Trial Outcomes & Findings for Valproic Acid for the Prevention of Post-Amputation Pain (NCT NCT01928849)

NCT ID: NCT01928849

Last Updated: 2018-12-19

Results Overview

The primary endpoint is the incidence of chronic pain after surgery. The study team will use the average pain score over the past week as noted on the Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS) for the assessment of pain, and define chronic pain as a score greater than or equal to 3.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

128 participants

Primary outcome timeframe

3 months or time of final adjudication assessment, up to 6 months

Results posted on

2018-12-19

Participant Flow

Participant milestones

Participant milestones
Measure	Cherry Syrup Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Overall Study STARTED	66	62
Overall Study COMPLETED	52	55
Overall Study NOT COMPLETED	14	7

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Valproic Acid for the Prevention of Post-Amputation Pain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cherry Syrup n=66 Participants Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=62 Participants "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.	Total n=128 Participants Total of all reporting groups
Age, Continuous	50.3 years STANDARD_DEVIATION 16.6 • n=5 Participants	51.1 years STANDARD_DEVIATION 18.2 • n=7 Participants	50.7 years STANDARD_DEVIATION 17.3 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	11 Participants n=7 Participants	22 Participants n=5 Participants
Sex: Female, Male Male	55 Participants n=5 Participants	51 Participants n=7 Participants	106 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	63 Participants n=5 Participants	59 Participants n=7 Participants	122 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	1 Participants n=5 Participants	0 Participants n=7 Participants	1 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	15 Participants n=5 Participants	12 Participants n=7 Participants	27 Participants n=5 Participants
Race (NIH/OMB) White	49 Participants n=5 Participants	49 Participants n=7 Participants	98 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	66 Participants n=5 Participants	62 Participants n=7 Participants	128 Participants n=5 Participants

PRIMARY outcome

Timeframe: 3 months or time of final adjudication assessment, up to 6 months

Population: Participants who completed the study.

Outcome measures

Outcome measures
Measure	Cherry Syrup n=52 Participants Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=55 Participants "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Number of Patients With Chronic Post-amputation Pain	37 Participants	36 Participants

SECONDARY outcome

Timeframe: Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months)

Population: Participants who completed the study. For the cherry syrup (placebo) arm, only 50 participants completed the full adjudication process necessary to determine phantom pain sub-type.

The incidence of neuropathic limb or post-amputation pain sub-types as defined by adjudication classification at each assessment time point.

Outcome measures

Outcome measures
Measure	Cherry Syrup n=52 Participants Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=55 Participants "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Incidence of Pain Sub-types Residual limb pain	29 Participants	31 Participants
Incidence of Pain Sub-types Phantom limb	22 Participants	26 Participants

SECONDARY outcome

Timeframe: Assessments during hospitalization (0-24 hours and 24-48 hours post-surgery)

Population: Patients who completed the study

The effect of study drug on perioperative analgesic consumption and corresponding analysis of pain/sedation scales. Outcome defined as total opioid consumption (mg) during each 24-hour periods following surgery.

Outcome measures

Outcome measures
Measure	Cherry Syrup n=52 Participants Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=55 Participants "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Effect on Analgesic Requirement Postoperative hours 0-24	59 morphine milligram equivalents Interval 20.0 to 89.0	33 morphine milligram equivalents Interval 20.0 to 114.0
Effect on Analgesic Requirement Postoperative hours 24-48	49 morphine milligram equivalents Interval 24.0 to 159.0	45 morphine milligram equivalents Interval 20.0 to 114.0

SECONDARY outcome

Timeframe: Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months)

Population: Those completing questionnaires at both time points

The BPI short form is a multidimensional patient-completed measure that assesses the sensory component of pain intensity. We will analyze the change in average pain score question (ranges 0-10) and the sum of the 7 interference questions (total range 0-70) from baseline. Higher score indicates greater pain and interference.

Outcome measures

Outcome measures
Measure	Cherry Syrup n=49 Participants Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=53 Participants "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Brief Pain Inventory (BPI) Short Form Score BPI Average Pain Score	-2 score on a scale Interval -3.0 to 0.0	-1 score on a scale Interval -3.0 to 0.0
Brief Pain Inventory (BPI) Short Form Score BPI interference question sum	-15 score on a scale Interval -33.0 to -4.0	-7 score on a scale Interval -31.0 to 0.0

SECONDARY outcome

Timeframe: Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months)

Population: Patients who completed questionnaire at both time points

The S-LANSS is a self-reported version of the Leeds Assessment of Neuropathic Symptoms and Signs pain scale. It aims to differentiate neuropathic pain from somatic or nociceptive pain. We will analyze the change in numeric average pain score during the past week (range from 0-10) from baseline. Higher scores indicate greater pain.

Outcome measures

Outcome measures
Measure	Cherry Syrup n=52 Participants Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=55 Participants "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Change in Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (S-LANSS)	-2 score on a scale Interval -5.0 to -1.0	-2 score on a scale Interval -5.0 to 0.0

SECONDARY outcome

Timeframe: Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months)

Population: Patients who completed questionnaires at both time points

The DVPRS is a pain assessment tool developed by the military in an effort to improve reliability and interpretability of pain assessment in the military population. It has been found to be an effective and valid tool in this population. We will analyze the change in numeric pain response (range 0-10) and the sum of the four supplemental questions (range 0-40) from baseline. Higher scores indicate greater pain and functional limitations.

