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To assess the safety, tolerability, analgesic, efficacy and pharmacokinetics of high dose acetaminophen relative to placebo and low dose acetaminophen relative to placebo over a 24 hour period in patient experiencing moderate to severe pain following the surgical removal of third molar.
This will be a randomized, double-blind, single-site, placebo-controlled, parallel-group study to assess similarities in safety, tolerability, efficacy, and pharmacokinetics of high dose acetaminophen given relative to placebo, and low dose acetaminophen given relative to placebo over a 24-hour period in patients experiencing moderate to severe postsurgical pain within 7 hours following surgical removal of 2 or more molars
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High Dose Acetaminophen | Active Comparator | High Dose Acetaminophen Post Op |
|
| Low Dose Acetaminophen | Active Comparator | Low Dose Acetaminophen Post Op |
|
| Placebo | Placebo Comparator | Placebo Post Op |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetaminophen | Drug | Acetaminophen is an analgesic and antipyretic |
|
| Measure | Description | Time Frame |
|---|---|---|
| Sum of Pain Intensity Difference From 0 to 24 Hours (SPID24) Based on the 11 Point Numeric Pain Rating Scale | 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 = worst imaginable pain). Time weighted sum of pain intensity difference from 0 to 24 hours was reported. Pain Intensity (PI-NPRS) was collected at initiation of Dose 1 (T0) and post dose 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min). SPID24 was include all nominal timepoints from T0 to T24.25 hours. SPID is calculated as Σ[T(i) -T(i-1)] x [(PID(i-1) + PID(i))/2], where T(0)=0, T(i) is the scheduled time, and PID(i) is the pain intensity difference (PID) score at time i. Pain intensity differences were calculated with respect to Baseline. A baseline assessment is defined as the last non-missing result prior to administration of the first dose of study medication. | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours |
| Sum of Pain Relief From 0 to 24 Hours (TOTPAR24) Based on a 5-point Likert Scale. | Pain Relief Rating (PR) was scored on a 5-point scale (0=no-, 1=a little-, 2=some-, 3=a lot of-, and 4=complete- PR). PR was collected at initiation of Dose 1 (T0) and post dose 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours. TOTPAR24 is calculated as Sum ([T(i) - T(i-1)] x (PR(i-1) + PR(i)) / 2), where T(0)=0, T(i) is the actual time, and PR(i) is the pain relief score at time i. and calculated as Σ[T(i) -T(i-1)] x [(PR(i-1) + PR(i))/2], where T(0)=0, T(i) is the scheduled time, and PR(i) is the pain relief (PR) score at time i. | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Perceptible Pain Relief Confirmed (FPR-C) After Dose 1 Administration Stratified by Baseline Pain Score of Moderate or Severe for the 3 Treatment Groups | Upon initiation of the infusion of Dose 1, the participants were given stopwatch #1 and asked to press the stopwatch when they first perceived any pain relief (first perceptible pain relief [FPR]) ; a record of the time was noted in the participant record. If a participant does not record perceptible pain relief and prematurely discontinued from the study prior to 24 hours, then the participant was censored at time of drop out. If a participant does not record perceptible pain relief prior to taking rescue medication, the participant was censored at 24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Change From Baseline to 24 Hours in Vital Signs (Systolic Blood Pressure) | Change from Baseline in systolic blood pressure is the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Systolic blood pressure is obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min). |
Inclusion Criteria:
Patients must be capable of reading, comprehending, and signing the informed consent/assent form;
Male and female patients between 17-55 years of age;
Body Mass Index (BMI) ≤35.0 kg/m2
Body weight of >50 kg
Patients are American Society of Anaesthesiologists (ASA) Category I or II and are in good physical health as judged by a thorough history and physical examination;
Patients without infections in the area of the impacted teeth;
Patients must agree to refrain from ingesting any systemic or applying any topical analgesic medication for 3 days or 5 half-lives of the drug prior to and during the study;
No alcohol for a minimum of 24 hours prior to the surgery;
Female patients must be of non-child bearing potential, defined as postmenopausal for more than 1 year or surgically sterile (hysterectomy, tubal ligation/occlusion) or practicing an acceptable method of contraception (hormonal oral, patch, or implant, double barrier method, intrauterine device, vasectomized or same sex partner, or abstinence). Patients using hormonal birth control must have been on a stable dose of treatment for at least 30 days and received at least 1 cycle of treatment prior to randomization. At Screening and at the day of surgery, all females of childbearing potential must have a negative (serum at screening and urine on day of surgery 1) pregnancy test and not be breastfeeding;
Patients must have a negative urine drug screen for drugs of abuse at Screening and on the day of surgery. At the discretion of the Principal Investigator, a positive drug screen result may be permitted if the patient has been on a stable dose of an allowed medication for >30 days;
Patients who are scheduled to undergo the surgical removal of up to 4 third molars of which at least two have to be mandibular molars with a difficulty rating of 4 or 5 and meeting the following criteria:
Patients able to comprehend and follow the requirements of the study (including availability on scheduled visit dates) based upon the research site's judgment.
