Abstract
Introduction
MR-107A-02 is a novel, fast-absorbing oral meloxicam formulation designed to deliver effective analgesia in moderate-to-severe acute pain settings.
Methods
This phase 3, randomized, double-blind, placebo- and active-controlled, parallel-group study assessed the efficacy and safety of MR-107A-02 in participants following bunionectomy. Participants with a postoperative pain numerical rating scale at rest (NRS-R) score ≥ 4 and a moderate or severe qualifying categorical pain score were randomized in a 1:1:1 ratio to receive MR-107A-02 15 mg (BID), placebo, or tramadol 50 mg (q6h). The primary endpoint was the summed pain intensity difference over 48 h (SPID0–48) for MR-107A-02 versus placebo, based on NRS-R. Tramadol was included as an active control for assay sensitivity and comparisons between MR-107A-02 and tramadol were exploratory. Key secondary endpoints included the use of opioid rescue medication, proportion of opioid-free participants and time to perceptible and meaningful pain relief.
Results
Of the 410 randomized participants, 397 completed the study. Baseline NRS-R scores were similar across groups. MR-107A-02 met the primary endpoint, with a significantly greater SPID0-48 than placebo (183.9 vs. 101.2; difference, 82.7; p < 0.001). Assay sensitivity was confirmed with tramadol versus placebo (difference, 58.0; p < 0.001). In an exploratory, post hoc analysis that was not powered for hypothesis testing in this protocol, the estimated SPID0–48 was numerically higher with MR-107A-02 in comparison to tramadol (174.3 vs. 148.1; difference, 26.2; nominal p = 0.013). MR-107A-02 reduced opioid rescue use by 59% versus placebo (p < 0.001), with more participants remaining opioid-free in the MR-107A-02 group than in the placebo (56.9% vs. 33.1%; difference 23.8%; p < 0.001). The median time to perceptible (0.7 h vs. 0.9 h, p = 0.037) and meaningful pain relief (2.4 h vs. 5.1 h, p = 0.012) were earlier in the MR-107A-02 than the placebo. MR-107A-02 was well-tolerated. In the MR-107A-02 group, all treatment emergent adverse events (TEAEs) were mild or moderate in severity, and no severe TEAEs, serious adverse events, or study discontinuations due to TEAEs were reported. The incidence of opioid-related adverse events in the MR-107A-02 group was 16.1%, which was lower than that observed with tramadol (46.0%), and was comparable to placebo (16.9%) during the first 48 h of treatment.
Conclusions
MR-107A-02 provided statistically significant analgesic efficacy, faster onset of action, good tolerability, and reduced opioid rescue medication compared with placebo, highlighting its opioid-sparing potential. These findings should be interpreted within the constraints of the bunionectomy model, and confirmation in broader surgical settings is warranted.
Clinical Trial Registration
ClinicalTrials.gov identifier: NCT06215820.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s40122-026-00870-7.
Keywords: Acute pain, Bony-surgical model, Efficacy, Fast-release, Meloxicam, Non-opioid analgesic
Key Summary Points
| Why carry out this study? |
| Acute moderate-to-severe postoperative pain remains a common and clinically significant problem, with inadequate pain control associated with impaired recovery and continued reliance on opioids, underscoring the need for effective non-opioid analgesic options suitable for acute pain settings |
| MR-107A-02 is a novel, fast-absorbing oral formulation of meloxicam developed to overcome the delayed onset of conventional oral meloxicam; earlier phase pharmacokinetic and dental pain studies demonstrated rapid absorption and analgesic efficacy, supporting evaluation in further acute postoperative surgical pain models |
| The study hypothesized that MR-107A-02 15 mg BID would provide significant analgesic efficacy compared with placebo, demonstrate opioid-sparing effects, and be well tolerated in patients with acute moderate-to-severe postoperative pain, as assessed in a standardized bunionectomy pain model |
| What was learned from the study? |
| MR-107A-02 met the primary endpoint, demonstrated significantly greater reduction in pain intensity over 48 h (SPID0–48) compared with placebo, along with faster onset of perceptible and meaningful pain relief and a significant reduction in opioid rescue medication use. MR-107A-02 achieved effective postoperative analgesia with lower rates of opioid-related adverse events than tramadol, supporting its potential role as a non-opioid analgesic within multimodal postoperative pain management strategies |
Introduction
Globally, over 300 million major surgical procedures are performed annually, with approximately 40 million surgeries occurring annually in the United States (US) [1]. When inadequately controlled, postoperative pain can significantly impair the quality of life (QoL), limit daily activities, hinder functional recovery, and increase the risk of postsurgical complications [2]. The American Society of Anesthesiologists/American Society of Regional Anesthesia and Pain Medicine (ASA/ASRA) guidelines recommend multimodal analgesia and emphasize the use of non-opioid analgesics, such as acetaminophen and/or non-steroidal anti-inflammatory drugs (NSAIDs), as core components of postoperative pain management [3]. For patients who undergo surgery, opioid drugs are also commonly used in perioperative and postoperative pain management, but overreliance on these drugs in this setting can lead to consequences associated with opioid-related adverse effects, particularly respiratory depression, nausea, vomiting, and constipation, in addition to the risk of opioid dependence and abuse [4, 5].
