A Phase 2 Study to Evaluate Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy

• Sponsor: Nevakar, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04495283
• Collaborator: Nevakar Injectables, Inc. (Industry)
• Enrollment: 87
• Locations: 2
• Arms: 3
• Actual Duration (Months): 3.5
• Patients Per Site: 43.5
• Patients Per Site Per Month: 12.4

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain	Drug: Pregabalin; Drug: Acetaminophen; Other: Placebo 1; Other: Placebo 2	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Parallel AssignmentParallel Assignment
• Masking: Triple (Participant, Care Provider, 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).
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination of Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy
• Actual Study Start Date: Jul 28, 2020
• Actual Primary Completion Date: Nov 12, 2020
• Actual Study Completion Date: Nov 12, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PGB and APAP (Group A) Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Drug: Pregabalin; Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma aminobutyric acid with anticonvulsant, anxiolytic and sleep-modulating properties.; Other Names: PGB ; Drug: Acetaminophen; Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent.; Other Names: APAP
Experimental: APAP (Group B) Group B receives placebo 2 prior to surgery and APAP post-surgery.	Drug: Acetaminophen; Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent.; Other Names: APAP ; Other: Placebo 2; Placebo for combination
Experimental: Placebo (Group C). Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.	Other: Placebo 1; Placebo for APAP; Other: Placebo 2; Placebo for combination

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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)

2. 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.

3. 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.

4. 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

5. 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.

6. 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

7. Total Consumption of Rescue Medication [7 days]

   The total consumption of rescue analgesia was reported.

8. 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).

9. Percentage of Participants Who Used Rescue Medication [7 days]

   Percentage of participants who used rescue medication is reported

10. 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

11. 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.

12. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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.

1. Diabetes mellitus (uncontrolled). Diabetes mellitus must be controlled without known end organ damage.

2. History of malignancy in the past 2 years with the exception of squamous cell carcinoma or basal cell carcinoma.

3. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lotus Clinical Resarch,LLC	Pasadena	California	United States	91105
2	Lotus HD Research	Bellaire	Texas	United States	77401

Sponsors and Collaborators

• Nevakar, Inc.
• Nevakar Injectables, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 19, 2020

More Information

Publications

None provided.

• Responsible Party: Nevakar, Inc.
• ClinicalTrials.gov Identifier: NCT04495283
• Other Study ID Numbers: CP-NVK009-0005
• First Posted: Jul 31, 2020
• Last Update Posted: Nov 23, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Pain, Postoperative; Acetaminophen; Pregabalin

Study Results

Participant Flow

Recruitment Details	Participants were recruited from 28 July 2020 till 26 Oct 2020 across the sites.
Pre-assignment Detail	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.

Arm/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives pregabalin (PGB) plus acetaminophen (APAP) prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Period Title: Overall Study
STARTED	35	35	17
COMPLETED	34	34	14
NOT COMPLETED	1	1	3

Baseline Characteristics

Arm/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).	Total
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.	Total of all reporting groups
Overall Participants	35	35	17	87
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.7 (13.33)	42.1 (11.68)	43.3 (11.98)	43.0 (12.31)
Sex: Female, Male (Count of Participants)
Female	25 71.4%	31 88.6%	17 100%	73 83.9%
Male	10 28.6%	4 11.4%	0 0%	14 16.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 25.7%	12 34.3%	7 41.2%	28 32.2%
Not Hispanic or Latino	26 74.3%	23 65.7%	10 58.8%	59 67.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.9%	0 0%	1 5.9%	2 2.3%
Asian	1 2.9%	2 5.7%	0 0%	3 3.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	7 20%	7 20%	4 23.5%	18 20.7%
White	24 68.6%	26 74.3%	12 70.6%	62 71.3%
More than one race	2 5.7%	0 0%	0 0%	2 2.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.03 (3.213)	26.55 (3.471)	26.05 (3.406)	26.24 (3.326)

Outcome Measures

1. Primary Outcome

Title	Summed Pain Intensity (SPI) Between Group A and Group C
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Measure Participants	35	17
Least Squares Mean (Standard Error) [score on a scale]	153.08 (15.238)	267.51 (21.864)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PGB and APAP (Group A), Placebo (Group C).
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-114.43
	Confidence Interval	(1-Sided) 90%; to -80.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 26.650
	Estimation Comments

