Evaluation of N1539 Following Bunionectomy Surgery

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate the analgesic efficacy of N1539 in subjects with acute moderate to severe pain following unilateral bunionectomy.

Official Title
-----------------
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Evaluation of the Efficacy and Safety of N1539 Following Bunionectomy

Conditions
-----------------
Pain, Post-operative

Intervention / Treatment
-----------------
* Drug: N1539
* Drug: Intravenous Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Voluntarily provide written informed consent. Male or female between 18 and 75 years of age, inclusive. Be scheduled to undergo a primary unilateral first metatarsal bunionectomy repair Be American Society of Anesthesiology (ASA) physical class 1 or 2. Female subject are eligible only if all the following apply: Not pregnant; Not lactating; Not planning to become pregnant during the study; Commit to the use of an acceptable form of birth control for the duration of the study. Have a body mass index ≤35 kg/m2 Be able to understand the study procedures, comply with all study procedures, and agree to participate in the study program. Exclusion Criteria: Have a known allergy to meloxicam or any excipient of N1539, D5W, aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs) or to any peri- or postoperative medications used in this study. Have a clinically significant abnormal clinical laboratory test value. Have history of or positive test results for HIV, or hepatitis B or C. Have a history or clinical manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, psychiatric, or other condition that would preclude participation in the study. Have a history of myocardial infarction or coronary artery bypass graft surgery within the preceding 12 months Have a history of migraine or frequent headaches, seizures, or are currently taking anticonvulsants. Have active or recent (within 6 months) gastrointestinal ulceration or bleeding. Have a known bleeding disorder or be taking agents affecting coagulation Have another painful physical condition that may confound the assessments of post operative pain. Have evidence of a clinically significant 12 lead ECG abnormality. Have a history of alcohol abuse (regularly drinks > 4 units of alcohol per day; 8 oz. beer, 3 oz. wine, 1 oz. spirits) within the past 5 years or a history of prescription/illicit drug abuse. Have positive results on the urine drug screen or alcohol breath test indicative of illicit drug or alcohol abuse. Have been receiving or have received chronic opioid therapy defined as greater than 15 morphine equivalents units per day for greater than 3 out of 7 days per week over a one-month period within 12 months of surgery. Use concurrent therapy that could interfere with the evaluation of efficacy or safety, such as any drugs which in the investigator's opinion may exert significant analgesic properties or act synergistically with N1539. Unable to discontinue medications, that have not been at a stable dose for at least 14 days prior to the scheduled bunionectomy procedure, within 5 half lives of the specific prior medication (or, if half life is not known, within 48 hours) before dosing with study medication. Have utilized corticosteroids, either systemically or by intra-articular injection, within 6 weeks prior to the surgical procedure. Have received any investigational product within 30 days before dosing with study medication. Be receiving warfarin, lithium, or a combination of furosemide with either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker Be currently receiving treatment with oral meloxicam (Mobic®) within 7 days prior to surgery Have previously received N1539 in clinical trials, or had major surgery in the last 3 months that would interfere with study outcomes or increase the risk of study participation.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N1539 30mg<br>N1539 (Intravenous meloxicam) 30mg every 24 hours for up to 3 doses. | Drug: N1539<br> <br> * Other names: Intravenous meloxicam;|
| Placebo Comparator: IV Placebo<br>IV Placebo every 24 hours for up to 3 doses. | Drug: Intravenous Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed Pain Intensity Difference Over the First 48 Hours (SPID48) | Pain intensity was recorded using a Numeric Pain Rating Scale (Range 0-10) where 0 equates to no pain (better), and 10 equates to the worst pain imaginable (worse). Pain intensity scores were to be recorded at the following time points: 0.25, 0.5, 0.75, 1, and 2 hours post Dose 1. Thereafter pain assessments were to be recorded every 2 hours until 48 hours post Dose 1. Pain intensity differences from baseline at each time point were calculated and a time weighted summed pain intensity difference (SPID) was then calculated. Time weighted SPID calculations were computed by multiplying a weight factor to each score prior to summation. The weight factor at each time point was the time elapsed since the previous observation. A smaller SPID value (i.e. more negative) was better. | 48 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed Pain Intensity Difference (SPID) at Other Intervals | Pain intensity was recorded using a Numeric Pain Rating Scale (Range 0-10) where 0 equates to no pain (better), and 10 equates to the worst pain imaginable (worse). Pain intensity scores were to be recorded at the following time points: 0.25, 0.5, 0.75, 1, and 2 hours post Dose 1. Thereafter pain assessments were to be recorded every 2 hours until 48 hours post Dose 1. Pain intensity differences from baseline at each time point were calculated and a time weighted summed pain intensity difference (SPID) was then calculated. Time weighted SPID calculations were computed by multiplying a weight factor to each score prior to summation. The weight factor at each time point was the time elapsed since the previous observation. A smaller SPID value (i.e. more negative) was better. | 48 Hours | 
