Trial Outcomes & Findings for A Phase 2 Study to Evaluate Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy (NCT NCT04495283)

Last Updated: 2021-11-23

Results Overview

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)

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

87 participants

Primary outcome timeframe

0 to 48 hours

Results posted on

2021-11-23

Participant Flow

Participants were recruited from 28 July 2020 till 26 Oct 2020 across the sites.

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.

Participant milestones

Participant milestones
Measure	PGB and APAP (Group A) Group A receives pregabalin (PGB) plus acetaminophen (APAP) prior to surgery and placebo 1 post-surgery.	APAP (Group B) Group B receives placebo 2 prior to surgery and APAP post-surgery.	Placebo (Group C). Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Overall Study STARTED	35	35	17
Overall Study COMPLETED	34	34	14
Overall Study NOT COMPLETED	1	1	3

Reasons for withdrawal

Reasons for withdrawal
Measure	PGB and APAP (Group A) Group A receives pregabalin (PGB) plus acetaminophen (APAP) prior to surgery and placebo 1 post-surgery.	APAP (Group B) Group B receives placebo 2 prior to surgery and APAP post-surgery.	Placebo (Group C). Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Overall Study Physician Decision	0	0	1
Overall Study Withdrawal by Subject	0	1	1
Overall Study Other	1	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	APAP (Group B) n=35 Participants Group B receives placebo 2 prior to surgery and APAP post-surgery.	Placebo (Group C). n=17 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.	Total n=87 Participants Total of all reporting groups
Age, Continuous	43.7 years STANDARD_DEVIATION 13.33 • n=5 Participants	42.1 years STANDARD_DEVIATION 11.68 • n=7 Participants	43.3 years STANDARD_DEVIATION 11.98 • n=5 Participants	43.0 years STANDARD_DEVIATION 12.31 • n=4 Participants
Sex: Female, Male Female	25 Participants n=5 Participants	31 Participants n=7 Participants	17 Participants n=5 Participants	73 Participants n=4 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	14 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=5 Participants	12 Participants n=7 Participants	7 Participants n=5 Participants	28 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	26 Participants n=5 Participants	23 Participants n=7 Participants	10 Participants n=5 Participants	59 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	7 Participants n=5 Participants	7 Participants n=7 Participants	4 Participants n=5 Participants	18 Participants n=4 Participants
Race (NIH/OMB) White	24 Participants n=5 Participants	26 Participants n=7 Participants	12 Participants n=5 Participants	62 Participants n=4 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Body Mass Index	26.03 kg/m^2 STANDARD_DEVIATION 3.213 • n=5 Participants	26.55 kg/m^2 STANDARD_DEVIATION 3.471 • n=7 Participants	26.05 kg/m^2 STANDARD_DEVIATION 3.406 • n=5 Participants	26.24 kg/m^2 STANDARD_DEVIATION 3.326 • n=4 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=17 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Summed Pain Intensity (SPI) Between Group A and Group C	153.08 score on a scale Standard Error 15.238	267.51 score on a scale Standard Error 21.864	—

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=35 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Summed Pain Intensity (SPI) Compared Between Group A and Group B	153.08 score on a scale Standard Error 15.238	223.24 score on a scale Standard Error 5.238	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=35 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). n=17 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
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	49.09 score on a scale Standard Error 3.728	58.89 score on a scale Standard Error 5.349
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	69.35 score on a scale Standard Error 5.082	88.95 score on a scale Standard Error 7.292
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	184.33 score on a scale Standard Error 13.128	221.58 score on a scale Standard Error 18.837

SECONDARY outcome

Timeframe: 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.

Outcome measures

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

SECONDARY outcome

Timeframe: 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

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

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=35 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). n=17 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Number of Participants With Treatment-Related Adverse Events (TRAE)	22 participants	9 participants	7 participants

SECONDARY outcome

Timeframe: 12 to 48 hours

Percentages of participants who did not take opioid (rescue medication) over time.

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=35 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). n=17 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Percentage of Participants Who Were Opioid Free Over Time During 12-24 Hours	65.7 percentage of participants	45.7 percentage of participants	35.3 percentage of participants
Percentage of Participants Who Were Opioid Free Over Time During 12-48 Hours	48.6 percentage of participants	28.6 percentage of participants	29.4 percentage of participants

SECONDARY outcome

Timeframe: 24 hours and 48 hours

The total consumption of opioid rescue analgesia through 24 hours and through 48 hours was reported

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=35 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). n=17 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
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	19.24 oral morphine equivalents Standard Deviation 17.019	28.88 oral morphine equivalents Standard Deviation 20.981
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	33.39 oral morphine equivalents Standard Deviation 30.847	43.88 oral morphine equivalents Standard Deviation 32.419

SECONDARY outcome

Timeframe: 7 days

The total consumption of rescue analgesia was reported.

