Pain, Pain, Acute, Postoperative Pain
Conditions
Brief summary
MR-107A-01 is being studied to investigate its efficacy, safety, and dose-response after dental surgery.
Interventions
DRUGMR-107A-01
Oral tablet
DRUGPlacebo
Oral tablet
Sponsors
Mylan Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females ≥18 years of age. 2. Requirement for dental surgery for extraction of ≥2 x third molars, at least 1 of which involves partial or complete mandibular bony impaction. 3. Pain Intensity (PI) using a Numeric Pain Rating Scale (NPRS) ≥5 during the 5 hours following the end of surgery. 4. Rating of moderate or severe pain on a 4-point categorical pain rating scale (i.e., none, mild, moderate, severe) during the 5 hours following the end of surgery.
Exclusion criteria
1. Previously dosed with MR-107A-01. 2. Subject with known hypersensitivity to nonsteroidal antiinflammatory drugs (NSAIDs). 3. Active GI bleeding or a history of peptic ulcer disease, active inflammatory bowel disease, e.g., Crohn's Disease or ulcerative colitis, bleeding disorders that may affect coagulation. 4. Use of any investigational drug within 28 days, or 5 half-lives, prior to screening whichever is longer. 5. Use of medications with the potential to interact with MR-107A-01. 6. Other acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Summed Pain Intensity Difference (SPID) | 24 hours after the first dose | Participants assessed Pain Intensity (PI) using a 0-10 numeric pain rating scale (NPRS) where 0 is no pain and 10 is worst pain imaginable. PI was assessed 17 times within 24 hours after the first study dose, and immediately before any rescue medication and/or at early termination. The participant's baseline PI was subtracted from the timepoint PI, to derive a Pain Intensity Difference (PID) for each timepoint. Overall Summed Pain Intensity Difference (SPID) measures pain intensity change relative to baseline over the 24 hour period after dosing, and corresponds to the Area Under the Curve (AUC) of the PID. In this study, higher positive Overall SPID indicates better pain improvement. Overall SPID could range from -120 to 240. Two hour windowed last observation carried forward was used as applicable where PI score obtained before a rescue medication replaced PI score for each timepoint within 2 hours following rescue dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Intensity Using a Numeric Pain Rating Scale Utilizing 2-hour Windowed Last Observation Carried Forward (W2LOCF) | 24 hours after the first dose | 10 point scale, where 0 is no pain and 10 is the worst pain imaginable; 2-hour windowed last observation carried forward (W2LOCF) utilizes pain right now just prior to rescue medication use and censors subsequent pain intensity values for 2 hours when calculating SPIDs |
| Total Pain Relief | 24 hours after the first dose | Pain relief was assessed by participants using a 5 point scale, where 0 = none, 1 = slight, 2 = moderate, 3 = good or a lot, and 4 = complete. Pain relief was measured 17 times within 24 hours after the first study medication dose, and immediately before any rescue medication and/or at the time of early termination. Two-hour windowed last observation carried forward approach was used whereby the pain relief score obtained before a given rescue medication was carried forward to replace the pain relief scores collected at each observation timepoint within 2 hours following the rescue dose. Total pain relief (TOTPAR) had Areas Under the Curve (AUCs) calculated for each time point. The range for 24 hours post dose TOTPAR AUC was 0 to 96. Higher positive values indicate a better outcome with larger pain improvements. |
| Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | 24 hours after the first dose | The time to onset of first perceptible relief was defined as the post dose time at which the subject first begins to feel pain relief. The time to meaningful pain relief was defined as the post dose time at which the subject begins to feel meaningful pain relief. The assessments of perceptible and meaningful pain relief were ceased when rescue medication was taken. |
| Patient's Global Assessment of Pain Control | 24 hours after the first dose | 5 point scale, where 0 is poor, 1 is fair, 2 is good, 3 is very good, and 4 is excellent Responder = 2 is good, 3 is very good, and 4 is excellent, Non-responder = 1 is fair, 0 is poor, and missing values |