Conventional oral meloxicam, typically administered once daily (OD), exhibits a slow onset due to its inherent poor aqueous solubility and low gastrointestinal (GI) dissolution rates, leading to late peak plasma concentrations (~ 5–6 h), limiting its utility in acute pain settings [6, 7]. Although IV meloxicam 30 mg OD is approved for moderate-to-severe pain and used in postoperative settings, its use may be restricted by the need for IV administration and the potential for delayed discharge from monitored-care settings [8].
To address these challenges, MR-107A-02 is being developed as a novel, fast-absorbing oral formulation of meloxicam designed to achieve rapid absorption and onset of analgesia while maintaining an efficacy and safety profile consistent with that determined for meloxicam as an established medicine in the NSAID class. MR‑107A‑02 is an investigational drug for which an NDA has been submitted and is currently under FDA review. Initial trial data established the pharmacokinetic profile of the investigational compound in healthy fasted adults, and a phase 2 dental pain study supported efficacy over a 24 h period at 5 mg and 15 mg BID doses.
These early findings warranted further evaluation in a hard tissue postoperative pain model. Bunionectomy is a highly standardized, common (up to 350,000 procedures annually in the US) and well-controlled surgical model, characterized by severe and sustained postoperative pain, making it particularly suitable for assessing the efficacy of investigational analgesics. Bunionectomy procedures are typically conducted in specialized research settings with relatively homogeneous patient populations, and the model offers high assay sensitivity and reliably distinguishes effective treatments from placebo [8–12].
The following paper describes a phase 3, placebo‑controlled study in bunionectomy patients, in which tramadol was selected as the active control as it ranks among the most commonly prescribed opioids for postoperative pain [13]. The study was designed to test the hypothesis that MR-107A-02 15 mg BID would provide effective postoperative analgesia, reduce opioid rescue medication requirements, and maintain an acceptable safety and tolerability profile in patients with acute moderate-to-severe postoperative pain.
Methods
The study protocol and consent forms were reviewed and approved by the Advara-Institutional Review Board (IRB) which served as the single IRB for all participating centers. The study was conducted in accordance with the principles of Good Clinical Practice (as referenced in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline E6), local regulatory requirements and the principles of the Declaration of Helsinki. All study participants provided written informed consent prior to participation.
Study Design
This was a multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group study conducted in adult male and female participants who underwent primary unilateral bunionectomy surgery (first metatarsal osteotomy with internal fixation). The study was conducted at 14 centers in the United States (US) between December 2023 and October 2024. The study design was aligned with the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for short‑duration acute pain trials and utilized a standardized postoperative bony trauma pain model [14].
Study Population
Inclusion Criteria
Patients aged ≥ 18 years who required primary unilateral bunionectomy with first metatarsal osteotomy and internal fixation without collateral procedures under regional anesthesia and had an American Society of Anesthesiologists (ASA) physical status of I, II, or III were considered for the study. Participants were enrolled in the study if they reported a pain intensity score ≥ 4 on the numeric rating scale at rest (NRS-R), and moderate or severe pain on the categorical pain rating scale within 9 h post-removal of the popliteal sciatic block.
Exclusion Criteria
Participants were not eligible if they had undergone contralateral foot bunionectomy within the past 6 months; had prior exposure to meloxicam within 7 days; NSAIDs or other analgesics within 72 h; minor tranquilizers or muscle relaxants within 60 days; or known hypersensitivity to the study drug or surgical materials. Participants with a history of active GI bleeding or peptic ulcer disease, stroke, moderate-to-severe hypertension, inflammatory bowel disease, or bleeding disorders were also excluded. The detailed exclusion criteria are provided in the Supplementary material.
Study Procedure
Study participation involved screening (visit 1), inpatient surgery (Day 1), randomization, and dosing on Days 1 and 2 (visit 2; inpatient treatment phase), continued treatment on Days 3–9 (visit 3; outpatient treatment phase) and two follow-up telephone calls (visit 4; Days 5–7 and Days 38–45).
Participants were screened for eligibility 1–30 days before surgery. On Day 1, the participants underwent bunionectomy under IV sedation, a regional popliteal block (0.5% ropivacaine), and a local mayo block (2% xylocaine plain), and received prophylactic antibiotics per routine care. The popliteal block was maintained until approximately 03:00–06:00 AM on Day 1. Pain assessments (pain intensity and categorical pain rating) were performed for up to 9 h post-cessation of popliteal block. Participants with NRS-R ≥ 4 and a rating of moderate or severe pain on a 4-point categorical pain rating scale (i.e., none, mild, moderate, severe) during this time were eligible for randomization to receive oral doses of MR-107A-02 (meloxicam 15 mg BID), tramadol [50 mg every 6 h (q6h)], or a matching placebo during the inpatient treatment phase (0–48 h). To maintain the blind, participants in the MR‑107A‑02 group received MR‑107A‑02 active and MR‑107A‑02 placebo alternately starting with MR‑107A‑02 active to allow for a q6h dosing of all participants during the inpatient treatment phase.
Randomization was conducted in a 1:1:1 ratio using an interactive web response system (IWRS) and treatment was administered in a double-blind manner. Following the inpatient phase and discharge, participants in the meloxicam and placebo groups continued their assigned treatment during the 5-day outpatient phase, while participants in the tramadol group received placebo during this outpatient phase.