Exclusion Criteria:
Patients with a history of any significant medical condition that, in the opinion of the Principal Investigator or his designee, would place the patient at increased risk such as: hepatic, renal, endocrine, cardiac, neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic disorders, including glaucoma, diabetes, emphysema, and chronic bronchitis;
Patients with a history of any type of malignancy within the past 5 years other than minor skin related cancers;
Patients with a history of alcohol or substance abuse in the past three years according to Diagnostic and Statistical Manual (DSM) V and who do not satisfy Inclusion Criteria 10 (including a positive urine drug screen test);
Patients with a known allergy or hypersensitivity to any local anesthetic drug, acetaminophen, ibuprofen, or other NSAIDS;
Patients who are taking any concomitant medications that might confound assessments of pain relief, such as psychotropic drugs, antidepressants, sedative hypnotics or any analgesics taken within three days or five times of their elimination half-lives, whichever is longer. Selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs) are permitted if the patient has been on a stable dose for at least 30 days prior to screening;
Patients who have smoked or chewed tobacco-containing substances within 48 hours prior to the day of surgery;
Patients judged by the Principal Investigator to be unable or unwilling to comply with the requirements of the protocol;
Patients who have used an investigational drug within 30 days prior to the screening day or have previously participated in any Nevakar trial;
Patients who have donated blood within 3 months prior to the screening day;
Patients who are employees or relatives of employees of JBR Clinical Research or Nevakar, Inc.
Patients with liver function tests (ALT, AST) that are above the normal reference range.
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| Name | Affiliation | Role |
|---|---|---|
| Eric Lang, MD | Nevakar, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| JBR | Salt Lake City | Utah | 84107 | United States |
A total of 226 participants were screened from Day-30 to Day 0 before getting randomized
Participants were recruited from April 2019 till July 2019 from the site
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| ID | Title | Description |
|---|---|---|
| FG000 | High Dose APAP | Acetaminophen (APAP) administered post-operatively at a high dose |
| FG001 | Low Dose APAP | Acetaminophen (APAP) administered post-operatively at a low dose |
| FG002 | Placebo | Placebo given post-operatively |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Baseline analysis population was the Safety Population that included all randomized participants who received the study medication.
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| ID | Title | Description |
|---|---|---|
| BG000 | High Dose APAP | Acetaminophen (APAP) administered post-operatively at a high dose |
| BG001 | Low Dose APAP | Acetaminophen (APAP) administered post-operatively at a low dose |
| 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 of Pain Intensity Difference From 0 to 24 Hours (SPID24) Based on the 11 Point Numeric Pain Rating Scale | 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 = worst imaginable pain). Time weighted sum of pain intensity difference from 0 to 24 hours was reported. Pain Intensity (PI-NPRS) was collected at initiation of Dose 1 (T0) and post dose 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min). SPID24 was include all nominal timepoints from T0 to T24.25 hours. SPID is calculated as Σ[T(i) -T(i-1)] x [(PID(i-1) + PID(i))/2], where T(0)=0, T(i) is the scheduled time, and PID(i) is the pain intensity difference (PID) score at time i. Pain intensity differences were calculated with respect to Baseline. A baseline assessment is defined as the last non-missing result prior to administration of the first dose of study medication. | The Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours |
Up to 7 days (± 2 days)
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 | High Dose APAP | Acetaminophen (APAP) administered post-operatively at a high dose |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Tachycardia | Cardiac disorders | MedDRA Version 22.0 | 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 | Aug 9, 2019 | Jan 11, 2022 | Prot_SAP_002.pdf |
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| ID | Term |
|---|---|
| D010149 | Pain, Postoperative |
| D014098 | Toothache |
| ID | Term |
|---|---|
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010146 | Pain |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
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High Dose Acetaminophen (APAP) versus Placebo, Low Dose APAP versus Placebo
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Double Blind, Placebo controlled
| Placebo | Other | Saline |
|
| 0 to 24 Hours |
| Time to Meaningful Perceptible Relief (MPR) Measure Stratified by Baseline Pain Score of Moderate or Severe for the 3 Treatment Groups | Upon initiation of the infusion of Dose 1, the participants were given a second stopwatch and asked to press the stopwatch if and when they feel any meaningful perceptible relief; a record of the time was noted in the participant record. If a participant does not record perceptible pain relief and was prematurely discontinued from the study prior to 24 hours, then the participant was censored at time of drop out. If a participant does not record perceptible pain relief prior to taking rescue medication, the participant was censored at 24 hours. | 0 to 24 Hours |