| Rescue Medication Use | 24 hours after the first dose | Number of rescue medication doses |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MR-107A-01 10 mg Once in a 24-hour Period Oral tablet one day of dosing
MR-107A-01: Oral tablet | 21 |
| MR-107A-01 15 mg Once in a 24-hour Period Oral tablet one day of dosing
MR-107A-01: Oral tablet | 24 |
| MR-107A-01 10 mg Twice in a 24-hour Period Oral tablet one day of dosing
MR-107A-01: Oral tablet | 23 |
| MR-107A-01 15 mg Twice in a 24-hour Period Oral tablet one day of dosing
MR-107A-01: Oral tablet | 23 |
| Placebo Twice in a 24-hour Period Placebo tablet one day of dosing
Placebo: Oral tablet | 21 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | insufficient pain | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | MR-107A-01 10 mg Twice in a 24-hour Period | MR-107A-01 15 mg Twice in a 24-hour Period | Placebo Twice in a 24-hour Period | Total | MR-107A-01 10 mg Once in a 24-hour Period | MR-107A-01 15 mg Once in a 24-hour Period |
|---|---|---|---|---|---|---|
| Age, Continuous | 19.8 years STANDARD_DEVIATION 2.37 | 19.4 years STANDARD_DEVIATION 2.39 | 20.1 years STANDARD_DEVIATION 2.41 | 19.7 years STANDARD_DEVIATION 2.17 | 20.1 years STANDARD_DEVIATION 2.17 | 19.2 years STANDARD_DEVIATION 1.46 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 7 Participants | 3 Participants | 23 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 16 Participants | 18 Participants | 89 Participants | 19 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 2 Participants | 4 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 23 Participants | 17 Participants | 104 Participants | 20 Participants | 24 Participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 8 Participants | 60 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 13 Participants | 52 Participants | 10 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 24 | 0 / 23 | 0 / 23 | 0 / 21 |
| other Total, other adverse events | 4 / 21 | 6 / 24 | 6 / 23 | 0 / 23 | 2 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 24 | 0 / 23 | 0 / 23 | 0 / 21 |
Outcome results
Primary
Overall Summed Pain Intensity Difference (SPID)
Participants assessed Pain Intensity (PI) using a 0-10 numeric pain rating scale (NPRS) where 0 is no pain and 10 is worst pain imaginable. PI was assessed 17 times within 24 hours after the first study dose, and immediately before any rescue medication and/or at early termination. The participant's baseline PI was subtracted from the timepoint PI, to derive a Pain Intensity Difference (PID) for each timepoint. Overall Summed Pain Intensity Difference (SPID) measures pain intensity change relative to baseline over the 24 hour period after dosing, and corresponds to the Area Under the Curve (AUC) of the PID. In this study, higher positive Overall SPID indicates better pain improvement. Overall SPID could range from -120 to 240. Two hour windowed last observation carried forward was used as applicable where PI score obtained before a rescue medication replaced PI score for each timepoint within 2 hours following rescue dose.
Time frame: 24 hours after the first dose
Population: Modified Intent to Treat Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MR-107A-01 10 mg Once in a 24-hour Period | Overall Summed Pain Intensity Difference (SPID) | 109.5 score on a scale * hours | Standard Deviation 32.82 |
| MR-107A-01 15 mg Once in a 24-hour Period | Overall Summed Pain Intensity Difference (SPID) | 111.8 score on a scale * hours | Standard Deviation 40.37 |
| MR-107A-01 10 mg Twice in a 24-hour Period | Overall Summed Pain Intensity Difference (SPID) | 108.8 score on a scale * hours | Standard Deviation 33.85 |
| MR-107A-01 15 mg Twice in a 24-hour Period | Overall Summed Pain Intensity Difference (SPID) | 108.6 score on a scale * hours | Standard Deviation 40.2 |
| Placebo Twice in a 24-hour Period | Overall Summed Pain Intensity Difference (SPID) | 80.0 score on a scale * hours | Standard Deviation 39.78 |
p-value: 0.00395% CI: [9.9, 46.6]Emax
p-value: <0.00195% CI: [13.8, 45.3]Emax
p-value: <0.00195% CI: [14.4, 46.2]Emax
p-value: <0.00195% CI: [13.5, 48.6]Emax
Secondary
Pain Intensity Using a Numeric Pain Rating Scale Utilizing 2-hour Windowed Last Observation Carried Forward (W2LOCF)