Rescue medication followed a stepwise manner. Participants were encouraged to wait at least 1 h after study drug administration before taking oral acetaminophen (1 g per dose, maximum 4 g/day). If pain relief remained insufficient, they were advised to wait an additional hour before escalating to immediate‑release oxycodone (up to 5 mg every 4 h [q4h] and q6h during the inpatient and outpatient treatment phase, respectively). Intravenous morphine sulfate (up to 2 mg hourly) was permitted only within the first 4 h after the initial study‑drug dose for pain not controlled with oxycodone. A pain assessment (NRS‑R) was measured immediately prior to each rescue‑medication dose.
Participants remained inpatient for 48 h after randomization, followed by a 5-day outpatient treatment phase (Day 3 to Day 7/8). A scheduled telephone safety check was conducted on Day 6 (± 1 day), and an in-person follow-up visit occurred on Day 9 (± 1 day). During the outpatient treatment phase, participants in the MR‑107A‑02 and placebo groups received MR‑107A‑02 or a placebo as assigned during the inpatient treatment phase. Tramadol active and tramadol placebo were discontinued during the outpatient treatment phase. Participants in the tramadol group received a placebo during the outpatient treatment phase. Dosing was BID (10 doses in total). A final end-of-study telephone follow-up was completed between Day 38 and Day 45 to assess ongoing safety.
Dose Selection
A dosing regimen of MR-107A-02 15 mg BID was selected based on the results of the phase 2b MELO-TFZ-2001 trial in acute postoperative dental pain [15].
Efficacy and Safety
Efficacy Assessments
Pain intensity (PI) was measured on an 11-point numerical rating score at rest (NRS-R) and with activity (NRS-A), ranging from 0 (“no pain”) to 10 (“the worst imaginable pain”). The NRS-R was recorded at baseline and at prespecified time points throughout the first 48 h after the initial dose (Days 1–3) as well as immediately prior to any rescue medication use. The NRS‑A was assessed at 24 h and 48 h. Additional NRS-R and NRS-A assessments were performed at the follow‑up visit (Day 9) or at early termination if applicable.
The first perceptible and first meaningful pain relief were assessed using the double‑stopwatch method, in which participants activated one stopwatch when they first noticed any pain relief and a second stopwatch when they first experienced meaningful relief.
Efficacy Endpoints
Primary Efficacy Endpoints
The primary efficacy endpoint was the time-weighted summed pain intensity difference (SPID) over 0–48 h (SPID0–48) for MR-107A-02 versus placebo based on NRS-R.
Secondary Efficacy Endpoints
The key secondary efficacy endpoints were the number of doses of opioid rescue medication and the number and proportion of participants using no opioid rescue medication (opioid-free) during the entire treatment phase.
Other secondary endpoints included: (1) assay sensitivity, assessed by comparing SPID0–48 for tramadol versus placebo; (2) comparison of SPID0–48 for MR‑107A‑02 versus tramadol; (3) time to first perceptible pain relief and time to first meaningful pain relief; and (4) time to first rescue medication use and elapsed time from study drug administration to first rescue use.
Safety
Safety was evaluated throughout the study period. Safety assessments during the inpatient treatment phase included monitoring treatment-emergent adverse events (TEAE), laboratory investigations, ECG, and vital signs (heart rate, systolic and diastolic blood pressure). During the outpatient phase, participants were monitored for adverse events (AEs) through scheduled telephone follow‑ups and at the in‑person visit. The safety endpoints included the incidence of TEAEs, serious adverse events (SAEs), and TEAEs leading to treatment discontinuation. The frequency and proportion of participants experiencing predefined opioid-related AEs (ORAE), including nausea, vomiting, dizziness, somnolence, constipation, pruritus, respiratory depression, changes in mental status, ileus, urinary retention, and falls, were also assessed. Additional safety data collection included the incidence of adverse events of special interest (AESI) related to potential effects with NSAIDs regarding gastrointestinal (GI) and cardiovascular events. These included myocardial infarction/unstable angina, stroke/transient ischemic attack (TIA), heart failure, cardiac arrhythmia (atrial and ventricular), GI hemorrhage (not elsewhere classified), and GI ulceration and perforation.
Statistical Analyses
The enrollment of 408 participants (136 per arm) provided approximately 90% and 92% power to detect statistically significant differences versus placebo at the 2-sided 5% significance level for the primary and key secondary endpoints, respectively, after accounting for the expected attrition between participants being randomized and treated. For the tramadol–placebo comparison, the sample size provided 86% power for the planned analysis based on a 1-sided 5% significance level.
An analysis of covariance (ANCOVA) model was used to analyze SPID0–48 (based on NRS-R scores) between the MR-107A-02 and placebo groups in the full analysis set (FAS), with higher positive values indicating greater analgesic efficacy. The censoring of NRS-R scores due to rescue medication use was managed by the windowed last observation carried forward (WLOCF) approach, and missing data for NRS-R scores were managed using the multiple imputation (MI) approach. SPID0–48 was also compared between tramadol and placebo and the difference between MR-107A-02 and tramadol was estimated, using similar ANCOVA models. Only the two treatment groups being compared were included in each ANCOVA model as appropriate for each comparison.