| Patient Global Evaluation of the Study Medication | Patients Global Evaluation was assessed on a scale of 0 (Poor), 1 (Fair), 2 (Good), 3 (Very Good) and 4 (Excellent) at 24.25 hours post-dose 1 or at participant withdrawal (if applicable), whichever occurred first. Least squares mean of the score are reported. | 0 to 24 Hours |
| Pain Intensity Difference Rating (PID) at Different Timepoints After Dose 1 Administration | 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 = worst imaginable pain). Pain intensity differences were calculated with respect to Baseline at each time point after Dose 1 administration. A baseline assessment was defined as the last non-missing result prior to administration of the first dose of study medication | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 hours (± 10 min) |
| Pain Intensity Rating at Different Timepoints After Dose 1 Administration | Pain intensity is reported using the 11-point Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = worst imaginable pain). | 0 to 24 hours |
| Pain Relief (PR) Ratings at Each Observation Time After Dose 1 Administration | Pain Relief is reported on a 5-Point Categorical Pain Relief Assessment scale: 0 = No Pain Relief, 1 = A Little Pain Relief, 2 = Some Pain Relief, 3 = A Lot of Pain Relief, 4 = Complete Pain Relief. | 0 to 24 hours |
| Time to Treatment Failure | Time to treatment failure is defined as time to first dose of rescue medication after Dose 1 or withdrawal from the study for any reason. If a participant does not take rescue medication or withdraw from the study prior to 24 hours, the participant was censored at 24 hours | 0 to 24 Hours |
| 0 to 24 hours |
| Mean Change From Baseline to 24 Hours in Vital Signs (Diastolic Blood Pressure) | Change from Baseline in diastolic blood pressure is the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Diastolic blood pressure is obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min) | 0 to 24 hours |
| Mean Change From Baseline to 24 Hours in Vital Signs (Temperature) | Change from Baseline in temperature is the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Temperature is obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min) | 0 to 24 hours |
| Mean Change From Baseline to 24 Hours in Vital Signs (Pulse Rate) | Change from Baseline in pulse rate is the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Pulse rate is obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min) | 0 to 24 hours |
| Mean Change From Baseline to 24 Hours in Vital Signs (Respiratory Rate) | Change from Baseline in respiratory rate was the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Respiratory rate was obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min) | 0 to 24 hours |
| Area Under the Plasma Concentration-Time Curve From Time of Administration to 24 Hours After Dosing (AUC 0-24h) | The Area Under the Plasma Concentration-Time Curve (AUC) is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption. The values for pharmacokinetic (PK) evaluable population-excluding participants with positive pre-dose concentrations have been populated. The samples were collected at 5 min prior to Dose 1, and at 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose 1. | Pre-dose, and 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) | The AUC(0-infinity) is area under the plasma concentration-time curve from time zero to infinite time. The samples were collected at 5 min prior to Dose 1, and at 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose 1. | Pre-dose, and 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose |
| Half-life | The half-life (t 1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. | Pre-dose, and 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose |
| Maximum Observed Plasma Concentration (Cmax) | The Plasma Concentration (Cmax) is defined as maximum observed concentration | Pre-dose, and 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose |
| BG002 | Placebo | Placebo given post-operatively |
| BG003 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
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| Categorical pain intensity score | Count of Participants | Participants |
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| NRS pain intensity | Count of Participants | Participants |
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| Primary | Sum of Pain Relief From 0 to 24 Hours (TOTPAR24) Based on a 5-point Likert Scale. | Pain Relief Rating (PR) was scored on a 5-point scale (0=no-, 1=a little-, 2=some-, 3=a lot of-, and 4=complete- PR). PR was collected at initiation of Dose 1 (T0) and post dose 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours. TOTPAR24 is calculated as Sum ([T(i) - T(i-1)] x (PR(i-1) + PR(i)) / 2), where T(0)=0, T(i) is the actual time, and PR(i) is the pain relief score at time i. and calculated as Σ[T(i) -T(i-1)] x [(PR(i-1) + PR(i))/2], where T(0)=0, T(i) is the scheduled time, and PR(i) is the pain relief (PR) score at time i. | The Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Mean | Standard Error | score on a scale | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours |
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|
|
| Secondary | Time to Perceptible Pain Relief Confirmed (FPR-C) After Dose 1 Administration Stratified by Baseline Pain Score of Moderate or Severe for the 3 Treatment Groups | Upon initiation of the infusion of Dose 1, the participants were given stopwatch #1 and asked to press the stopwatch when they first perceived any pain relief (first perceptible pain relief [FPR]) ; a record of the time was noted in the participant record. If a participant does not record perceptible pain relief and prematurely discontinued from the study prior to 24 hours, then the participant was censored at time of drop out. If a participant does not record perceptible pain relief prior to taking rescue medication, the participant was censored at 24 hours | The Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Median | Full Range | hours | 0 to 24 Hours |
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|
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| Secondary | Time to Meaningful Perceptible Relief (MPR) Measure Stratified by Baseline Pain Score of Moderate or Severe for the 3 Treatment Groups | Upon initiation of the infusion of Dose 1, the participants were given a second stopwatch and asked to press the stopwatch if and when they feel any meaningful perceptible relief; a record of the time was noted in the participant record. If a participant does not record perceptible pain relief and was prematurely discontinued from the study prior to 24 hours, then the participant was censored at time of drop out. If a participant does not record perceptible pain relief prior to taking rescue medication, the participant was censored at 24 hours. | The Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Median | Full Range | hours | 0 to 24 Hours |
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| Secondary | Patient Global Evaluation of the Study Medication | Patients Global Evaluation was assessed on a scale of 0 (Poor), 1 (Fair), 2 (Good), 3 (Very Good) and 4 (Excellent) at 24.25 hours post-dose 1 or at participant withdrawal (if applicable), whichever occurred first. Least squares mean of the score are reported. | The Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Least Squares Mean | Standard Error | score on a scale | 0 to 24 Hours |
|
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| Secondary | Pain Intensity Difference Rating (PID) at Different Timepoints After Dose 1 Administration | 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 = worst imaginable pain). Pain intensity differences were calculated with respect to Baseline at each time point after Dose 1 administration. A baseline assessment was defined as the last non-missing result prior to administration of the first dose of study medication | The Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Mean | Standard Deviation | score on a scale | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 hours (± 10 min) |
|
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| Secondary | Pain Intensity Rating at Different Timepoints After Dose 1 Administration | Pain intensity is reported using the 11-point Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = worst imaginable pain). | The Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Mean | Standard Deviation | score on a scale | 0 to 24 hours |
|
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| Secondary | Pain Relief (PR) Ratings at Each Observation Time After Dose 1 Administration | Pain Relief is reported on a 5-Point Categorical Pain Relief Assessment scale: 0 = No Pain Relief, 1 = A Little Pain Relief, 2 = Some Pain Relief, 3 = A Lot of Pain Relief, 4 = Complete Pain Relief. | The Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Mean | Standard Deviation | score on a scale | 0 to 24 hours |
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| Secondary | Time to Treatment Failure | Time to treatment failure is defined as time to first dose of rescue medication after Dose 1 or withdrawal from the study for any reason. If a participant does not take rescue medication or withdraw from the study prior to 24 hours, the participant was censored at 24 hours | The Evaluable Population included all randomized participant who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1. | Posted | Median | Full Range | hours | 0 to 24 Hours |
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| Other Pre-specified | Mean Change From Baseline to 24 Hours in Vital Signs (Systolic Blood Pressure) | Change from Baseline in systolic blood pressure is the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Systolic blood pressure is obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min). | The Safety Population included all randomized participants who received the study medication. This population was used for all safety summaries. | Posted | Mean | Standard Deviation | mm Hg | 0 to 24 hours |
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| Other Pre-specified | Mean Change From Baseline to 24 Hours in Vital Signs (Diastolic Blood Pressure) | Change from Baseline in diastolic blood pressure is the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Diastolic blood pressure is obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min) | The Safety Population included all randomized participants who received the study medication. This population was used for all safety summaries. | Posted | Mean | Standard Deviation | mm Hg | 0 to 24 hours |
