Trial Outcomes & Findings for Predicting, Understanding and Speeding Recovery After TKA (NCT NCT02685735)

NCT ID: NCT02685735

Last Updated: 2025-08-15

Results Overview

Daily pain intensity report for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for gabapentin and placebo group separately. The daily pain intensity was the WORST pain (not the average pain) in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain. Values represent an intercept of modeled worst daily pain on the first day after hospital discharge across all participants, extracted from the mixed effect model. The intercept is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.

• Recruitment status: TERMINATED
• Study phase: PHASE4
• Target enrollment: 350 participants
• Primary outcome timeframe: The first day after hospital discharge up to 5 days post surgery
• Results posted on: 2025-08-15

Participant Flow

Enrollment occurred from June 2, 2016 to August 2, 2021 at the Orthopeadic Clinics of Atrium Wake Forest Baptist and Davie County facilities and May 9, 2017 to July 21, 2020 at Cleveland Clinic facilities. Change in clinical practice resulted in inability to recruit subjects on high doses of opioid preoperatively, so recruitment of 50 subject in Aim 3 which was intended to separately examine interactions in this population did not occur.

Enrollment occurred greater or equal to 2 weeks prior to surgery. A total of 76 individuals were excluded prior to assignment to groups during the period prior to surgery because of cancellation of the planned surgery.

Participant milestones

Measure	Gabapentin Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Overall Study STARTED	135	139
Overall Study COMPLETED	117	123
Overall Study NOT COMPLETED	18	16

Reasons for withdrawal

Measure	Gabapentin Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Overall Study Surgery Cancelled	4	9
Overall Study Adverse Event	10	3
Overall Study Preop testing found to be incomplete	2	2
Overall Study Withdrawal by Subject	1	2
Overall Study Death	1	0

Baseline Characteristics

Predicting, Understanding and Speeding Recovery After TKA

Baseline characteristics by cohort

Measure	Gabapentin n=117 Participants Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=123 Participants Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Total n=240 Participants Total of all reporting groups
Age, Continuous	60.8 years STANDARD_DEVIATION 7.8 • n=5 Participants	60.7 years STANDARD_DEVIATION 9.1 • n=7 Participants	60.8 years STANDARD_DEVIATION 8.5 • n=5 Participants
Sex: Female, Male Female	60 Participants n=5 Participants	71 Participants n=7 Participants	131 Participants n=5 Participants
Sex: Female, Male Male	57 Participants n=5 Participants	52 Participants n=7 Participants	109 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	116 Participants n=5 Participants	121 Participants n=7 Participants	237 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 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
Race (NIH/OMB) Black or African American	18 Participants n=5 Participants	15 Participants n=7 Participants	33 Participants n=5 Participants
Race (NIH/OMB) White	98 Participants n=5 Participants	107 Participants n=7 Participants	205 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	117 participants n=5 Participants	123 participants n=7 Participants	240 participants n=5 Participants
Worst daily pain	4.78 units on a scale STANDARD_DEVIATION 2.77 • n=5 Participants	4.71 units on a scale STANDARD_DEVIATION 2.31 • n=7 Participants	4.75 units on a scale STANDARD_DEVIATION 2.54 • n=5 Participants
Resting pupil diameter	6.1 mm STANDARD_DEVIATION 1.9 • n=5 Participants	5.9 mm STANDARD_DEVIATION 1.8 • n=7 Participants	6.0 mm STANDARD_DEVIATION 1.8 • n=5 Participants
Optimism/acceptance of pain to catastrophizing cognitive style	-0.12 units on a scale STANDARD_DEVIATION 1.0 • n=5 Participants	0.00 units on a scale STANDARD_DEVIATION 1.08 • n=7 Participants	0.00 units on a scale STANDARD_DEVIATION 1.0 • n=5 Participants

PRIMARY outcome

Timeframe: The first day after hospital discharge up to 5 days post surgery

Population: The intention-to-treat population included all randomized patients who had at least one baseline pupil measurement, received at least one dose of study drug, and provided at least one pain score after the day of surgery.

Daily pain intensity report for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for gabapentin and placebo group separately. The daily pain intensity was the WORST pain (not the average pain) in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain.

Values represent an intercept of modeled worst daily pain on the first day after hospital discharge across all participants, extracted from the mixed effect model. The intercept is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.

Outcome measures

Measure	Gabapentin n=117 Participants Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=123 Participants Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo--Intercept	7.57 score on a scale Interval 7.17 to 7.88	7.52 score on a scale Interval 7.16 to 7.88

PRIMARY outcome

Timeframe: Postoperative Day 1 through Postoperative Day 60

Population: The intention-to-treat population included all randomized patients who had at least one baseline pupil measurement, received at least one dose of study drug, and provided at least one pain score after the day of surgery.