The primary endpoint, the key secondary endpoint (the number of opioid rescue medication doses) and the proportion of opioid-free participants, were included in a prespecified multiplicity-controlled testing hierarchy. Only these three endpoints were included in the multiplicity-controlled testing hierarchy; therefore, p values associated with these endpoints were controlled for type I error. All remaining endpoints were outside the hierarchy, and their p values are reported as nominal and should be interpreted accordingly.
The number of opioid rescue medication doses was analyzed using a negative binomial regression model with treatment as a fixed effect and baseline NRS-R score as a covariate. Missing opioid rescue medication data were handled using multiple imputation methods. The time to first opioid rescue medication use was evaluated using Kaplan–Meier methods with log-rank testing for treatment comparisons.
Time-to-event endpoints were analyzed using Kaplan–Meier curves with censoring at the time of the first rescue medication used, along with p values from log-rank tests. Differences in proportions were analyzed using Z-tests.
Safety data were summarized according to the treatment groups. AEs were coded using the Medical Dictionary for Regulatory Activities (version 26.1).
Statistical analyses were performed using SAS version 9.4 software. The analyses were conducted by an independent Contract Research Organization with expertise in pain-trial methodology, with oversight provided by a sponsor-employed statistician.
Results
Demographic Characteristics
A total of 793 participants were screened for the study, of which 410 were enrolled and randomized (137 participants each in the MR-107A-02 and tramadol groups and 136 participants in the placebo group). Overall, 397 (96.8%) participants completed the study (MR-107A-02, 97.8%; tramadol, 96.4%; and placebo, 96.3%). Treatment completion rates showed a comparable pattern, with 390 (95.1%) participants completing treatment (MR-107A-02, 97.1%; tramadol, 92.0%; placebo, 96.3%). The reasons for discontinuation and complete participant disposition are illustrated in Fig. 1. All randomized patients received the study medication and were included in the efficacy and safety analyses.
Fig. 1.
CONSORT flow diagram of participant disposition. Participants who discontinued study treatment could continue in the study and complete the remaining scheduled assessments if they wished
Most participants were female (85.9%), and the median age was 49.0 years (range, 18–77 years). The majority of the participants were White (60.0%) and were not Hispanic or Latino (68.3%). The median surgery duration was 32 min, and the median body mass index (BMI) was 28.3 kg/m2. Baseline pain intensity (NRS-R) had a mean [standard deviation (SD)] score of 7.3 (1.68). The three treatment groups were comparable with respect to demographic and baseline characteristics (Table 1).
Table 1.
Summary of patient demographics and baseline characteristics (FAS)
| Characteristics | MR-107A-02 (15 mg BID) (n = 137) |
Tramadol (50 mg q6h) (n = 137) |
Placebo (q6h) (n = 136) |
Total (n = 410) |
|---|---|---|---|---|
| Age (years) | ||||
| Mean (SD) | 47.8 (13.80) | 49.0 (13.13) | 47.2 (13.36) | 48.0 (13.42) |
| Range | 18–77 | 18–76 | 18–74 | 18–77 |
| Sex, n (%) | ||||
| Male | 19 (13.9) | 17 (12.4) | 22 (16.2) | 58 (14.1) |
| Female | 118 (86.1) | 120 (87.6) | 114 (83.8) | 352 (85.9) |
| Ethnicity, n (%) | ||||
| Hispanic or Latino | 42 (30.7) | 43 (31.4) | 41 (30.1) | 126 (30.7) |
| Not Hispanic or Latino | 93 (67.9) | 93 (67.9) | 94 (69.1) | 280 (68.3) |
| Not reported | 2 (1.5) | 1 (0.7) | 1 (0.7) | 4 (1.0) |
| Race, n (%) | ||||
| American Indian or Alaskan Native | 0 | 3 (2.2) | 3 (2.2) | 6 (1.5) |
| Asian | 5 (3.6) | 5 (3.6) | 7 (5.1) | 17 (4.1) |
| Black or African American | 43 (31.4) | 36 (26.3) | 53 (39.0) | 132 (32.2) |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| White | 86 (62.8) | 90 (65.7) | 70 (51.5) | 246 (60.0) |
| Not reported | 0 | 1 (0.7) | 0 | 1 (0.2) |
| Unknown | 0 | 1 (0.7) | 0 | 1 (0.2) |
| Other | 1 (0.7) | 0 | 1 (0.7) | 2 (0.5) |
| Multiple | 2 (1.5) | 1 (0.7) | 2 (1.5) | 5 (1.2) |
| Duration of surgery (min) | ||||
| Mean (SD) | 31.5 (12.06) | 32.5 (13.44) | 31.7 (12.18) | 31.9 (12.55) |
| Range | 12–61 | 12–92 | 12–69 | 12–92 |
| Baseline pain intensity (NRS-R) | ||||
| Mean (SD) | 7.2 (1.67) | 7.2 (1.64) | 7.6 (1.73) | 7.3 (1.68) |
| Range | 3–10 | 4–10 | 4–10 | 3–10 |
BID twice daily, FAS full analysis set, NRS-R numeric rating scale at rest, q6h every 6 h, SD standard deviation
Efficacy
The study met its primary endpoint. MR-107A-02 demonstrated superior analgesia versus placebo (p < 0.001) (Table 2; Figs. 2 and S1). Tramadol also demonstrated a statistically significant difference versus placebo (p < 0.001), confirming assay sensitivity. In a prespecified, non-hierarchical comparison, the estimated SPID0–48 was numerically higher with MR-107A-02 than with tramadol (difference in LS mean = 26.2; nominal post hoc p = 0.013). This comparison was not powered for hypothesis testing in this protocol and should be interpreted as exploratory. Differences in NRS pain score trajectories between the treatment groups were evident by 0.5 h and were maintained through 48 h (Fig. 2).