2. Secondary Outcome

Title	Summed Pain Intensity (SPI) Compared Between Group A and Group B
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.
Measure Participants	35	35
Least Squares Mean (Standard Error) [score on a scale]	153.08 (15.238)	223.24 (5.238)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PGB and APAP (Group A), Placebo (Group C).
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-70.16
	Confidence Interval	(1-Sided) 90%; to -42.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.549
	Estimation Comments

3. Secondary Outcome

Title	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).
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Measure Participants	35	35	17
SPI 0-12	33.09 (3.728)	49.09 (3.728)	58.89 (5.349)
SPI 12-24	50.92 (5.082)	69.35 (5.082)	88.95 (7.292)
SPI 24-48	126.83 (13.128)	184.33 (13.128)	221.58 (18.837)

4. Secondary Outcome

Title	Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Measure Participants	35	35	17
SPI 0-1	0.26 (0.509)	0.73 (0.870)	0.45 (0.951)
SPI 0-2	1.26 (1.591)	2.39 (2.539)	2.16 (2.560)
SPI 0-4	5.63 (5.120)	8.02 (6.703)	9.62 (6.196)
SPI 0-6	12.68 (9.650)	17.09 (10.606)	20.71 (10.368)
SPI 0-8	20.00 (14.211)	28.09 (14.266)	33.64 (14.203)
SPI 0-10	26.25 (18.413)	38.71 (18.140)	45.95 (18.510)
SPI 0-12	33.09 (22.725)	49.09 (21.692)	58.89 (21.362)
SPI 0-14	41.12 (27.035)	58.62 (25.009)	72.17 (24.820)
SPI 0-16	49.08 (30.480)	67.98 (27.401)	84.46 (27.487)
SPI 0-18	55.84 (33.985)	78.49 (31.847)	97.57 (32.420)
SPI 0-20	61.49 (36.259)	86.24 (35.453)	108.32 (37.011)
SPI 0-24	77.17 (43.864)	108.25 (43.928)	134.91 (42.035)
SPI 0-28	88.94 (50.680)	128.83 (52.561)	158.01 (45.579)
SPI 0-32	100.85 (56.483)	148.93 (59.923)	180.50 (54.648)
SPI 0-36	114.43 (63.776)	169.44 (67.178)	203.32 (64.342)
SPI 0-40	126.45 (69.998)	186.70 (73.308)	224.78 (72.951)
SPI 0-44	139.54 (78.396)	199.95 (78.945)	246.09 (84.178)
SPI 0-48	153.08 (87.398)	223.24 (91.581)	267.51 (92.791)

5. Secondary Outcome

Title	Number of Participants With Treatment-Related Adverse Events (TRAE)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Measure Participants	35	35	17
Number [participants]	22 62.9%	9 25.7%	7 41.2%

6. Secondary Outcome

Title	Percentage of Participants Who Were Opioid Free Over Time
Description	Percentages of participants who did not take opioid (rescue medication) over time.
Time Frame	12 to 48 hours

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Measure Participants	35	35	17
During 12-24 Hours	65.7 187.7%	45.7 130.6%	35.3 207.6%
During 12-48 Hours	48.6 138.9%	28.6 81.7%	29.4 172.9%

7. Secondary Outcome

Title	Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours
Description	The total consumption of opioid rescue analgesia through 24 hours and through 48 hours was reported
Time Frame	24 hours and 48 hours

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Measure Participants	35	35	17
Consumption of Rescue Medication through 24 hours	9.86 (14.134)	19.24 (17.019)	28.88 (20.981)
Consumption of Rescue Medication through 48 hours	17.36 (21.796)	33.39 (30.847)	43.88 (32.419)

8. Secondary Outcome

Title	Total Consumption of Rescue Medication
Description	The total consumption of rescue analgesia was reported.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Measure Participants	35	35	17
Mean (Standard Deviation) [oral morphine equivalents]	17.79 (22.344)	34.24 (32.496)	44.76 (33.609)

9. Secondary Outcome

Title	Time to First Use of Rescue Medication From Hour 0
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Measure Participants	20	28	14
Median (90% Confidence Interval) [hours]	11.60	5.78	4.31

10. Secondary Outcome

Title	Percentage of Participants Who Used Rescue Medication
Description	Percentage of participants who used rescue medication is reported
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Measure Participants	35	35	17
Number [percentage of participants]	57.1 163.1%	80.0 228.6%	82.4 484.7%