Daily pain intensity report for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for gabapentin and placebo group separately. The daily pain intensity was the WORST pain (not the average pain) in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain.

Slope is defined as change in pain . Values represent the slope of modeled worst daily pain (0-10 scale as described above) divided by the natural log of time (days) across all participants, extracted from the mixed effect model. The slope is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.

Outcome measures

Measure	Gabapentin n=117 Participants Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=123 Participants Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo-- Slope	-0.110 score on a scale/ln(day) Interval -0.113 to -0.107	-0.114 score on a scale/ln(day) Interval -0.117 to -0.111

PRIMARY outcome

Timeframe: Postoperative Day 1 through Postoperative Day 60

Population: The intention-to-treat population included all randomized patients who had at least one baseline pupil measurement, received at least one dose of study drug, and provided at least one pain score after the day of surgery. The primary analysis, as pre-specified in the statistical analysis plan and upon which sample size was determined, tested whether growth curve model for change in pain over 2 months was better fit when group, pupil diameter, and cognitive construct scores were added.

Daily pain intensity report for each subject was fitted using growth curve model, adjusted for pre-specified prognostic predictors . The daily pain intensity was the WORST pain (not the average pain) in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain.

Deviance values were calculated from the model fit with just pre-specified prognostic predictors (Model 1) and the model fit with these predictors plus pupil diameter, catastrophizing-optimism construct, gabapentin treatment and their interaction. Deviance is a goodness-of-fit statistic for a statistical model; it is often used for statistical hypothesis testing. It is a generalization of the idea of using the sum of squares of residuals (SSR) in ordinary least squares to cases where model-fitting is achieved by maximum likelihood. Deviance ranges from 0 to infinity. The smaller the number the better the model fits the sample data.

Model fits were compared using Chi-squared test.

Outcome measures

Measure	Gabapentin n=240 Participants Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=240 Participants Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Effect Pupil Diameter, Catastrophizing-optimism Construct, and Gabapentin on Model Fit of the Trajectory of Change in Worst Daily Pain After Surgery	43604 unitless	343523 unitless

SECONDARY outcome

Timeframe: Preoperative, 2 months after surgery, 6 months after surgery

Population: The total completed for this secondary outcome is 113 in the gabapentin group and 116 in the placebo group. The reason for not completing was failure to complete questionnaires on at least one of the three occasions that these were performed.

This is a physical card sorting game which measures attention to shifts in implicit rules as the game progresses. Perseverative errors are the number of sequential errors when rules of the game shift and reflect dysfunction of attention. This score ranges from 0 to 64 with larger numbers reflecting more dysfunction of attention.

Outcome measures

Measure	Gabapentin n=113 Participants Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=116 Participants Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Wisconsin Card Sort Task Preoperative	4 score on a scale Interval -8.0 to 20.0	2 score on a scale Interval -10.0 to 24.0
Wisconsin Card Sort Task 2 months after surgery	10 score on a scale Interval -4.0 to 42.0	8 score on a scale Interval -10.0 to 40.0
Wisconsin Card Sort Task 6 months after surgery	18 score on a scale Interval -4.0 to 45.0	18 score on a scale Interval -2.0 to 41.0

SECONDARY outcome

Timeframe: Preoperative, 2 months after surgery, 6 months after surgery

Population: The total completed for this secondary outcome is 111 in the gabapentin group and 115 in the placebo group. The reason for not completing was failure to complete the task on at least one of the three occasions that these were performed.

This is a computer based card game which assesses risk taking and impulsivity in which a score of -100 to 100 is calculated. Lower numbers indicate greater impulsiivity

Outcome measures

Measure	Gabapentin n=111 Participants Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=115 Participants Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Iowa Gambling Task Preoperative	8 score on a scale Interval 5.0 to 14.0	7 score on a scale Interval 5.0 to 10.0
Iowa Gambling Task 2 months after surgery	6 score on a scale Interval 4.0 to 10.0	6 score on a scale Interval 4.0 to 10.0
Iowa Gambling Task 6 months after surgery	5 score on a scale Interval 4.0 to 8.0	5 score on a scale Interval 4.0 to 8.0

SECONDARY outcome

Timeframe: Preoperative, 2 months after surgery, 6 months after surgery

Population: The total completed for secondary analyses is 113 in the gabapentin group and 117 in the placebo group. The reason for not completing was failure to complete questionnaires on at least one of the three occasions that these were performed.

This 17-question scale assesses the degree of fear of pain from joint movement and is commonly used in orthopedic injury or surgery studies. The scale ranges from 17 to 68 with 17 indicating no fear of movement and 68 indicating severe fear.