Table 2.
SPID0-48 (NRS-R), ANCOVA with MI (FAS)
| Variable statistic | MR-107A-02 (15 mg BID) (n = 137) |
Tramadol (50 mg q6h) (n = 137) |
Placebo (q6h) (n = 136) |
|---|---|---|---|
| SPID0-48 | |||
| MR-107A-02 versus placebo | |||
| Mean (SD) | 157.9 (100.21) | – | 85.0 (90.56) |
| LS mean (SE) | 183.9 (10.64) | – | 101.2 (10.83) |
| 95% CI | (163.0, 204.7) | – | (80.0, 122.4) |
| Difference in LS means (SE) versus placebo | 82.7 (10.54) | – | |
| 95% CI for difference in LS meansa | (62.0, 103.4) | – | |
| p value for differenceb | <0.001 | – | |
| Tramadol versus placebo | |||
| Mean (SD) | – | 141.0 (95.43) | 85.0 (90.56) |
| LS mean (SE) | – | 156.1 (10.44) | 98.0 (10.42) |
| 95% CI | – | (138.9, 173.2) | (77.6, 118.5) |
| Difference in LS means (SE) versus placebo | – | 58.0 (10.39) | |
| CI for difference in LS meansa | – | (40.9, 75.1) | |
| p value for differencec | – | < 0.001 | |
| MR-107A-02 versus tramadol | |||
| Mean (SD) | 157.9 (100.21) | 141.0 (95.43) | – |
| LS Mean (SE) | 174.3 (10.45) | 148.1 (10.66) | – |
| 95% CI | (153.8, 194.7) | (130.5, 165.6) | – |
| Difference in LS means (SE) versus tramadol | 26.2 (10.58) | – | |
| 90% CI for difference in LS meansa | (8.8, 43.6) | – | |
| p value for differenceb | 0.013 | – | |
ANCOVA analysis of covariance, BID twice daily, CI confidence interval, FAS full analysis set, LS least squares, MI multiple imputations, NRS-R numeric rating scale at rest, SD standard deviation, SE standard error, SPID0–48 summed pain intensity difference from 0 to 48 h, WLOCF windowed last observation carried forward
a95% CI for MR-107A-02, placebo; 90% CI for tramadol
b2-sided p value
c1-sided p value for tramadol; nominal post-hoc
Fig. 2.
LS means of NRS-R pain scores, ANCOVA by time point (WLOCF, FAS). ANCOVA analysis of covariance, BID twice daily, CI confidence interval, LS least squares, WLOCF windowed last observation carried forward
The time-to-onset outcomes demonstrated earlier analgesia with MR-107A-02. A greater proportion of participants reported perceptible pain relief with MR-107A-02 (70.8%) and tramadol (65.7%) compared to the placebo (55.9%). MR-107A-02 had a shorter time to perceptible pain relief among the three treatment groups and was significantly faster than placebo (median 0.7 h vs. 0.9 h; p = 0.037) (Table 3).
Table 3.
Time to first perceptible and meaningful pain relief across treatment groups (FAS)
| MR-107A-02 (15 mg BID) (n = 137) |
Tramadol (50 mg q6h) (n = 137) |
Placebo (q6h) (n = 136) |
|
|---|---|---|---|
| Time to onset of first perceptible pain relief | |||
| Participants with event n (%) | 97 (70.8) | 90 (65.7) | 76 (55.9) |
| Time to first event (h)a | |||
| 25th percentile | 0.4 | 0.4 | 0.5 |
| Median (95% CI)b | 0.7 (0.6, 0.9) | 0.8 (0.6, 0.9) | 0.9 (0.6, 5.8) |
| 75th percentile | 2.6 | NA | NA |
| p value (vs. placebo)c^ | 0.037 | – | – |
| Time to onset of first meaningful pain relief | |||
| Participants with event n (%) | 65 (47.4) | 55 (40.1) | 39 (28.7) |
| Time to first event (h)a | |||
| 25th percentile | 1.1 | 1.2 | 2.0 |
| Median (95% CI)b | 2.4 (1.9, 3.0) | 3.4 (2.6, 4.9) | 5.1 (3.1, NA) |
| 75th percentile | NA | NA | NA |
| p value (vs. placebo)c | 0.012 | – | – |
BID twice daily, CI confidence interval, FAS full analysis set, NA insufficient events for estimation
aPercentiles and comparisons were based on Kaplan–Meier estimates and log-rank tests. Participants without a reported event were censored at 6 h. Participants who took rescue medication before reporting perceptible pain relief and meaningful pain relief were censored at the time of rescue medication use.
b95% CI for MR-107A-02 and placebo; 90% CI for tramadol
bTwo-sided p value for MR-107A-02 versus placebo
Meaningful pain relief was reported more frequently in the MR-107A-02 (47.4%) and tramadol (40.1%) compared to the placebo group (28.7%). MR-107A-02 demonstrated the shortest median time to meaningful pain relief across the treatment groups and achieved a significant reduction versus placebo (median 2.4 h vs. 5.1 h; p = 0.012) (Table 3).
