Dental Pain
Conditions
Brief summary
* Accessing the efficacy and safety of pregabalin when used alone and in combo with acetaminophen in a dental pain model. * To test whether pre-operative dose of pregabalin increases the time to significant post-operative pain (NRS ≥ 5), and hence time to first analgesia consumed post-operatively.
Detailed description
This is a 5 arm randomized, double-blind, parallel group, single-center, placebo-controlled study to evaluate the efficacy and safety of pregabalin-acetaminophen combination in the prevention and treatment of post-surgical dental pain in healthy patients. Subjects in every treatment arm will receive a dose 60 min prior to surgery. It is not required to receive a post-operative dose if patient does not feel pain at a scale of NRS≥ 5. Dose 2 will be given post-surgically when patients report at least moderate pain on the categorical scale and a score of ≥5 on 0-10 PI-NRS. Subsequent to dose 2, patients can request rescue analgesic at any time.
Interventions
DRUGPre-Op pregabalin
Pre-op pregabalin will be administered 60 min prior to surgery.
DRUGPre-Op Placebo 1
Placebo 1 will be administered 60 min prior to surgery.
DRUGPost-Op pregabalin
Post-op pregabalin will be administered Post-operatively.
DRUGPost-Op Placebo 1
Placebo 1 will be administered post-operatively.
DRUGPost-Op Placebo 2
Placebo 2 will be administered post-operatively.
DRUGPost-Op acetaminophen
Acetaminophen will be administered Post-operatively.
Sponsors
Nevakar, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The sponsor, patients, investigators and study staff involved in the protocol procedures or those involved in data collection, data entry, data analysis will be blinded.
Eligibility
Sex/Gender
ALL
Age
17 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients who are scheduled to undergo the surgical removal of up to 4 third molars of which at least 2 have to be mandibular molars with a difficulty rating of 4 or 5. * Patient must have a negative urine drug screen for drugs of abuse (including tobacco) at screening and at the day of surgery. * No alcohol for a minimum of 1 day prior to the surgery.
Exclusion criteria
* Patients should not be experiencing oral infections or symptoms of concomitant illness at the time of a scheduled surgery. * Patients with a history of any type of malignancy within the past 5 years other than minor skin related cancers. * Patients who currently have or have had a history of uncontrolled hypertension. * Patients with a known allergy or hypersensitivity to any local anesthetic drug, NSAIDs, gabapentin or pregabalin;. * Patients with conditions that affect the absorption, metabolism, or passage of drugs out of the body (e.g., sprue, celiac disease, crohn's disease, etc.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sum Pain Intensity Difference Scores | 0.5, 0.75, 1, 1.25, 1.75, 2.25 hours (± 5 min) and 3.25, 4.25, 5.25, 6.25, 8.25, 10.25, 12.25, 24 hours (± 10 min) | Beginning post-surgery (at initiation of Dose 2), Pain Intensity was self-reported over 24 hours, using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = pain as bad as can be). Time weighted sum pain intensity difference scores are reported over 0 to 24 hours. Last observation carried forward method was used. |
| Total Pain Relief Measure | 0.5, 0.75, 1, 1.25, 1.75, 2.25 hours (± 5 min) and 3.25, 4.25, 5.25, 6.25, 8.25, 10.25, 12.25, 24 hours (± 10 min) | Beginning post-surgery (at initiation of Dose 2), Pain Relief was self-reported over 24 hours, using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = pain as bad as can be). Time-weighted sum pain total pain relief scores over 24 hours is reported Last observation carried forward method was used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Differing Patient Global Evaluation Scores | Upto 12.25 hours | Patient global evaluation was self-reported at time of first rescue or at 12.25 hours post-surgery, whichever was first, using a 0-4 categorical rating scale of: (0) poor, (1) fair, (2) good, (3) very good, and (4) excellent. The number of participants with differing patient global evaluation scores were reported. |
| Cumulative Number of Participants With Onset of First Perceptible Relief (FPR) Confirmed at 24 Hours After Dose 2 | 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24 hours | Beginning post-surgery (at initiation of Dose 2), participants were given a stopwatch and asked to press the stopwatch if and when they feel first perceptible relief; a record of the time was noted in the participants record. Cumulative number of participants with onset of FPR confirmed after dose 2 and was recorded from 0.25 hour till 24 hours after administration of dose 2. |
| Cumulative Number of Participants With Onset of Meaning Pain Relief (MPR) Confirmed at 24 Hours After Dose 2 | 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24 hours | Beginning post-surgery (at initiation of Dose 2), participants were given a stopwatch and asked to press the stopwatch if and when they feel first perceptible relief; a record of the time was noted in the participants record. Cumulative number of participants with onset of MPR confirmed after dose 2 and was recorded from 0.25 hour till 24 hours after administration of dose 2. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from June 2018 till September 2018 from the site
