Study Of The Efficacy And Safety Of Pregabalin Compared To Placebo For Treatment Of Post-Surgical Pain From Hysterectomy

Study Overview
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Brief Summary
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To assess the efficacy of pregabalin compared to placebo on pain following hysterectomy , measured using subject reported assessments of pain.

Official Title
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A Multiple Dose, Randomized, Double-Blind Multicenter Study Of The Efficacy And Safety Of Pregabalin Compared To Placebo In The Treatment Of Patients With Post-Surgical Pain From Hysterectomy

Conditions
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Pain, Postoperative

Intervention / Treatment
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* Drug: pregabalin (Lyrica)
* Drug: pregabalin (Lyrica)
* Drug: matched placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject will have elective total abdominal hysterectomy using a transverse incision with or without bilateral salpingo-oophorectomy. The total hysterectomy may, however, be cervix-sparing. The subject is expected to remain at the hospital (or intermediate care facility) for a minimum of 2 days following surgery. The subject's preoperative health is graded as the American Society of Anesthesiologist P1 to P2. Exclusion Criteria: Subjects having vaginal hysterectomy (whether laparoscopically assisted or not) Subjects having additional procedures (such as those involving the bladder) at the same time as the total abdominal hysterectomy The use of nerve block, spinal anesthesia or epidural anesthesia for post-surgical pain control Subjects who have been using any opioid medications 2 weeks or more continuously within 3 months prior to the screening visit. The subject has taken any NSAID or any analgesic other than acetaminophen within 3 days prior to surgery or is unwilling to abstain from NSAIDs or other analgesics, except as specified in the protocol, during the study. (Subjects taking <325 mg per day of aspirin at a stable dose for at least 30 days before the first dose of study medication will be allowed to continue their aspirin regimen for the duration of the study).