Importantly, MR‑107A‑02 consistently demonstrated a greater proportion of participants remaining opioid‑free across all postoperative intervals. Over the entire treatment phase, significantly more participants receiving MR‑107A‑02 required no opioid rescue (56.9%) compared with placebo (33.1%) (p < 0.001).
MR-107A-02 was associated with a statistically significant reduction in opioid rescue medication use compared with placebo. Over the entire treatment phase, the LS geometric mean number of opioid rescue doses in the MR-107A-02 group was 59% lower than in the placebo group (p < 0.001) (Table 4).
Table 4.
Number of doses of opioid (oxycodone and/or morphine) rescue medication (entire treatment phase) (FAS)
| MR-107A-02 (15 mg BID) (n = 137) |
Placebo (q6h) (n = 136) |
|
|---|---|---|
| Mean (SD) | 1.3 (2.16) | 2.9 (3.64) |
| Difference in means | − 1.6 | – |
| LS geometric mean (95% CI) | 0.12 (0.08, 0.18) | 0.29 (0.20, 0.43) |
| Ratio of LS geometric means versus placebo (95% CI) | 0.41 (0.29, 0.58) | |
| p value | < 0.001 | |
CI confidence interval, SD standard deviation
Time to first opioid (oxycodone and/or morphine) rescue medication use was longer with MR-107A-02 and tramadol than with placebo. Fewer than 50% of participants in the MR-107A-02 group required opioid rescue medication; therefore, the median time to first opioid use was not estimable. The median time to first opioid use was 64.7 h for tramadol and 10.0 h for placebo. MR-107A-02 significantly delayed opioid rescue medication use versus placebo (nominal p < 0.001) (Table S2).
In the MR-107A-02 group, 26.7% and 21.3% of participants did not require any rescue medication during the first 48 h, or over the 7-day treatment phase, respectively. For tramadol, the corresponding proportions were 17.1% and 8.2%, and for placebo, 8.3% and 6.9%, respectively. The median time to first rescue medication use was longer in MR‑107A‑02 (4.3 h) compared with placebo (2.2 h) (p < 0.001) (Table 5).
Table 5.
Time to first rescue medication use across treatment arms (FAS)
| MR-107A-02 (15 mg BID) (n = 137) |
Tramadol (50 mg q6h) (n = 137) |
Placebo (q6h) (n = 136) |
|
|---|---|---|---|
| Participants with event n (%) | 110 (80.3) | 127 (92.7) | 128 (94.1) |
| Time to event (h)a | |||
| 25th percentile | 1.5 | 1.5 | 1.3 |
| Median (95% CI)b | 4.3 (2.8, 5.1) | 3.1 (2.4, 3.8) | 2.2 (1.6, 2.6) |
| 75th percentile | 49.9 | 9.1 | 4.0 |
| p value (vs. placebo)c^ | < 0.001 | – | – |
BID twice daily, CI confidence interval, FAS full analysis set
aPercentiles and comparisons were based on Kaplan–Meier estimates and log-rank tests. P values are nominal and are generated using a log rank test. Participants who discontinued early were censored at the time of discontinuation. This analysis includes only rescue medications given in clinic during the confinement (day 1 and 2) period
b95% CI for MR-107A-02 and placebo; 90% CI for tramadol
cTwo-sided p value for MR-107A-02 versus placebo
Safety
Safety evaluations demonstrated that MR-107A-02 was well-tolerated and exhibited a favorable safety profile. In the MR-107A-02 group, all TEAEs were mild or moderate in severity, and no severe TEAEs, serious adverse events (SAEs), or study discontinuations due to TEAEs were reported. Treatment discontinuations were rare, with only 4 participants (2.9%) discontinuing during the study in the MR‑107A‑02 group, rates similar to placebo and lower than tramadol. TEAEs were reported by 74 participants (53.2%) in the MR‑107A‑02, 101 (74.3%) in the tramadol, and 75 (55.6%) in the placebo groups. At least one TEAE related to the study drug was reported by 45 participants (32.4%) in the MR-107A-02 group compared to 77 (56.6%) in the tramadol group and 42 (31.1%) in the placebo group.
Constipation was the most common TEAE in all three groups during the entire treatment phase (MR-107A-02, 10.8%; tramadol, 17.6%; and placebo, 7.4%) (Table 6).
Table 6.