11. Secondary Outcome

Title	Patient Global Assessment of Pain
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Measure Participants	35	34	15
(0) Poor	1 2.9%	1 2.9%	1 5.9%
(1) Fair	4 11.4%	7 20%	7 41.2%
(2) Good	6 17.1%	7 20%	3 17.6%
(3) Very good	10 28.6%	10 28.6%	3 17.6%
(4) Excellent	14 40%	9 25.7%	1 5.9%

12. Secondary Outcome

Title	Maximum Observed Concentration for PGB and APAP
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Measure Participants	34	33	0
Mean Cmax Values of Pregabalin- First Dose	10068 (36)
Mean Cmax Values of Pregabalin- Last Dose	12960 (27)
Mean Cmax Values of Acetaminophen-First Dose	28700 (34)	16847 (39)

13. Secondary Outcome

Title	Minimum Observed Concentration for PGB and APAP
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PGB and APAP (Group A)	APAP (Group B)	Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Group B receives placebo 2 prior to surgery and APAP post-surgery.	Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Measure Participants	34	33	0
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/ml)]	NA (NA)	NA (NA)

Adverse Events

Time Frame	Up to 7 days (± 1 day)
Adverse Event Reporting Description	An adverse event (AE) is defined as any untoward medical occurrence and does not necessarily have to have causal relationship with the study medication. An AE can therefore be an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease, which is a change from baseline and is temporally associated with the use of the study medication, whether or not it is considered related to the study medication.
Arm/Group Title	PGB and APAP (Group A)		APAP (Group B)		Placebo (Group C).
Arm/Group Description	Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.		Group B receives placebo 2 prior to surgery and APAP post-surgery		Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
All Cause Mortality
	PGB and APAP (Group A)		APAP (Group B)		Placebo (Group C).
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/35 (0%)		0/17 (0%)
Serious Adverse Events
	PGB and APAP (Group A)		APAP (Group B)		Placebo (Group C).
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/35 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	PGB and APAP (Group A)		APAP (Group B)		Placebo (Group C).
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/35 (77.1%)		15/35 (42.9%)		9/17 (52.9%)
Cardiac disorders
Tachycardia	0/35 (0%)		1/35 (2.9%)		0/17 (0%)
Eye disorders
Diplopia	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Vision blurred	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Gastrointestinal disorders
Constipation	0/35 (0%)		1/35 (2.9%)		0/17 (0%)
Nausea	9/35 (25.7%)		5/35 (14.3%)		5/17 (29.4%)
Vomiting	5/35 (14.3%)		2/35 (5.7%)		4/17 (23.5%)
General disorders
Application site rash	0/35 (0%)		0/35 (0%)		1/17 (5.9%)
Chest discomfort	0/35 (0%)		1/35 (2.9%)		0/17 (0%)
Infusion site extravasation	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Injection site erythema	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Injection site extravasation	2/35 (5.7%)		0/35 (0%)		1/17 (5.9%)
Pain	0/35 (0%)		1/35 (2.9%)		0/17 (0%)
Pyrexia	0/35 (0%)		1/35 (2.9%)		0/17 (0%)
Infections and infestations
COVID-19	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Post procedural cellulitis	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Investigations
Alanine aminotransferase increased	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Aspartate aminotransferase increased	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Transaminases abnormal	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Transaminases increased	2/35 (5.7%)		2/35 (5.7%)		0/17 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Pain in extremity	0/35 (0%)		0/35 (0%)		1/17 (5.9%)
Nervous system disorders
Dizziness	18/35 (51.4%)		3/35 (8.6%)		3/17 (17.6%)
Headache	3/35 (8.6%)		2/35 (5.7%)		2/17 (11.8%)
Presyncope	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Psychiatric disorders
Euphoric mood	1/35 (2.9%)		0/35 (0%)		0/17 (0%)
Skin and subcutaneous tissue disorders
Blister	0/35 (0%)		0/35 (0%)		1/17 (5.9%)
Dermatitis contact	0/35 (0%)		1/35 (2.9%)		0/17 (0%)
Rash	1/35 (2.9%)		1/35 (2.9%)		0/17 (0%)
Vascular disorders
Hot flush	0/35 (0%)		1/35 (2.9%)		0/17 (0%)
Hypotension	1/35 (2.9%)		0/35 (0%)		0/17 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.