10 point scale, where 0 is no pain and 10 is the worst pain imaginable; 2-hour windowed last observation carried forward (W2LOCF) utilizes pain right now just prior to rescue medication use and censors subsequent pain intensity values for 2 hours when calculating SPIDs
Time frame: 24 hours after the first dose
Population: Modified Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MR-107A-01 10 mg Once in a 24-hour Period | Pain Intensity Using a Numeric Pain Rating Scale Utilizing 2-hour Windowed Last Observation Carried Forward (W2LOCF) | 2.5 score on a scale | Standard Deviation 1.86 |
| MR-107A-01 15 mg Once in a 24-hour Period | Pain Intensity Using a Numeric Pain Rating Scale Utilizing 2-hour Windowed Last Observation Carried Forward (W2LOCF) | 2.1 score on a scale | Standard Deviation 1.6 |
| MR-107A-01 10 mg Twice in a 24-hour Period | Pain Intensity Using a Numeric Pain Rating Scale Utilizing 2-hour Windowed Last Observation Carried Forward (W2LOCF) | 1.5 score on a scale | Standard Deviation 1.34 |
| MR-107A-01 15 mg Twice in a 24-hour Period | Pain Intensity Using a Numeric Pain Rating Scale Utilizing 2-hour Windowed Last Observation Carried Forward (W2LOCF) | 2.3 score on a scale | Standard Deviation 1.98 |
| Placebo Twice in a 24-hour Period | Pain Intensity Using a Numeric Pain Rating Scale Utilizing 2-hour Windowed Last Observation Carried Forward (W2LOCF) | 2.5 score on a scale | Standard Deviation 2.39 |
95% CI: [-1.4, 1.1]
95% CI: [-1.5, 0.9]
95% CI: [-1.8, 0.6]
95% CI: [-1.1, 1.3]
Secondary
Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief
The time to onset of first perceptible relief was defined as the post dose time at which the subject first begins to feel pain relief. The time to meaningful pain relief was defined as the post dose time at which the subject begins to feel meaningful pain relief. The assessments of perceptible and meaningful pain relief were ceased when rescue medication was taken.
Time frame: 24 hours after the first dose
Population: Modified Intent to Treat Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MR-107A-01 10 mg Once in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Perceptible Pain Relief | 15 Participants |
| MR-107A-01 10 mg Once in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Meaningful Pain Relief | 10 Participants |
| MR-107A-01 15 mg Once in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Perceptible Pain Relief | 22 Participants |
| MR-107A-01 15 mg Once in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Meaningful Pain Relief | 17 Participants |
| MR-107A-01 10 mg Twice in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Perceptible Pain Relief | 16 Participants |
| MR-107A-01 10 mg Twice in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Meaningful Pain Relief | 13 Participants |
| MR-107A-01 15 mg Twice in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Meaningful Pain Relief | 15 Participants |
| MR-107A-01 15 mg Twice in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Perceptible Pain Relief | 19 Participants |
| Placebo Twice in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Perceptible Pain Relief | 10 Participants |
| Placebo Twice in a 24-hour Period | Pain Relief: Number and Percentage of Subjects With Perceptible and Meaningful Pain Relief | Meaningful Pain Relief | 3 Participants |
Comparison: Time to Perceptible Pain Relief Subjects are censored at 24 hours if they do not report relief.p-value: 0.208Log Rank
Comparison: Time to Perceptible Pain Relief Subjects are censored at 24 hours if they do not report relief.p-value: 0.005Log Rank
Comparison: Time to Perceptible Pain Relief Subjects are censored at 24 hours if they do not report relief.p-value: 0.192Log Rank
Comparison: Time to Perceptible Pain Relief Subjects are censored at 24 hours if they do not report relief.p-value: 0.067Log Rank
Comparison: Time to Meaningful Pain Relief Subjects are censored at 24 hours if they do not report relief.p-value: 0.059Log Rank
Comparison: Time to Meaningful Pain Relief Subjects are censored at 24 hours if they do not report relief.p-value: <0.001Log Rank
Comparison: Time to Meaningful Pain Relief Subjects are censored at 24 hours if they do not report relief.p-value: 0.017Log Rank
Comparison: Time to Meaningful Pain Relief Subjects are censored at 24 hours if they do not report relief.p-value: 0.002Log Rank
Secondary
Patient's Global Assessment of Pain Control