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=35 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). n=17 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Total Consumption of Rescue Medication	17.79 oral morphine equivalents Standard Deviation 22.344	34.24 oral morphine equivalents Standard Deviation 32.496	44.76 oral morphine equivalents Standard Deviation 33.609

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=20 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=28 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). n=14 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Time to First Use of Rescue Medication From Hour 0	11.60 hours Interval 5.93 to 16.12	5.78 hours Interval 4.27 to 7.97	4.31 hours Interval 3.57 to 5.87

SECONDARY outcome

Timeframe: 7 days

Percentage of participants who used rescue medication is reported

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=35 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). n=17 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Percentage of Participants Who Used Rescue Medication	57.1 percentage of participants	80.0 percentage of participants	82.4 percentage of participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=35 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=34 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). n=15 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Patient Global Assessment of Pain (3) Very good	10 Participants	10 Participants	3 Participants
Patient Global Assessment of Pain (0) Poor	1 Participants	1 Participants	1 Participants
Patient Global Assessment of Pain (1) Fair	4 Participants	7 Participants	7 Participants
Patient Global Assessment of Pain (2) Good	6 Participants	7 Participants	3 Participants
Patient Global Assessment of Pain (4) Excellent	14 Participants	9 Participants	1 Participants

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=34 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=33 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
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	—	—
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	—	—
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	16847 nanogram per milliliter (ng/ml) Geometric Coefficient of Variation 39	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	PGB and APAP (Group A) n=34 Participants Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	Placebo (Group C). n=33 Participants Group C receives placebo 1 prior to surgery and placebo 2 post-surgery	Placebo (Group C). Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Minimum Observed Concentration for PGB and APAP	NA nanogram per milliliter (ng/ml) Geometric Coefficient of Variation NA Aside from the pre-dose sample collected just before the start of the first dose, there were no samples taken prior to each dose. Therefore, Cmin was unable to be estimated from the available samples.	NA nanogram per milliliter (ng/ml) Geometric Coefficient of Variation NA Aside from the pre-dose sample collected just before the start of the first dose, there were no samples taken prior to each dose. Therefore, Cmin was unable to be estimated from the available samples.	—

Adverse Events

PGB and APAP (Group A)

Serious events: 0 serious events

Other events: 27 other events

Deaths: 0 deaths

APAP (Group B)

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Placebo (Group C).

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Eric Lang, MD

Nevakar, Inc.

Phone: (908) 367-7400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	PGB and APAP (Group A) n=35 participants at risk Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery.	APAP (Group B) n=35 participants at risk Group B receives placebo 2 prior to surgery and APAP post-surgery	Placebo (Group C). n=17 participants at risk Group C receives placebo 1 prior to surgery and placebo 2 post-surgery
Cardiac disorders Tachycardia	0.00% 0/35 • Up to 7 days (± 1 day) 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.	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Eye disorders Diplopia	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Eye disorders Vision blurred	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Gastrointestinal disorders Constipation	0.00% 0/35 • Up to 7 days (± 1 day) 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.	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Gastrointestinal disorders Nausea	25.7% 9/35 • Up to 7 days (± 1 day) 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.	14.3% 5/35 • Up to 7 days (± 1 day) 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.	29.4% 5/17 • Up to 7 days (± 1 day) 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.
Gastrointestinal disorders Vomiting	14.3% 5/35 • Up to 7 days (± 1 day) 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.	5.7% 2/35 • Up to 7 days (± 1 day) 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.	23.5% 4/17 • Up to 7 days (± 1 day) 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.
General disorders Application site rash	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	5.9% 1/17 • Up to 7 days (± 1 day) 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.
General disorders Chest discomfort	0.00% 0/35 • Up to 7 days (± 1 day) 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.	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
General disorders Infusion site extravasation	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
General disorders Injection site erythema	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
General disorders Injection site extravasation	5.7% 2/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	5.9% 1/17 • Up to 7 days (± 1 day) 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.
General disorders Pain	0.00% 0/35 • Up to 7 days (± 1 day) 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.	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
General disorders Pyrexia	0.00% 0/35 • Up to 7 days (± 1 day) 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.	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Infections and infestations COVID-19	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Infections and infestations Post procedural cellulitis	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Investigations Alanine aminotransferase increased	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Investigations Aspartate aminotransferase increased	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Investigations Transaminases abnormal	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Investigations Transaminases increased	5.7% 2/35 • Up to 7 days (± 1 day) 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.	5.7% 2/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	5.9% 1/17 • Up to 7 days (± 1 day) 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.
Nervous system disorders Dizziness	51.4% 18/35 • Up to 7 days (± 1 day) 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.	8.6% 3/35 • Up to 7 days (± 1 day) 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.	17.6% 3/17 • Up to 7 days (± 1 day) 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.
Nervous system disorders Headache	8.6% 3/35 • Up to 7 days (± 1 day) 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.	5.7% 2/35 • Up to 7 days (± 1 day) 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.	11.8% 2/17 • Up to 7 days (± 1 day) 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.
Nervous system disorders Presyncope	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Psychiatric disorders Euphoric mood	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Skin and subcutaneous tissue disorders Blister	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	5.9% 1/17 • Up to 7 days (± 1 day) 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.
Skin and subcutaneous tissue disorders Dermatitis contact	0.00% 0/35 • Up to 7 days (± 1 day) 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.	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Skin and subcutaneous tissue disorders Rash	2.9% 1/35 • Up to 7 days (± 1 day) 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.	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Vascular disorders Hot flush	0.00% 0/35 • Up to 7 days (± 1 day) 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.	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.
Vascular disorders Hypotension	2.9% 1/35 • Up to 7 days (± 1 day) 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.	0.00% 0/35 • Up to 7 days (± 1 day) 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.	0.00% 0/17 • Up to 7 days (± 1 day) 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.