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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A | Experimental | Pre-op Placebo 1; Post-op Placebo 1; Post-op Placebo 2 |
|
| Group B | Experimental | Pre-op Placebo 1; Post-op Placebo 2; Post-op acetaminophen. |
|
| Group C | Experimental | Pre-op Placebo 1; Post-op pregabalin; Post-op Placebo 2. |
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| Group D | Experimental | Pre-op Placebo 1; Post-op pregabalin Post-op acetaminophen. |
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| Group E | Experimental | Pre-op pregabalin; Post-op Placebo 1; Post-op acetaminophen. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pre-Op pregabalin | Drug | Pre-op pregabalin will be administered 60 min prior to surgery. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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) |
| 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. | 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Upto 12.25 hours |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kenneth Somberg, MD | Nevakar, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Jean Brown Research | Salt Lake City | Utah | 84124 | United States |
Participants were screened from Day-30 to Day 0 before getting randomized
Participants were recruited from June 2018 till September 2018 from the site
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| ID | Title | Description |
|---|---|---|
| FG000 | Group A/ Placebo Group | Participants received matching placebo capsule orally 60 ± 10 minutes (min) prior to initiating the surgical procedure. Post-surgically the participants received matching placebo capsule orally and matching placebo (saline 100mL) intravenously (IV). The IV infusion was administered over a 15 min period and the capsule was administered immediately prior to the initiation of the IV infusion |
| FG001 | Group B/ Acetaminophen (APAP) 1000 mg IV Group | Participants received matching placebo capsule orally 60 ± 10 mins prior to initiating the surgical procedure. Post-surgically the participants received matching placebo capsule orally and APAP 1000 milligram (mg) IV. The IV infusion was administered over a 15 min period and the capsule was administered immediately prior to the initiation of the IV infusion. |
| FG002 | Group C/ Pregabalin (PGB) 300 mg Capsule Group | Participants received matching placebo capsule orally 60 ± 10 mins prior to initiating the surgical procedure. Post-surgically the participants received PGB 300 mg capsule orally and matching placebo (saline 100mL) IV. The IV infusion was administered over a 15 min period and the capsule was administered immediately prior to the initiation of the IV infusion. |
| FG003 | Group D/ Combination Co-dosing Group (Post-surgery PGB +APAP) | Participants received matching placebo capsule orally 60 ± 10 mins prior to initiating the surgical procedure. Post-surgically the participants received PGB 300 mg capsule orally and APAP 100 mg IV. The IV infusion was administered over a 15 min period and the capsule was administered immediately prior to the initiation of the IV infusion. |
| FG004 | Group E/ Combination Split-dosing Group (PGB Pre-surgery + APAP Post-surgery) | Participants received PGB 300 mg capsule orally 60 ± 10 mins prior to initiating the surgical procedure. Post-surgically the participants received matching placebo capsule orally and APAP 1000 mg IV. The IV infusion was administered over a 15 min period and the capsule was administered immediately prior to the initiation of the IV infusion |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Baseline analysis population was randomized population, that included all randomized participants
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| ID | Title | Description |
|---|---|---|
| BG000 | Group A/ Placebo Group | Pre-surgery placebo and post-surgery placebo 1 and placebo 2 |
| BG001 | Group B/ APAP Group | Pre-surgery placebo 1 and post-surgery placebo 1 and acetaminophen (APAP) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Efficacy Analysis Population included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations | Posted | Least Squares Mean | Standard Error | score on a scale | 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) |
|
Up to Day 15 (± 1 day)
An adverse event (AE) is defined as any untoward medical occurrence and does not necessarily have to have causal relationship with the study medication. An AE can therefore be an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease, which is a change from baseline and is temporally associated with the use of the study medication, whether or not it is considered related to the study medication.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group A/ Placebo Group | Pre-surgery placebo and post-surgery placebo 1 and placebo 2 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vision blurred | Eye disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eric Lang, MD | Nevakar, Inc. | (908) 367-7400 | Clinicaltrials@nevakar.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 10, 2018 | Aug 28, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D014098 | Toothache |
| ID | Term |
|---|---|
| D014076 | Tooth Diseases |
| D009057 | Stomatognathic Diseases |
| D005157 | Facial Pain |
| D010146 | Pain |
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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.