5 point scale, where 0 is poor, 1 is fair, 2 is good, 3 is very good, and 4 is excellent Responder = 2 is good, 3 is very good, and 4 is excellent, Non-responder = 1 is fair, 0 is poor, and missing values
Time frame: 24 hours after the first dose
Population: Modified Intent to Treat Analysis Set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MR-107A-01 10 mg Once in a 24-hour Period | Patient's Global Assessment of Pain Control | Responders | 14 Participants |
| MR-107A-01 10 mg Once in a 24-hour Period | Patient's Global Assessment of Pain Control | Non-responders | 7 Participants |
| MR-107A-01 15 mg Once in a 24-hour Period | Patient's Global Assessment of Pain Control | Non-responders | 8 Participants |
| MR-107A-01 15 mg Once in a 24-hour Period | Patient's Global Assessment of Pain Control | Responders | 16 Participants |
| MR-107A-01 10 mg Twice in a 24-hour Period | Patient's Global Assessment of Pain Control | Responders | 18 Participants |
| MR-107A-01 10 mg Twice in a 24-hour Period | Patient's Global Assessment of Pain Control | Non-responders | 5 Participants |
| MR-107A-01 15 mg Twice in a 24-hour Period | Patient's Global Assessment of Pain Control | Responders | 13 Participants |
| MR-107A-01 15 mg Twice in a 24-hour Period | Patient's Global Assessment of Pain Control | Non-responders | 10 Participants |
| Placebo Twice in a 24-hour Period | Patient's Global Assessment of Pain Control | Non-responders | 14 Participants |
| Placebo Twice in a 24-hour Period | Patient's Global Assessment of Pain Control | Responders | 7 Participants |
p-value: 0.051Regression, Logistic
p-value: 0.035Regression, Logistic
p-value: 0.016Regression, Logistic
p-value: 0.18Regression, Logistic
Secondary
Rescue Medication Use
Number of rescue medication doses
Time frame: 24 hours after the first dose
Population: Modified Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MR-107A-01 10 mg Once in a 24-hour Period | Rescue Medication Use | 0.8 Medication doses | Standard Deviation 1.03 |
| MR-107A-01 15 mg Once in a 24-hour Period | Rescue Medication Use | 0.8 Medication doses | Standard Deviation 0.92 |
| MR-107A-01 10 mg Twice in a 24-hour Period | Rescue Medication Use | 0.7 Medication doses | Standard Deviation 0.7 |
| MR-107A-01 15 mg Twice in a 24-hour Period | Rescue Medication Use | 0.7 Medication doses | Standard Deviation 1.14 |
| Placebo Twice in a 24-hour Period | Rescue Medication Use | 1.8 Medication doses | Standard Deviation 1.58 |
p-value: 0.022Wilcoxon Rank Sum
p-value: 0.028Wilcoxon Rank Sum
p-value: 0.007Wilcoxon Rank Sum
p-value: 0.005Wilcoxon Rank Sum
Secondary
Total Pain Relief
Pain relief was assessed by participants using a 5 point scale, where 0 = none, 1 = slight, 2 = moderate, 3 = good or a lot, and 4 = complete. Pain relief was measured 17 times within 24 hours after the first study medication dose, and immediately before any rescue medication and/or at the time of early termination. Two-hour windowed last observation carried forward approach was used whereby the pain relief score obtained before a given rescue medication was carried forward to replace the pain relief scores collected at each observation timepoint within 2 hours following the rescue dose. Total pain relief (TOTPAR) had Areas Under the Curve (AUCs) calculated for each time point. The range for 24 hours post dose TOTPAR AUC was 0 to 96. Higher positive values indicate a better outcome with larger pain improvements.
Time frame: 24 hours after the first dose
Population: Modified Intent to Treat Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MR-107A-01 10 mg Once in a 24-hour Period | Total Pain Relief | 55.5 score on a scale * hours | Standard Deviation 12.31 |
| MR-107A-01 15 mg Once in a 24-hour Period | Total Pain Relief | 57.3 score on a scale * hours | Standard Deviation 11.29 |
| MR-107A-01 10 mg Twice in a 24-hour Period | Total Pain Relief | 60.2 score on a scale * hours | Standard Deviation 13.48 |
| MR-107A-01 15 mg Twice in a 24-hour Period | Total Pain Relief | 56.6 score on a scale * hours | Standard Deviation 16.82 |
| Placebo Twice in a 24-hour Period | Total Pain Relief | 41.2 score on a scale * hours | Standard Deviation 17.05 |
p-value: <0.00195% CI: [9.3, 22.9]Emax
p-value: <0.00195% CI: [9.7, 23.4]Emax
p-value: <0.00195% CI: [7.3, 23.1]Emax
p-value: <0.00195% CI: [9.4, 24.7]Emax