Pre-assignment details
Participants were screened from Day-30 to Day 0 before getting randomized
Participants by arm
| Arm | Count |
|---|---|
| Group A/ Placebo Group Pre-surgery placebo and post-surgery placebo 1 and placebo 2 | 24 |
| Group B/ APAP Group Pre-surgery placebo 1 and post-surgery placebo 1 and acetaminophen (APAP) | 23 |
| Group C/ PGB Group Pre-surgery placebo 1 and post-surgery placebo 2 and pregabalin (PGB) | 22 |
| Group D/ Combination Co-dosing Group Pre-surgery placebo 1 and post-surgery APAP and PGB | 23 |
| Group E/ Combination Split-dosing Group Pre-surgery PGB and post-surgery placebo 1 and APAP | 23 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 2 | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Group A/ Placebo Group | Group B/ APAP Group | Group C/ PGB Group | Group D/ Combination Co-dosing Group | Group E/ Combination Split-dosing Group | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 17.8 years STANDARD_DEVIATION 1.79 | 17.8 years STANDARD_DEVIATION 1.48 | 17.9 years STANDARD_DEVIATION 1.39 | 17.7 years STANDARD_DEVIATION 0.93 | 17.6 years STANDARD_DEVIATION 1.31 | 17.7 years STANDARD_DEVIATION 1.39 |
| Body Mass Index | 22.86 kg/m^2 STANDARD_DEVIATION 3.716 | 22.54 kg/m^2 STANDARD_DEVIATION 3.227 | 22.78 kg/m^2 STANDARD_DEVIATION 3.825 | 24.02 kg/m^2 STANDARD_DEVIATION 3.788 | 23.85 kg/m^2 STANDARD_DEVIATION 3.695 | 23.21 kg/m^2 STANDARD_DEVIATION 3.642 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 4 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 21 Participants | 22 Participants | 19 Participants | 21 Participants | 106 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of Participants With Mandibular Molar - 17 Full bony impaction | 21 Participants | 16 Participants | 18 Participants | 18 Participants | 19 Participants | 92 Participants |
| Number of Participants With Mandibular Molar - 17 Moderate to severe partial bony | 2 Participants | 7 Participants | 4 Participants | 5 Participants | 4 Participants | 22 Participants |
| Number of Participants With Mandibular Molar - 32 Full bony impaction | 19 Participants | 16 Participants | 17 Participants | 19 Participants | 19 Participants | 90 Participants |
| Number of Participants With Mandibular Molar - 32 Moderate to severe partial bony | 4 Participants | 7 Participants | 5 Participants | 4 Participants | 3 Participants | 23 Participants |
| Number of Participants With Maxillary Molar -1 Erupted in tissue | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants |
| Number of Participants With Maxillary Molar -1 Full bony impaction | 20 Participants | 17 Participants | 17 Participants | 21 Participants | 22 Participants | 97 Participants |
| Number of Participants With Maxillary Molar -1 Moderate to severe partial bony | 0 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 7 Participants |
| Number of Participants With Maxillary Molar -1 Soft tissue impaction | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Number of Participants With Maxillary Molar -16 Erupted in tissue | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Number of Participants With Maxillary Molar -16 Full bony impaction | 22 Participants | 19 Participants | 15 Participants | 20 Participants | 21 Participants | 97 Participants |
| Number of Participants With Maxillary Molar -16 Mild partial bony impaction | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Number of Participants With Maxillary Molar -16 Moderate to severe partial bony | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 1 Participants | 9 Participants |
| Number of Participants With Maxillary Molar -16 Soft tissue impaction | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 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 | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 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 | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 22 Participants | 21 Participants | 22 Participants | 22 Participants | 23 Participants | 110 Participants |
| Sex: Female, Male Female | 12 Participants | 11 Participants | 11 Participants | 12 Participants | 11 Participants | 57 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 11 Participants | 11 Participants | 12 Participants | 58 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 / 24 | 0 / 23 | 0 / 22 | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 2 / 24 | 3 / 23 | 14 / 22 | 15 / 23 | 12 / 23 |
| serious Total, serious adverse events | 0 / 24 | 0 / 23 | 0 / 22 | 0 / 23 | 0 / 23 |
Outcome results
Primary
Sum Pain Intensity Difference Scores
Beginning post-surgery (at initiation of Dose 2), Pain Intensity was self-reported over 24 hours, using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = pain as bad as can be). Time weighted sum pain intensity difference scores are reported over 0 to 24 hours. Last observation carried forward method was used.