| Pre-Op Placebo 1 |
| Drug |
Placebo 1 will be administered 60 min prior to surgery. |
|
|
| Post-Op pregabalin | Drug | Post-op pregabalin will be administered Post-operatively. |
|
| Post-Op Placebo 1 | Drug | Placebo 1 will be administered post-operatively. |
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| Post-Op Placebo 2 | Drug | Placebo 2 will be administered post-operatively. |
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| Post-Op acetaminophen | Drug | Acetaminophen will be administered Post-operatively. |
|
| 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. | 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24 hours |
| 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. | 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24 hours |
| Physician Decision |
|
| Lost to Follow-up |
|
| BG002 | Group C/ PGB Group | Pre-surgery placebo 1 and post-surgery placebo 2 and pregabalin (PGB) |
| BG003 | Group D/ Combination Co-dosing Group | Pre-surgery placebo 1 and post-surgery APAP and PGB |
| BG004 | Group E/ Combination Split-dosing Group | Pre-surgery PGB and post-surgery placebo 1 and APAP |
| BG005 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
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| Number of Participants With Mandibular Molar - 17 | One participant from Placebo group (Group A) was withdrawn by physician prior to surgery due to emesis hence Baseline (Day 1) oral examinations was not conducted for this participant. | Count of Participants | Participants |
|
| Number of Participants With Mandibular Molar - 32 | One participant from Placebo group (Group A) was withdrawn by physician prior to surgery due to emesis hence Baseline (Day 1) oral examinations was not conducted for this participant. | Count of Participants | Participants |
|
| Number of Participants With Maxillary Molar -1 | One participant from Placebo group (Group A) was withdrawn by physician prior to surgery due to emesis hence Baseline (Day 1) oral examinations was not conducted for this participant. | Count of Participants | Participants |
|
| Number of Participants With Maxillary Molar -16 | One participant from Placebo group (Group A) was withdrawn by physician prior to surgery due to emesis hence Baseline (Day 1) oral examinations was not conducted for this participant. | Count of Participants | Participants |
|
| OG001 | Group B/ APAP Group | Pre-surgery placebo 1 and post-surgery placebo 1 and acetaminophen (APAP) |
| OG002 | Group C/ PGB Group | Pre-surgery placebo 1 and post-surgery placebo 2 and pregabalin (PGB) |
| OG003 | Group D/ Combination Co-dosing Group | Pre-surgery placebo 1 and post-surgery APAP and PGB |
| OG004 | Group E/ Combination Split-dosing Group | Pre-surgery PGB and post-surgery placebo 1 and APAP |
|
|
|
| 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. | Efficacy Analysis Population: Included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations | Posted | Least Squares Mean | Standard Error | score on a scale | 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) |
|
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| 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. | Efficacy Analysis Population: Included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations | Posted | Count of Participants | Participants | Upto 12.25 hours |
|
|
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| 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. | Efficacy Analysis Population: Included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations | Posted | Count of Participants | Participants | 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24 hours |
|
|
|
| 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. | Efficacy Analysis Population: Included all randomized participants who received study medication post-surgically and did not experience emesis or other major protocol deviations | Posted | Count of Participants | Participants | 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24 hours |
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|
| 0 |
| 24 |
| 0 |
| 24 |
| 2 |
| 24 |
| EG001 | Group B/ APAP Group | Pre-surgery placebo 1 and post-surgery placebo 1 and acetaminophen (APAP) | 0 | 23 | 0 | 23 | 3 | 23 |
| EG002 | Group C/ PGB Group | Pre-surgery placebo 1 and post-surgery placebo 2 and pregabalin (PGB) | 0 | 22 | 0 | 22 | 14 | 22 |
| EG003 | Group D/ Combination Co-dosing Group | Pre-surgery placebo 1 and post-surgery APAP and PGB | 0 | 23 | 0 | 23 | 15 | 23 |
| EG004 | Group E/ Combination Split-dosing Group | Pre-surgery PGB and post-surgery placebo 1 and APAP | 0 | 23 | 0 | 23 | 12 | 23 |
| Nausea | Gastrointestinal disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Retching | Gastrointestinal disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Asthenia | General disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Body temperature increased | Investigations | MedDRA Version 21.0 | Systematic Assessment |
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| Muscle twitching | Musculoskeletal and connective tissue disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Dizziness postural | Nervous system disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Paraesthesia | Nervous system disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Presyncope | Nervous system disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA Version 21.0 | Systematic Assessment |
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| Hypotension | Vascular disorders | MedDRA Version 21.0 | Systematic Assessment |
|
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| D009461 |
| Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Male |
|
| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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Group C vs. Group B |
| LS Mean Difference |
| 6.1658 |
| Standard Error of the Mean |
| 20.3312 |
| 1-Sided |
| 90 |
| -20.0868 |
Statistics are from ANCOVA including treatment and sex as fixed effects with baseline PI score prior to Dose 2 as a covariate. The upper limit was ∞ |
| Superiority |
| Group C vs. Group A | LS Mean Difference | 77.3395 | Standard Error of the Mean | 21.4347 | 1-Sided | 90 | 49.6620 | Statistics are from ANCOVA including treatment and sex as fixed effects with baseline PI score prior to Dose 2 as a covariate. The upper limit was ∞ | Superiority |
| Group B vs. Group A | LS Mean Difference | 71.1737 | Standard Error of the Mean | 21.0123 | 1-Sided | 90 | 44.0417 | Statistics are from ANCOVA including treatment and sex as fixed effects with baseline PI score prior to Dose 2 as a covariate. The upper limit was ∞ | Superiority |
| Group D vs. Group A | LS Mean Difference | 104.8558 | Standard Error of the Mean | 21.2975 | 1-Sided | 90 | 77.3555 | Statistics are from ANCOVA including treatment and sex as fixed effects with baseline PI score prior to Dose 2 as a covariate. The upper limit was ∞ | Superiority |
| Group D vs. Group C | LS Mean Difference | 27.5163 | Standard Error of the Mean | 20.5918 | 1-Sided | 90 | 0.9272 | Statistics are from ANCOVA including treatment and sex as fixed effects with baseline PI score prior to Dose 2 as a covariate. The upper limit was ∞ | Superiority |
| Group E vs. Group D | LS Mean Difference | -30.1223 | Standard Error of the Mean | 26.1776 | 1-Sided | 90 | -63.9240 | Statistics are from ANCOVA including treatment and sex as fixed effects with baseline PI score prior to Dose 2 as a covariate. The upper limit was ∞ | Superiority |
| (1) Fair |
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| (2) Good |
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| (3) Very good |
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| (4) Excellent |
|