Outcome measures

Outcome measures
Measure	Cherry Syrup n=43 Participants Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=46 Participants "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Defense and Veterans Pain Rating Scale (DVPRS) Score DVPRS numeric pain	-2 score on a scale Interval -3.0 to 0.0	0 score on a scale Interval -3.5 to 0.0
Defense and Veterans Pain Rating Scale (DVPRS) Score DVPRS Supplemental Question Sum	-9 score on a scale Interval -18.0 to -1.0	-4.5 score on a scale Interval -17.0 to 0.0

SECONDARY outcome

Timeframe: during hospitalization (0-24 hours and 24-48 hours post-surgery)

Population: Participants who completed the RASS assessment on post-op day 1.

The RASS is a commonly used, valid and reliable assessment tool for use in hospitalized patients. Validity testing reveals good inter-rater reliability among medical, surgical, and intensive care units. We will analyze the numeric score at each assessment (range -5 (unarousable) to 4 (combative)).

Outcome measures

Outcome measures
Measure	Cherry Syrup n=47 Participants Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=51 Participants "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Richmond Agitation-Sedation Scale (RASS) Post-op hours 24-48	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 0.0
Richmond Agitation-Sedation Scale (RASS) Post-op hours 0-24	0 score on a scale Interval 0.0 to 0.0	0 score on a scale Interval 0.0 to 0.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Changes between enrollment, end of study drug and 3 months or time of final adjudication

Epigenetic analysis (DNA methylation) will be correlated with pain sub-type and use of Valproic Acid.

Outcome measures

Outcome data not reported

Adverse Events

Cherry Syrup

Serious events: 26 serious events

Other events: 31 other events

Deaths: 4 deaths

Valproic Acid

Serious events: 20 serious events

Other events: 27 other events

Deaths: 2 deaths

Serious adverse events

Serious adverse events
Measure	Cherry Syrup n=66 participants at risk Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=62 participants at risk "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Cardiac disorders Cardiac Disorders	1.5% 1/66 • Number of events 1 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	3.2% 2/62 • Number of events 2 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Blood and lymphatic system disorders Blood and lymphatic system disorder	3.0% 2/66 • Number of events 2 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	0.00% 0/62 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Endocrine disorders Endocrine disorder	1.5% 1/66 • Number of events 1 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	0.00% 0/62 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Gastrointestinal disorders Gastrointestinal discorder	0.00% 0/66 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	1.6% 1/62 • Number of events 1 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Vascular disorders Vascular Disorder	0.00% 0/66 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	1.6% 1/62 • Number of events 1 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Infections and infestations Infections and infestations	10.6% 7/66 • Number of events 7 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	6.5% 4/62 • Number of events 4 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Nervous system disorders Nervous system disorders	4.5% 3/66 • Number of events 3 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	1.6% 1/62 • Number of events 1 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders	1.5% 1/66 • Number of events 1 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	0.00% 0/62 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Injury, poisoning and procedural complications Injury, poisoning and procedural complications	3.0% 2/66 • Number of events 2 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	1.6% 1/62 • Number of events 1 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Surgical and medical procedures Surgical and medical procedures	10.6% 7/66 • Number of events 7 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	12.9% 8/62 • Number of events 8 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
General disorders General Disorder	10.6% 7/66 • Number of events 7 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	3.2% 2/62 • Number of events 2 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Renal and urinary disorders Renal and urinary disorder	0.00% 0/66 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	1.6% 1/62 • Number of events 1 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)

Other adverse events

Other adverse events
Measure	Cherry Syrup n=66 participants at risk Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. Cherry Syrup: Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.	Valproic Acid n=62 participants at risk "Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. Valproic Acid: "Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Hepatobiliary disorders Hepatobiliary disorder	10.6% 7/66 • Number of events 7 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	6.5% 4/62 • Number of events 4 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Gastrointestinal disorders Gastrointestinal disorder	6.1% 4/66 • Number of events 4 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	16.1% 10/62 • Number of events 10 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Infections and infestations Infection and infestations	13.6% 9/66 • Number of events 9 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	12.9% 8/62 • Number of events 8 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Nervous system disorders Nervous System disorder	7.6% 5/66 • Number of events 5 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	4.8% 3/62 • Number of events 3 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Injury, poisoning and procedural complications Injury, poisoning and procedural complication	6.1% 4/66 • Number of events 4 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	4.8% 3/62 • Number of events 3 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
Surgical and medical procedures Surgical and medical procedures	9.1% 6/66 • Number of events 6 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	4.8% 3/62 • Number of events 3 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)
General disorders General Disorders	10.6% 7/66 • Number of events 7 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)	4.8% 3/62 • Number of events 3 • Severe adverse events were collected from surgery to 3 months or time of final adjudication assessment (up to 6 months)

Additional Information

Thomas Buchheit, MD Division Chief, Pain Medicine

Duke University Department of Anesthesiology

Phone: 9196811924

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place