Time frame: 0.5, 0.75, 1, 1.25, 1.75, 2.25 hours (± 5 min) and 3.25, 4.25, 5.25, 6.25, 8.25, 10.25, 12.25, 24 hours (± 10 min)
Population: Efficacy Analysis Population included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A/ Placebo Group | Sum Pain Intensity Difference Scores | -2.4292 score on a scale | Standard Error 12.498 |
| Group B/ APAP Group | Sum Pain Intensity Difference Scores | -68.0778 score on a scale | Standard Error 11.2879 |
| Group C/ PGB Group | Sum Pain Intensity Difference Scores | -68.3533 score on a scale | Standard Error 11.8092 |
| Group D/ Combination Co-dosing Group | Sum Pain Intensity Difference Scores | -93.3645 score on a scale | Standard Error 11.5794 |
| Group E/ Combination Split-dosing Group | Sum Pain Intensity Difference Scores | -82.4099 score on a scale | Standard Error 17.4418 |
Comparison: Group D vs. Group B
Comparison: Group C vs. Group B
Comparison: Group C vs. Group A
Comparison: Group B vs. Group A
Comparison: Group D vs. Group A
Comparison: Group D vs. Group C
Comparison: Group E vs. Group D
Primary
Total Pain Relief Measure
Beginning post-surgery (at initiation of Dose 2), Pain Relief was self-reported over 24 hours, using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = pain as bad as can be). Time-weighted sum pain total pain relief scores over 24 hours is reported Last observation carried forward method was used.
Time frame: 0.5, 0.75, 1, 1.25, 1.75, 2.25 hours (± 5 min) and 3.25, 4.25, 5.25, 6.25, 8.25, 10.25, 12.25, 24 hours (± 10 min)
Population: Efficacy Analysis Population: Included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A/ Placebo Group | Total Pain Relief Measure | 17.1038 score on a scale | Standard Error 15.5619 |
| Group B/ APAP Group | Total Pain Relief Measure | 88.2775 score on a scale | Standard Error 14.0551 |
| Group C/ PGB Group | Total Pain Relief Measure | 94.4433 score on a scale | Standard Error 14.7042 |
| Group D/ Combination Co-dosing Group | Total Pain Relief Measure | 121.9596 score on a scale | Standard Error 14.418 |
| Group E/ Combination Split-dosing Group | Total Pain Relief Measure | 91.8373 score on a scale | Standard Error 21.7176 |
Comparison: Group D vs. Group B
Comparison: Group C vs. Group B
Comparison: Group C vs. Group A
Comparison: Group B vs. Group A
Comparison: Group D vs. Group A
Comparison: Group D vs. Group C
Comparison: Group E vs. Group D
Secondary
Cumulative Number of Participants With Onset of First Perceptible Relief (FPR) Confirmed at 24 Hours After Dose 2
Beginning post-surgery (at initiation of Dose 2), participants were given a stopwatch and asked to press the stopwatch if and when they feel first perceptible relief; a record of the time was noted in the participants record. Cumulative number of participants with onset of FPR confirmed after dose 2 and was recorded from 0.25 hour till 24 hours after administration of dose 2.
Time frame: 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24 hours
Population: Efficacy Analysis Population: Included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A/ Placebo Group | Cumulative Number of Participants With Onset of First Perceptible Relief (FPR) Confirmed at 24 Hours After Dose 2 | 12 Participants |
| Group B/ APAP Group | Cumulative Number of Participants With Onset of First Perceptible Relief (FPR) Confirmed at 24 Hours After Dose 2 | 23 Participants |
| Group C/ PGB Group | Cumulative Number of Participants With Onset of First Perceptible Relief (FPR) Confirmed at 24 Hours After Dose 2 | 17 Participants |
| Group D/ Combination Co-dosing Group | Cumulative Number of Participants With Onset of First Perceptible Relief (FPR) Confirmed at 24 Hours After Dose 2 | 22 Participants |
| Group E/ Combination Split-dosing Group | Cumulative Number of Participants With Onset of First Perceptible Relief (FPR) Confirmed at 24 Hours After Dose 2 | 10 Participants |
Secondary
Cumulative Number of Participants With Onset of Meaning Pain Relief (MPR) Confirmed at 24 Hours After Dose 2
Beginning post-surgery (at initiation of Dose 2), participants were given a stopwatch and asked to press the stopwatch if and when they feel first perceptible relief; a record of the time was noted in the participants record. Cumulative number of participants with onset of MPR confirmed after dose 2 and was recorded from 0.25 hour till 24 hours after administration of dose 2.