| Time to First Dose of Rescue Analgesia | Rescue analgesia (oral oxycodone 5 mg) was available to subjects with inadequately controlled pain upon request. Time to first rescue was calculated as the elapsed time from administration of Dose 1 to the administration of the first dose of rescue analgesia. | 48 Hours | 
| Number of Subjects Utilizing Rescue Analgesia | Rescue analgesia (oral oxycodone 5 mg) was available to subjects with inadequately controlled pain upon request. | 48 Hours | 
| Number of Doses of Rescue Analgesia Utilized Per Subject | Rescue analgesia (oral oxycodone 5 mg) was available to subjects with inadequately controlled pain upon request. | 48 Hours | 
| Time to Perceptible Pain Relief (TTPPR) | Time to perceptible and meaningful pain relief was measured using the double stopwatch method. For each randomized subject, two stopwatches were started immediately after administration of the first study dose (Hour 0). The subject was to stop the first watch when they first perceived pain relief to occur (time to perceptible relief). Once the first watch was stopped, the second stopwatch was given to the subject with the instructions to stop the watch when they first experienced meaningful pain relief (time to meaningful relief). | 12 Hours | 
| Time to Meaningful Pain Relief (TTMPR) | Time to perceptible and meaningful pain relief was measured using the double stopwatch method. For each randomized subject, two stopwatches were started immediately after administration of the first study dose (Hour 0). The subject was to stop the first watch when they first perceived pain relief to occur (time to perceptible relief). Once the first watch was stopped, the second stopwatch was given to the subject with the instructions to stop the watch when they first experienced meaningful pain relief (time to meaningful relief). | 12 Hours | 
| Subjects With ≥ 30% Improvement in Pain From Baseline to Hour 6 | Percent improvement in pain is the cumulative pain intensity percent reduction from baseline over the defined interval (6 or 24 hours), calculated as SPID for the defined interval (SPID6 or SPID24) divided by the baseline pain intensity (BaselinePI) extrapolated across that interval. Example: % Improvement through Hour 6 = 100 * SPID6 / (BaselinePI * 6 * 60), and SPID6 < 0 as an indication for improvement. | 6 Hours | 
| Subjects With ≥ 30% Improvement in Pain From Baseline to Hour 24 | Percent improvement in pain is the cumulative pain intensity percent reduction from baseline over the defined interval (6 or 24 hours), calculated as SPID for the defined interval (SPID6 or SPID24) divided by the baseline pain intensity (BaselinePI) extrapolated across that interval. Example: % Improvement through Hour 24 = 100 * SPID24 / (BaselinePI * 24 * 60), and SPID24 < 0 as an indication for improvement. | 24 Hours | 
| Subjects With ≥ 50% Improvement in Pain From Baseline to Hour 6 | Percent improvement in pain is the cumulative pain intensity percent reduction from baseline over the defined interval (6 or 24 hours), calculated as SPID for the defined interval (SPID6 or SPID24) divided by the baseline pain intensity (BaselinePI) extrapolated across that interval. Example: % Improvement through Hour 6 = 100 * SPID6 / (BaselinePI * 6 * 60), and SPID6 < 0 as an indication for improvement. | 6 Hours | 
| Subjects With ≥ 50% Improvement in Pain From Baseline to Hour 24 | Percent improvement in pain is the cumulative pain intensity percent reduction from baseline over the defined interval (6 or 24 hours), calculated as SPID for the defined interval (SPID6 or SPID24) divided by the baseline pain intensity (BaselinePI) extrapolated across that interval. Example: % Improvement through Hour 24 = 100 * SPID24 / (BaselinePI * 24 * 60), and SPID24 < 0 as an indication for improvement. | 24 Hours | 
| Patient Global Assessment (PGA) of Pain Control at Hour 24 | PGA of pain control was evaluated at Hour 24 and Hour 48 with subject reported degree of pain control over the preceding interval according to a 5 point scale (0-4) with categories of 0-poor, 1-fair, 2-good, 3-very good, or 4-excellent. | 24 Hours | 
| Patient Global Assessment (PGA) of Pain Control at Hour 48 | PGA of pain control was evaluated at Hour 24 and Hour 48 with subject reported degree of pain control over the preceding interval according to a 5 point scale (0-4) with categories of 0-poor, 1-fair, 2-good, 3-very good, or 4-excellent. | 48 Hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bunion, Bunionectomy, Pain, Analgesia, N1539, Phase 3