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: pregabalin (Lyrica)<br>* 150 mg/day double blind (divided doses)<br>|
| Experimental: 2<br> | Drug: pregabalin (Lyrica)<br>* 300 mg/day double blind (divided doses)<br>|
| Placebo Comparator: 3<br> | Drug: matched placebo<br>* matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Worst Pain Using the Modified Brief Pain Inventory - Short Form (m-BPI-sf) | Modified Brief Pain Inventory - Short Form (m-BPI-sf): participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable). Least Square (LS) Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Day 2 (24 hours post surgery [PS]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Current Pain - Pain With Movement Caused by Sitting | Participant sat upright from supine position, followed by 120 second (sec) rest period, during which participant asked to rate pain with movement. Assessment performed 3 times each day of hospital stay, with 1 daily assessment at 24 (+/- 2) hour interval from end of surgery. Current pain reported on 11 point Likert scale 0 (no pain) to 10 (worst pain imaginable). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Day 1 (day of surgery), up to 7 days PS, Discharge, 2 and 4 weeks PS | 
| Current Pain - Pain With Movement Caused by Peak Expiratory (PEF) Test | Current pain with movement caused by peak expiratory flow (PEF) test as reported by participant on 11 point Likert scale 0 (no pain) to 10 (worst pain). Assessment performed 3 times each day of hospital stay, with 1 daily assessment at 24 (+/- 2) hour interval from end of surgery. PEF test performed 3 times, with 120sec rest periods in between. At beginning of each rest period, participant asked to rate pain caused by forced expiration. LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Day 1, up to 7 days PS, 2 and 4 weeks PS | 
| Area Under the Curve (AUC) Pain - Pain With Movement Caused by Sitting | Time-normalized AUC of pain with movement caused by sitting reported by participants. Participant sat upright from supine position, followed by a 120sec rest period, during which the participant asked to rate pain with movement. Assessment performed 3 times each day of hospital stay, with 1 daily assessment at 24 (+/- 2) hour interval from end of surgery. Current pain reported on 11 point Likert scale 0 (no pain) to 10 (worst pain imaginable). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | 48 +/- 4 hours PS | 
| Area Under the Curve (AUC) Pain - Pain With Movement Caused by Peak Expiratory Flow (PEF) Test | Time-normalized AUC of pain reported by participants with movement caused by PEF test. Pain reported by participant on 11 point Likert scale 0 (no pain) to 10 (worst pain). PEF test performed 3 times, with 120sec rest periods in between. At beginning of each rest period, participant asked to rate pain caused by forced expiration. LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | 48 +/- 4 hours PS | 
| Current Pain at Rest | Pain reported by participants at rest (numeric rating scale (NRS) - Current Pain) on an 11 point Likert scale 0 (no pain) - 10 (worst pain). Pain at rest during the hospital stay was assessed just before each Pain with Movement assessment. Assessment performed 3 times each day of hospital stay, with 1 of daily assessments at 24 (+/- 2 ) hour intervals from end of surgery. LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | 8, 16, 24, 32, 40, 48 hours PS | 
| Area Under the Curve (AUC) of Pain at Rest During the First Two Days of Hospital Stay | Time-normalized AUC of pain reported by participants on 11 point Likert scale 0 (no pain) to 10 (worst pain). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | 48 +/- 4 hours PS | 
| Total Cumulative Dose of Opioids Following Surgery | Total cumulative dose was calculated as milligram (mg) of morphine equivalent and included opioids administered by any route. LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | 24, 48 Hours PS, Discharge (day 3 up to day 7 PS) | 
| Integrated Analgesic Score | The integrated analgesic score (a combination of opioid use and either worst pain, or pain at rest, or pain caused by sitting, or pain caused by forced expiration as defined by Silverman et al 1993) was the sum of percent differences from mean rank for pain and opioids and ranged from -200 to 200 where lower values represent improvement. LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | 0-24, 24-48, 48-72 hours PS | 
| Non-opioid Rescue Medication - Paracetamol | The amounts of non-opioid rescue medications, paracetamol, used by the participants during the study, including anti-emetic medications. | 24, 48, 72 hours PS, Discharge (day 3 up to day 7 PS), Week 1, 2, 3, 4 PS, | 
| Anxiety Before and After Surgery | Participant anxiety reported on Visual Anxiety Scale (VAS), 0 (not at all anxious) to 100 (extremely anxious). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata | Surgery day before first dose and 1 hour after first dose, Day 1, 2, 3, 4, 5 PS and Discharge (day 3 up to day 7 PS) | 
| Non-opioid Rescue Medication - Ibuprofen | The amounts of non-opioid rescue medications, ibuprofen, used by the participants during the study, including anti-emetic medications. | 24, 48, 72 hours PS, Discharge (day 3 up to day 7 PS), Week 1, 2, 3, 4 PS | 
| Percent Change From Baseline in Peak Expiratory Flow | Change from baseline= PEF at x hours minus PEF at baseline; possible values ranged from 0-900 liters/minute (higher values indicated better lung function). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Baseline, every 8 hours (up to 232 hours) PS, and Discharge (Day 3-7 PS flexible) | 
| Timed Up-and-Go (TUG) | Functional mobility test performed once a day at 24 hour intervals from surgery after the pain with movement assessment. LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Day 1, 2, 3, 4, 5 PS and Discharge (day 3 up to day 7 PS) | 