Time frame: 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24 hours
Population: Efficacy Analysis Population: Included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A/ Placebo Group | Cumulative Number of Participants With Onset of Meaning Pain Relief (MPR) Confirmed at 24 Hours After Dose 2 | 3 Participants |
| Group B/ APAP Group | Cumulative Number of Participants With Onset of Meaning Pain Relief (MPR) Confirmed at 24 Hours After Dose 2 | 20 Participants |
| Group C/ PGB Group | Cumulative Number of Participants With Onset of Meaning Pain Relief (MPR) Confirmed at 24 Hours After Dose 2 | 11 Participants |
| Group D/ Combination Co-dosing Group | Cumulative Number of Participants With Onset of Meaning Pain Relief (MPR) Confirmed at 24 Hours After Dose 2 | 17 Participants |
| Group E/ Combination Split-dosing Group | Cumulative Number of Participants With Onset of Meaning Pain Relief (MPR) Confirmed at 24 Hours After Dose 2 | 10 Participants |
Secondary
Number of Participants With Differing Patient Global Evaluation Scores
Patient global evaluation was self-reported at time of first rescue or at 12.25 hours post-surgery, whichever was first, using a 0-4 categorical rating scale of: (0) poor, (1) fair, (2) good, (3) very good, and (4) excellent. The number of participants with differing patient global evaluation scores were reported.
Time frame: Upto 12.25 hours
Population: Efficacy Analysis Population: Included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A/ Placebo Group | Number of Participants With Differing Patient Global Evaluation Scores | (4) Excellent | 0 Participants |
| Group A/ Placebo Group | Number of Participants With Differing Patient Global Evaluation Scores | (1) Fair | 3 Participants |
| Group A/ Placebo Group | Number of Participants With Differing Patient Global Evaluation Scores | (2) Good | 1 Participants |
| Group A/ Placebo Group | Number of Participants With Differing Patient Global Evaluation Scores | (0) Poor | 13 Participants |
| Group A/ Placebo Group | Number of Participants With Differing Patient Global Evaluation Scores | (3) Very good | 2 Participants |
| Group B/ APAP Group | Number of Participants With Differing Patient Global Evaluation Scores | (1) Fair | 2 Participants |
| Group B/ APAP Group | Number of Participants With Differing Patient Global Evaluation Scores | (2) Good | 7 Participants |
| Group B/ APAP Group | Number of Participants With Differing Patient Global Evaluation Scores | (4) Excellent | 5 Participants |
| Group B/ APAP Group | Number of Participants With Differing Patient Global Evaluation Scores | (0) Poor | 1 Participants |
| Group B/ APAP Group | Number of Participants With Differing Patient Global Evaluation Scores | (3) Very good | 8 Participants |
| Group C/ PGB Group | Number of Participants With Differing Patient Global Evaluation Scores | (0) Poor | 8 Participants |
| Group C/ PGB Group | Number of Participants With Differing Patient Global Evaluation Scores | (1) Fair | 2 Participants |
| Group C/ PGB Group | Number of Participants With Differing Patient Global Evaluation Scores | (3) Very good | 6 Participants |
| Group C/ PGB Group | Number of Participants With Differing Patient Global Evaluation Scores | (2) Good | 4 Participants |
| Group C/ PGB Group | Number of Participants With Differing Patient Global Evaluation Scores | (4) Excellent | 1 Participants |
| Group D/ Combination Co-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (2) Good | 4 Participants |
| Group D/ Combination Co-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (1) Fair | 3 Participants |
| Group D/ Combination Co-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (0) Poor | 0 Participants |
| Group D/ Combination Co-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (4) Excellent | 5 Participants |
| Group D/ Combination Co-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (3) Very good | 10 Participants |
| Group E/ Combination Split-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (4) Excellent | 2 Participants |
| Group E/ Combination Split-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (1) Fair | 1 Participants |
| Group E/ Combination Split-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (2) Good | 1 Participants |
| Group E/ Combination Split-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (3) Very good | 6 Participants |
| Group E/ Combination Split-dosing Group | Number of Participants With Differing Patient Global Evaluation Scores | (0) Poor | 0 Participants |