Treatment-emergent adverse events (≥ 2% of participants overall) by system organ class and preferred term (safety analysis set)
| Preferred term | MR-107A-02 (15 mg BID) (n = 137) n (%) |
Tramadol (50 mg q6h) n = 137) n (%) |
Placebo (q6h) (n = 136) n (%) |
|---|---|---|---|
| Constipation | 15 (10.8) | 24 (17.6) | 10 (7.4) |
| Nausea | 14 (10.1) | 55 (40.4) | 18 (13.3) |
| Headache | 13 (9.4) | 14 (10.3) | 9 (6.7) |
| Pruritus | 10 (7.2) | 21 (15.4) | 11 (8.1) |
| Vomiting | 7 (5.0) | 24 (17.6) | 0 (0.0) |
| Hyperhidrosis | 7 (5.0) | 5 (3.7) | 9 (6.7) |
| Dizziness | 7 (5.0) | 29 (21.3) | 18 (13.3) |
| Rash | 7 (5.0) | 5 (3.7) | 2 (1.5) |
| Fatigue | 7 (5.0) | 8 (5.9) | 12 (8.9) |
| Diarrhea | 6 (4.3) | 7 (5.1) | 8 (5.9) |
| Abdominal pain | 4 (2.9) | 5 (3.7) | 4 (3.0) |
| Dyspepsia | 1 (0.7) | 6 (4.4) | 3 (2.2) |
| Flatulence | 3 (2.2) | 2 (1.5) | 1 (0.7) |
| Urticaria | 3 (2.2) | 1 (0.7) | 0 (0.0) |
| Somnolence | 1 (0.7) | 3 (2.2) | 1 (0.7) |
| Dyspnoea | 0 (0.0) | 4 (2.9) | 1 (0.7) |
| C-reactive protein increased | 9 (6.5) | 11 (8.1) | 12 (8.9) |
The incidence of ORAEs in the MR-107A-02 group was 16.1%, which was lower than that observed with tramadol (46.0%), and was comparable to placebo (16.9%) during the first 48 h of treatment. MR-107A-02 demonstrated a favorable tolerability profile across the predefined set of ORAEs, with consistently lower observed rates than tramadol, notably nausea (10.1% vs. 40.4%), dizziness (5.0% vs. 21.3%), vomiting (5.0% vs. 17.6%), pruritus (6.5% vs. 15.4%), and constipation (10.8% vs. 17.6%) (Table S1). There was no treatment-emergent AESI in any of the groups.
Discussion
This phase 3, randomized, double-blind, active- and placebo-controlled study evaluated the efficacy and safety of MR-107A-02 15 mg BID, tramadol 50 mg (q6h), and placebo in patients experiencing acute postsurgical pain following unilateral bunionectomy. Tramadol was selected during the inpatient phase to confirm assay sensitivity through comparison with placebo on the primary endpoint and to enable the evaluation of MR-107A-02 relative to a standard opioid analgesic. Tramadol’s analgesic profile provides a reliable benchmark for detecting treatment effects while maintaining an appropriate safety and tolerability balance, making it a suitable comparator for this study. Additionally, Tramadol’s approved indication for moderate to severe pain aligns with the pain intensity typically observed in bunionectomy studies (baseline NRS ~ 6.7–7.7) [8, 9, 16–18]. Although an exploratory comparison with tramadol was performed, the study was not powered to formally test differences between MR-107A-02 and tramadol, and these findings should therefore be interpreted cautiously.
The primary efficacy endpoint was met, with MR‑107A‑02 demonstrating the greatest reduction in acute postoperative bunionectomy pain compared with placebo (p < 0.001) within 48 h. The trajectory of pain relief favored MR‑107A‑02 as early as 0.5 h post‑dose and was maintained across the 48-h inpatient period, with time‑to‑event analyses showing significantly faster onset of both perceptible (median 0.7 h) and meaningful (2.4 h) pain relief versus placebo.
In addition to achieving statistical significance, the observed treatment effects were accompanied by reductions in opioid rescue medication use, a higher proportion of opioid-free participants, and faster onset of perceptible and meaningful pain relief, supporting the clinical relevance of the analgesic benefit.
The reduced need for rescue medication and longer time to first rescue dose observed with MR-107A-02 may reflect effective early analgesia. A higher proportion of participants remained rescue-free with MR-107A-02 than with tramadol and placebo over the first 48 h and then with placebo over the 7-day treatment period. In addition to its analgesic benefits, lower reliance on opioid rescue medications is clinically important because lower postoperative opioid exposure is linked to fewer opioid-related adverse effects, improved recovery, and potentially reduced risk of persistent opioid use, including abuse, dependence, and addiction [5]. The observed opioid-sparing effect complements pain outcomes and supports the integration of MR‑107A‑02 within multimodal strategies that aim to limit opioid reliance without compromising analgesia.
The MR‑107A‑02 regimen was generally safe and well tolerated, with no severe TEAEs, SAEs, or treatment discontinuations. Overall TEAE rates were comparable to placebo and lower than tramadol, with no clinically concerning changes in laboratory values, vital signs, or ECGs, and no adverse events of special interest reported. Assessment of opioid‑related adverse events highlighted a good tolerability profile for MR‑107A‑02 compared with tramadol, a commonly used opioid often considered relatively well tolerated. Reductions in nausea, dizziness, vomiting, pruritus, and constipation may be clinically meaningful to patients, and may therefore improve treatment acceptability. These considerations are particularly relevant in ambulatory surgical settings, where minimizing opioid‑related adverse effects and limiting opioid exposure may reduce the potential for opioid‑associated dependence and facilitate earlier mobilization, timely discharge, and more efficient use of healthcare resources [19–21]. The provision of strong durable analgesia in the post-surgical setting may also reduce the likelihood of patients experiencing chronic pain associated downstream of the procedure with a recent study estimating this may be as high as 8.4% at 6 months post-procedure [22].