| Average Daily Pain | Post-discharge average pain as measured in daily participant diaries NRS an 11 point Likert scale ranged from 0 (no pain) to 10 (worst pain). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Day 2, 3, 4, 5, 6, 7, PS; week 2, 3, 4 PS | 
| Worst Daily Pain | Post-discharge worst pain as measured in daily participant diaries NRS an 11 point Likert scale that ranged from 0 (no pain) to 10 (pain as bad as you can imagine). LS Means from ANOVA model with terms of treatment, pooled center, salpingo-oophorectomy strata and baseline worst pain score. | Discharge (day 3 up to day 7 PS), Day 7, 14, 28 PS | 
| Sleep Interference | Sleep interference post surgery measured daily in participant diaries; NRS of how pain interfered with sleep during the last 24 hours, ranged from 0 (does not interfere) to 10 (completely interferes). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Daily post hospital discharge ( Day 2-7 PS), Week 2, 3, 4 PS | 
| Brief Pain Inventory-Short Form (m-BPI-sf): Pain Interference Index Scores | m-BPI-sf: participant-rated 11 point Likert rating scale ranging from 0 (does not interfere) to 10 (completely interferes) with functional activities (general activity, mood, walking ability, relations with other people, sleep, normal work, and enjoyment of life) in past 24 hours. LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Baseline, Discharge (day 3 up to day 7 PS), Day 7, 14, 28 PS | 
| Brief Pain Inventory-Short Form (m-BPI-sf): Pain Severity Index Scores | m-BPI-sf: participant rated 11-point Likert rating scale ranging from 0 (no pain) to 10 (worst pain possible). Pain severity index is the mean of item scores 2, 3, and 4 (pain right now, worst pain, and average pain level). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Baseline, Discharge (day 3 up to day 7 PS), Day 7, 14, 28 PS | 
| Participant Satisfaction With Study Medication - Surgery Day | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 1 | 
| Participant Satisfaction With Study Medication - Day 1 PS | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 1 PS | 
| Participant Satisfaction With Study Medication - Day 2 PS | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 2 PS | 
| Participant Satisfaction With Study Medication - Day 3 PS | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 3 PS | 
| Participant Satisfaction With Study Medication - Day 4 PS | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 4 PS | 
| Participant Satisfaction With Study Medication - Day 5 PS | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 5 PS | 
| Participant Satisfaction With Study Medication - Discharge | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Discharge (day 3 up to day 7 PS) | 
| Participant Satisfaction With Study Medication - Day 7 PS | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 7 PS | 
| Participant Satisfaction With Study Medication - Day 14 PS | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 14 PS | 
| Participant Satisfaction With Study Medication - Day 28 PS | Participant satisfaction with study medication using the Global Evaluation of Study Medication questionaire. Participants overall impression (global evaluation) of the study medication was recorded by the participant by answering the following question: How would you rate the study medication you received for pain? Excellent 4; Good 3; Fair 2; Poor 1. | Day 28 PS | 
| Pain Treatment Satisfaction Scale (PTSS): Satisfaction With Current Pain Medication | Satisfaction with current pain medication ranged from 0 (worst possible response) to100 (best possible response). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Discharge (day 3 up to day 7 PS), Day 28 PS | 
| Pain Treatment Satisfaction Scale (PTSS): Impact of Current Pain Medication | Impact of current pain medication response scale: 0 (worst possible response) to 100 (best possible response). LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Discharge (day 3 up to day 7 PS), Day 28 PS | 
| Quality of Life Using EuroQol (EQ-5D) Health State Profile | Participant rated questionnaire assessed current health for 6 domains: mobility/self-care/ usual activities/pain/discomfort/anxiety and depression. Scoring developed by EuroQol Group assigned a utility value for each domain in the profile. Scores ranged from 1 better health (no problems) to 3 worst health (eg, confined to bed). Score transformed and resulted in a total score range -0.594 to 1.000; higher score=better health state. Health profile scores estimated using Dolan computational algorithms 1997 and 2001. LS Means adjusted for treatment/pooled center/salpingo-oophorectomy strata. | Discharge (day 3 up to day 7 PS) and day 28 PS | 
| Time to Meet Hospital Discharge Criteria | Mean time from end of surgery to meet protocol defined hospital discharge criteria: participant no longer received parental opioids, was able to dress and mobilize without assistance, and had normal intake of food and fluids. | Day 1 up to Day 7 PS | 
| Time to Actual Discharge | Mean time from end of surgery to actual hospital discharge. Participant was expected to remain at the hospital for a minimum of 2 days following surgery. | Day 1 up to Day 7 PS | 
| Incidence of Chronic Post-operative Pain | Chronic post-operative pain as a result of abdominal hysterectomy as reported by participants on PS questionaire of pain within last 24 hours in area affected by surgery. | 3 and 6 Months PS | 
| Total Clinically Meaningful Event (CME) Score | Total CME score calculated by summing the number of Clinically Meaningful Events (CMEs) across symptoms. CME for each symptom will be defined using the Opioid-Related Symptom Distress Scale (OR-SDS) a participant rated scale of symptoms within the last 24 hours. Total CME score could range from 0 to 9. LS Means adjusted for treatment, pooled center and salpingo-oophorectomy strata. | Surgery Day, Day 1, 2, 3, 4, 5 PS, Discharge (day 3 up to day 7 PS), Day 7, 14, 28 PS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain after hysterectomy, amount of opioids used