Outcome measures

Measure	Gabapentin n=113 Participants Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=117 Participants Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Tampa Scale of Kinesiophobia Preoperative	37 score on a scale Interval 33.0 to 41.0	38 score on a scale Interval 35.0 to 41.0
Tampa Scale of Kinesiophobia 2 months after surgery	36 score on a scale Interval 33.0 to 39.0	37 score on a scale Interval 34.0 to 40.0
Tampa Scale of Kinesiophobia 6 months after surgery	37 score on a scale Interval 34.0 to 40.0	36 score on a scale Interval 34.0 to 40.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Preoperative

Population: Data were not collected

Blood and cerebrospinal fluid will be obtained and frozen for subsequent assessment of hormones, neurochemicals, and other secreted compounds indicative of stress. Analysis will be in the future and dependent upon new literature for ideal biomarkers.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Preoperative

Population: Data were not collected

Blood and cerebrospinal fluid will be obtained and frozen for subsequent assessment of compounds reflecting noradrenergic functioning. Analysis will be in the future and dependent upon new literature for ideal biomarkers.

Outcome measures

Outcome data not reported

Adverse Events

Gabapentin

Serious events: 1 serious events

Other events: 17 other events

Deaths: 1 deaths

Placebo

Serious events: 0 serious events

Other events: 2 other events

Deaths: 1 deaths

Serious adverse events

Measure	Gabapentin n=135 participants at risk Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=139 participants at risk Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Cardiac disorders Death	0.74% 1/135 • Number of events 1 • through study completion, an average of 1 year per participant Adverse events related to known effects of gabapentin (sedation, dizziness, nausea) were assessed daily via the daily digital diaries beginning two weeks prior to surgery (the time study drug began) and continuing for 3 weeks after surgery, when study drug was discontinued. Adverse events during hospitalization were captured via the electronic medical health record. Other adverse events were captured daily via digital diaries until 2 months after surgery, then at 6- and 12- month phone calls.	0.00% 0/139 • through study completion, an average of 1 year per participant Adverse events related to known effects of gabapentin (sedation, dizziness, nausea) were assessed daily via the daily digital diaries beginning two weeks prior to surgery (the time study drug began) and continuing for 3 weeks after surgery, when study drug was discontinued. Adverse events during hospitalization were captured via the electronic medical health record. Other adverse events were captured daily via digital diaries until 2 months after surgery, then at 6- and 12- month phone calls.

Other adverse events

Measure	Gabapentin n=135 participants at risk Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Placebo n=139 participants at risk Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.
Nervous system disorders Somnolence	7.4% 10/135 • Number of events 10 • through study completion, an average of 1 year per participant Adverse events related to known effects of gabapentin (sedation, dizziness, nausea) were assessed daily via the daily digital diaries beginning two weeks prior to surgery (the time study drug began) and continuing for 3 weeks after surgery, when study drug was discontinued. Adverse events during hospitalization were captured via the electronic medical health record. Other adverse events were captured daily via digital diaries until 2 months after surgery, then at 6- and 12- month phone calls.	0.00% 0/139 • through study completion, an average of 1 year per participant Adverse events related to known effects of gabapentin (sedation, dizziness, nausea) were assessed daily via the daily digital diaries beginning two weeks prior to surgery (the time study drug began) and continuing for 3 weeks after surgery, when study drug was discontinued. Adverse events during hospitalization were captured via the electronic medical health record. Other adverse events were captured daily via digital diaries until 2 months after surgery, then at 6- and 12- month phone calls.
Nervous system disorders Dizziness	5.2% 7/135 • Number of events 7 • through study completion, an average of 1 year per participant Adverse events related to known effects of gabapentin (sedation, dizziness, nausea) were assessed daily via the daily digital diaries beginning two weeks prior to surgery (the time study drug began) and continuing for 3 weeks after surgery, when study drug was discontinued. Adverse events during hospitalization were captured via the electronic medical health record. Other adverse events were captured daily via digital diaries until 2 months after surgery, then at 6- and 12- month phone calls.	1.4% 2/139 • Number of events 2 • through study completion, an average of 1 year per participant Adverse events related to known effects of gabapentin (sedation, dizziness, nausea) were assessed daily via the daily digital diaries beginning two weeks prior to surgery (the time study drug began) and continuing for 3 weeks after surgery, when study drug was discontinued. Adverse events during hospitalization were captured via the electronic medical health record. Other adverse events were captured daily via digital diaries until 2 months after surgery, then at 6- and 12- month phone calls.

Additional Information

Dr. James Eisenach

Wake Forest University School of Medicine

Phone: 336-716-4182

Email: jimeisenach@gmail.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place