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

Study Overview
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Brief Summary
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A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy

Detailed Description
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A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy Up to 80 subjects will be randomized (32 in each active treatment group, 16 placebo). To evaluate the efficacy of combination pregabalin (PGB) and acetaminophen (APAP) administered vs. placebo for pain control in subjects undergoing bunionectomy. The placebo will be the saline solution.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination of Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: Pregabalin
* Drug: Acetaminophen
* Other: Placebo 1
* Other: Placebo 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide informed consent by signing the informed consent form (ICF) approved by the Institutional Review Board (IRB); Be male or female aged 18-65 years; Be scheduled to undergo unilateral first metatarsal bunionectomy; Be in good health and capable of undergoing a bunionectomy under anesthesia as described in the study surgical and anesthetic protocol; Weigh between 50 and 100 kg (body mass index [BMI] <32 kg/m2); Have no additional planned surgeries other than bunionectomy during the course of the study; Have negative urine drug screen for drugs indicative of illicit drug use (unless results can be explained by a current prescription or acceptable over-the-counter medication at screening as determined by the investigator) and no detectable results on the alcohol test (breath or saliva) indicative of alcohol abuse at screening, and/or prior to surgery (may be repeated if the Investigator suspects a false-positive result). Note: For those subjects who test positive for tetrahydrocannabinol (THC), if they are willing to abstain from use or consumption of THC-containing products from screening through end of the subject's participation in the study, they may be allowed to participate in the study. Biological female subjects must be non-lactating, sterile (bilateral tubal ligation, bilateral salpingectomy, or hysterectomy), post-menopausal for at least 2 years, have a partner that is sterile, be abstinent, use a highly effective double- contraception method (hormonal protection is insufficient), or use an FDA-approved contraceptive for greater than 2 months prior to the screening visit and commit to an acceptable form of birth control for the duration of the study and for 30 days after completion of the study; Be willing and able to complete the study procedures and pain scales and communicate meaningfully in English with study personnel. Exclusion Criteria: Have a medical condition or history that in the Investigator's opinion could adversely impact the subject's participation or safety or the conduct of the study, or interfere with the pain assessments, including the following: Serious breathing difficulties or respiratory risk factors (including use of opioid pain medicines and other drugs that depress the central nervous system), and conditions such as chronic obstructive pulmonary disease that reduce lung function. Hypertension (uncontrolled), cardiovascular disease, or history of cerebrovascular events. Hypertension must be controlled without known end organ damage. Concurrent painful conditions that may require analgesic treatment during the study period. History of significantly reduced hepatic or renal function, angle closure glaucoma, or convulsive disorder. Recent history of urinary retention. Opioid tolerant, i.e., the subject is currently taking or has taken a chronic opioid at a dose greater than or equal to 20 mg morphine milligram equivalents (MME) per day (more than 30 consecutive days of daily use) for pain in the 2 months prior to surgery. Active cutaneous disease, or other disease, at the surgical site. Peripheral vascular disease, sickle cell disease, vascular grafts, or vasospastic disorders. Known bleeding disorder or is taking agents affecting coagulation preoperatively. Deep venous thrombosis (DVT) prophylaxis of the surgeon's choice is permitted postoperatively. Diabetes mellitus (uncontrolled). Diabetes mellitus must be controlled without known end organ damage. History of malignancy in the past 2 years with the exception of squamous cell carcinoma or basal cell carcinoma. Prior bunionectomy on the index foot or other foot surgery on the index foot that could impact the surgery or data collection endpoints. Use of disallowed medications including the following: Pain medication (opioids, NSAIDs, cyclooxygenase (COX)-2 inhibitors, tramadol, ketamine, clonidine, gabapentin, pregabalin, or cannabinoids) within 2 days prior to Day 1. Central nervous system (CNS) active drugs such as benzodiazepines, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors (SNRIs), or selective serotonin reuptake inhibitors (SSRIs) for pain within seven days prior to Day 1. These drugs are permitted for non-pain indications if the dose has been stable for at least 30 days prior to Day 1 and is planned to remain stable throughout the study. The use of lorazepam and other sleep medications, except those containing analgesic properties, is permitted. Use of parenteral or oral corticosteroid(s) within 14 days prior to Day 1. Antihypertensive agent or diabetic regimen at a dose that has not been stable for at least 30 days, or which is not expected to remain stable throughout the study. Digoxin, warfarin (see exception below), lithium, theophylline preparations, aminoglycosides, and all antiarrhythmics except beta-blockers, and use of anticonvulsants except benzodiazepines within 7 days prior to Day 1 and throughout the study. Use of warfarin is allowed, at the investigator's discretion, for DVT prophylaxis after the surgery. Significant history of allergic reactions or known intolerance to pregabalin or any gabapentinoid, to APAP, to any rescue medication used in the study, or any medication used in the surgical and anesthetic protocol. Female subjects (biological females only) who are pregnant or lactating, who plan to get pregnant, or who have a positive serum pregnancy test at Screening or a positive urine pregnancy test at either Day -1 or Day 1 prior to surgery. Participated in another clinical trial within 30 days, or previously participated in a clinical study with a similar investigational product.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed Pain Intensity (SPI) Between Group A and Group C | 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) | 0 to 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed Pain Intensity (SPI) Compared Between Group A and Group B | 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) | 0 to 48 hours | 
| 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). | 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. | 0, 12, 24, 48 hours | 
| Summed Pain Intensity (SPI) Assessed by Numeric Rating Scale Over Time | 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. | 0, 1, 2, 4, 6, 8, 10 ,12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, and 48 hours | 
| Number of Participants With Treatment-Related Adverse Events (TRAE) | 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 | 7 days | 
| Percentage of Participants Who Were Opioid Free Over Time | Percentages of participants who did not take opioid (rescue medication) over time. | 12 to 48 hours | 
| Total Consumption of Opioid Rescue Medication Through 24 Hours and 48 Hours | The total consumption of opioid rescue analgesia through 24 hours and through 48 hours was reported | 24 hours and 48 hours | 
| Total Consumption of Rescue Medication | The total consumption of rescue analgesia was reported. | 7 days | 
| Time to First Use of Rescue Medication From Hour 0 | 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). | 7 days | 
| Percentage of Participants Who Used Rescue Medication | Percentage of participants who used rescue medication is reported | 7 days | 
| Patient Global Assessment of Pain | 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 | 48 hours | 
| Maximum Observed Concentration for PGB and APAP | 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. | 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 | 
| Minimum Observed Concentration for PGB and APAP | 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. | 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 |