Study Strengths and Limitations
The strengths of this study include the robust, randomized, double‑blind design, inclusion of an active comparator (tramadol) alongside placebo, rigorous handling of rescue medication confounding (WLOCF) and missing data (MI), and concordance across multiple endpoints. Tramadol demonstrated sensitivity for the primary endpoint, confirming that the active comparator performed as expected and supporting assay sensitivity. Importantly, the results are consistent with the outcomes of the phase 2 dental pain study (NCT05317312) and the complementary phase 3 herniorrhaphy study (NCT06215859 is under separate manuscript development). This supports the consistency of the analgesic effects observed across postoperative pain models, evaluated within the clinical development program.
This study has limitations that warrant consideration. The inpatient-to-outpatient transition may introduce behavioral variability in rescue medication use and reporting. While the study was conducted in a controlled clinical trial setting, the transition between care settings may provide additional context for interpreting treatment effects during postoperative recovery. In addition, tramadol was administered only during the 48-h inpatient phase and was replaced with placebo during the outpatient phase. Because the primary endpoint (SPID0–48) and assay sensitivity assessment were completed during the inpatient period, this design did not affect the primary efficacy evaluation. However, it introduces asymmetry between treatment groups during the outpatient phase and should be considered when interpreting longer-term rescue medication use and tolerability outcomes. Second, while the minimum baseline pain intensity requirement ensured a rigorous and clinically relevant assessment of efficacy in moderate-to-severe pain, MR-107A-02 may also be used earlier in the pain trajectory in real-world settings.
Third, the study population was predominantly female, reflecting the known epidemiology of hallux valgus requiring bunionectomy [23, 24]. Although this sex distribution may limit the generalizability of the findings to male patients, the broader phase 3 clinical development program included a complementary herniorrhaphy study that enrolled a predominantly male population [25]. Together, these studies provide evidence for the efficacy and safety of MR-107A-02 across distinct surgical pain models and broad patient demographics.
Fourth, the bunionectomy pain model is a standardized setting which does not fully reflect real-world clinical practice. Finally, although statistical analyses were conducted by an independent contract research organization according to a prespecified statistical analysis plan, this study was sponsor funded.
Conclusions
MR‑107A‑02 15 mg BID provided significantly greater analgesic efficacy than placebo, delivering rapid and durable relief of acute postoperative pain following bunionectomy. MR‑107A‑02 also achieved opioid‑sparing effects with a favorable tolerability profile compared to tramadol. These findings should be interpreted within the constraints of the bunionectomy model, and confirmation in other surgical settings is warranted.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
Medical Writing/Editorial Assistance
Medical writing assistance and editorial support were provided by Dr. Mamatha K, PhD, a salaried employee of Viatris. Funding for medical writing and editorial assistance was provided by Viatris. The authors acknowledge the use of Microsoft Copilot, an AI-assisted tool, for support in language editing and formatting during manuscript preparation. All intellectual content, data interpretation, and conclusions were developed and verified by the authors. The authors thank the Principal Investigators (PI), study site staff, and study participants for their contributions to this study. A complete list of the contributing PIs is provided in the Supplementary material.
Author Contribution
Conceptualization: Susanne Vogt, Chris Walker and Jeffrey P. Smith; Methodology: Todd Bertoch, Susanne Vogt, Scott Haughie, Kathleen Ocasio, Chris Walker and Jeffrey P. Smith; Supervision and project administration: Susanne Vogt, Scott Haughie and Kathleen Ocasio; Validation: Susanne Vogt, Chris Walker and Scott Haughie; Writing—review and editing: Todd Bertoch, Jessica C. McCoun, Ira Gottlieb, Susanne Vogt, Scott Haughie, Kathleen Ocasio, Chris Walker and Jeffrey P. Smith.
Funding
This study and the rapid service fee was funded by Viatris, Inc.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Disclosures
Susanne Vogt, Scott Haughie, Kathleen Ocasio, Chris Walker and Jeffrey P. Smith are employees of Viatris; Few of these authors held Viatris stocks during the conduct of the program. Todd Bertoch and Jessica C. McCoun are employed at CenExel JBR.
Ethical Approval
The study was approved by the Advara Institutional Review Board (IRB), which served as the single IRB for all participating study centers. The study was conducted in accordance with the Declaration of Helsinki and its later amendments, ICH-GCP guidelines, and applicable regulatory requirements. All participants provided written informed consent before enrollment.
Footnotes
Prior Presentation: The abstract titled “Efficacy and safety of MR-107A-02 (novel fast-acting meloxicam formulation) for the treatment of acute moderate-to-severe pain following bunionectomy” was presented as Poster #39 (P- 039) at PAIN Week 2024, September 3–6, 2024, at Las Vegas, Nevada. In addition, it was presented as an encore poster (RA- 26) at 51st Annual Regional Anesthesiology and Acute Pain Medicine Meeting (ASRA), April 16–18, 2026, at Phoenix, Arizona.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.