard Deviation 18.413 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-12 | 33.09 score on a scale | Standard Deviation 22.725 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-14 | 41.12 score on a scale | Standard Deviation 27.035 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-16 | 49.08 score on a scale | Standard Deviation 30.48 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-18 | 55.84 score on a scale | Standard Deviation 33.985 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-20 | 61.49 score on a scale | Standard Deviation 36.259 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-24 | 77.17 score on a scale | Standard Deviation 43.864 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-28 | 88.94 score on a scale | Standard Deviation 50.68 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-32 | 100.85 score on a scale | Standard Deviation 56.483 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-36 | 114.43 score on a scale | Standard Deviation 63.776 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-40 | 126.45 score on a scale | Standard Deviation 69.998 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-44 | 139.54 score on a scale | Standard Deviation 78.396 |
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-48 | 153.08 score on a scale | Standard Deviation 87.398 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-48 | 223.24 score on a scale | Standard Deviation 91.581 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-1 | 0.73 score on a scale | Standard Deviation 0.87 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-18 | 78.49 score on a scale | Standard Deviation 31.847 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-28 | 128.83 score on a scale | Standard Deviation 52.561 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-2 | 2.39 score on a scale | Standard Deviation 2.539 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-36 | 169.44 score on a scale | Standard Deviation 67.178 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-40 | 186.70 score on a scale | Standard Deviation 73.308 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-4 | 8.02 score on a scale | Standard Deviation 6.703 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-20 | 86.24 score on a scale | Standard Deviation 35.453 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-44 | 199.95 score on a scale | Standard Deviation 78.945 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-6 | 17.09 score on a scale | Standard Deviation 10.606 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-16 | 67.98 score on a scale | Standard Deviation 27.401 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-32 | 148.93 score on a scale | Standard Deviation 59.923 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-8 | 28.09 score on a scale | Standard Deviation 14.266 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-14 | 58.62 score on a scale | Standard Deviation 25.009 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-24 | 108.25 score on a scale | Standard Deviation 43.928 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-10 | 38.71 score on a scale | Standard Deviation 18.14 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-12 | 49.09 score on a scale | Standard Deviation 21.692 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-10 | 45.95 score on a scale | Standard Deviation 18.51 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-12 | 58.89 score on a scale | Standard Deviation 21.362 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-14 | 72.17 score on a scale | Standard Deviation 24.82 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-36 | 203.32 score on a scale | Standard Deviation 64.342 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-16 | 84.46 score on a scale | Standard Deviation 27.487 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-48 | 267.51 score on a scale | Standard Deviation 92.791 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-18 | 97.57 score on a scale | Standard Deviation 32.42 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-20 | 108.32 score on a scale | Standard Deviation 37.011 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-40 | 224.78 score on a scale | Standard Deviation 72.951 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-24 | 134.91 score on a scale | Standard Deviation 42.035 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-1 | 0.45 score on a scale | Standard Deviation 0.951 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-2 | 2.16 score on a scale | Standard Deviation 2.56 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-28 | 158.01 score on a scale | Standard Deviation 45.579 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-4 | 9.62 score on a scale | Standard Deviation 6.196 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-6 | 20.71 score on a scale | Standard Deviation 10.368 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-8 | 33.64 score on a scale | Standard Deviation 14.203 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-32 | 180.50 score on a scale | Standard Deviation 54.648 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | SPI 0-44 | 246.09 score on a scale | Standard Deviation 84.178 |
Secondary
Summed Pain Intensity (SPI) Compared Between Group A and Group B
Pain Intensity using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with a score between 0-10 (0= no pain; 10 = worst imaginable pain). Summed Pain Intensity (SPI0-48) -was calculated using the trapezoidal method as the area under the curve (AUC) of pain intensity as measured using the NRS through various time intervals up to 48 hours. For SPI0-48 calculation, all available NRS pain intensity scores (scheduled pain intensity, unscheduled pain intensity and pre-rescue pain intensity) from 0 to 48 hours, including any imputed values, were used in the calculation. Hour 0 was defined as the time of the end of surgery. SPI0-48 was calculated using the formula: SUM (1/2 (SPIi + SPIi+1)\*Δt), where Δt was the time difference between Time i and Time (i+1). The represented values are sum of pain intensity scores at various time points. This outcome was compared between a combination of PGB and APAP (Group A) and APAP alone (Group B) from Hour 0 to Hour 48 (SPI0-48)
Time frame: 0 to 48 hours
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PGB and APAP (Group A) | Summed Pain Intensity (SPI) Compared Between Group A and Group B | 153.08 score on a scale | Standard Error 15.238 |
| Placebo (Group C). | Summed Pain Intensity (SPI) Compared Between Group A and Group B | 223.24 score on a scale | Standard Error 5.238 |
p-value: <0.001ANOVA
Secondary
Time to First Use of Rescue Medication From Hour 0
Time to first use of rescue medication from Hour 0 was reported. Hour 0 was defined as the end of surgery (i.e., completion of the last suture).
Time frame: 7 days
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PGB and APAP (Group A) | Time to First Use of Rescue Medication From Hour 0 | 11.60 hours |
| Placebo (Group C). | Time to First Use of Rescue Medication From Hour 0 | 5.78 hours |
| Placebo (Group C). | Time to First Use of Rescue Medication From Hour 0 | 4.31 hours |
Secondary
Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours
The total consumption of opioid rescue analgesia through 24 hours and through 48 hours was reported
Time frame: 24 hours and 48 hours
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PGB and APAP (Group A) | Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours | Consumption of Rescue Medication through 24 hours | 9.86 oral morphine equivalents | Standard Deviation 14.134 |
| PGB and APAP (Group A) | Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours | Consumption of Rescue Medication through 48 hours | 17.36 oral morphine equivalents | Standard Deviation 21.796 |
| Placebo (Group C). | Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours | Consumption of Rescue Medication through 24 hours | 19.24 oral morphine equivalents | Standard Deviation 17.019 |
| Placebo (Group C). | Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours | Consumption of Rescue Medication through 48 hours | 33.39 oral morphine equivalents | Standard Deviation 30.847 |
| Placebo (Group C). | Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours | Consumption of Rescue Medication through 24 hours | 28.88 oral morphine equivalents | Standard Deviation 20.981 |
| Placebo (Group C). | Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours | Consumption of Rescue Medication through 48 hours | 43.88 oral morphine equivalents | Standard Deviation 32.419 |
Secondary
Total Consumption of Rescue Medication
The total consumption of rescue analgesia was reported.
Time frame: 7 days
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least one dose of study drug. Subjects were analyzed according to the treatment group to which they were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PGB and APAP (Group A) | Total Consumption of Rescue Medication | 17.79 oral morphine equivalents | Standard Deviation 22.344 |
| Placebo (Group C). | Total Consumption of Rescue Medication | 34.24 oral morphine equivalents | Standard Deviation 32.496 |
| Placebo (Group C). | Total Consumption of Rescue Medication | 44.76 oral morphine equivalents | Standard Deviation 33.609 |