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| Other Pre-specified | Mean Change From Baseline to 24 Hours in Vital Signs (Temperature) | Change from Baseline in temperature is the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Temperature is obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min) | The Safety Population included all randomized participants who received the study medication. This population was used for all safety summaries. | Posted | Mean | Standard Deviation | degrees Celsius | 0 to 24 hours |
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| Other Pre-specified | Mean Change From Baseline to 24 Hours in Vital Signs (Pulse Rate) | Change from Baseline in pulse rate is the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Pulse rate is obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min) | The Safety Population included all randomized participants who received the study medication. This population was used for all safety summaries. | Posted | Mean | Standard Deviation | beats/minute | 0 to 24 hours |
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| Other Pre-specified | Mean Change From Baseline to 24 Hours in Vital Signs (Respiratory Rate) | Change from Baseline in respiratory rate was the value at 24 hours minus value at Baseline. Baseline was defined as the last non-missing result prior to administration of the first dose of study drug. Respiratory rate was obtained at screening, prior to surgery and at Hours 4, 8, 12, 16, 20 and 24 following initiation of dose (±10 min) | The Safety Population included all randomized participants who received the study medication. This population was used for all safety summaries. | Posted | Mean | Standard Deviation | breaths/minute | 0 to 24 hours |
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| Other Pre-specified | Area Under the Plasma Concentration-Time Curve From Time of Administration to 24 Hours After Dosing (AUC 0-24h) | The Area Under the Plasma Concentration-Time Curve (AUC) is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption. The values for pharmacokinetic (PK) evaluable population-excluding participants with positive pre-dose concentrations have been populated. The samples were collected at 5 min prior to Dose 1, and at 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose 1. | The PK Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate PK parameters. | Posted | Least Squares Mean | Standard Error | microgram*hour/milliliter | Pre-dose, and 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose |
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| Other Pre-specified | Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) | The AUC(0-infinity) is area under the plasma concentration-time curve from time zero to infinite time. The samples were collected at 5 min prior to Dose 1, and at 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose 1. | The PK Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate PK parameters | Posted | Geometric Mean | Geometric Coefficient of Variation | hour*nanogram per milliliter | Pre-dose, and 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose |
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| Other Pre-specified | Half-life | The half-life (t 1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. | The PK Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate PK parameters | Posted | Mean | Standard Deviation | hours | Pre-dose, and 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose |
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| Other Pre-specified | Maximum Observed Plasma Concentration (Cmax) | The Plasma Concentration (Cmax) is defined as maximum observed concentration | The PK Evaluable Population included all randomized participants who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate PK parameters | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram per milliliter (ng/ml) | Pre-dose, and 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, 6.25, 8.0, 8.25, 8.25, 12.0, 12.25, 16.0, 16.25, 18.0, 18.25, 24.25 hours post-dose |
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|
| 0 |
| 44 |
| 0 |
| 44 |
| 9 |
| 44 |
| EG001 | Low Dose APAP | Acetaminophen (APAP) administered post-operatively at a low dose | 0 | 44 | 0 | 44 | 13 | 44 |
| EG002 | Placebo | Placebo given post-operatively | 0 | 22 | 0 | 22 | 7 | 22 |
| Hypoaesthesia oral | Gastrointestinal disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Infusion site extravasation | General disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Infusion site haematoma | General disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Postoperative wound infection | Infections and infestations | MedDRA Version 22.0 | Systematic Assessment |
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| Arthropod bite | Injury, poisoning and procedural complications | MedDRA Version 22.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA Version 22.0 | Systematic Assessment |
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| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA Version 22.0 | Systematic Assessment |
|
Not provided
Not provided
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D014076 | Tooth Diseases |
| D009057 | Stomatognathic Diseases |
| D005157 | Facial Pain |
| Aniline Compounds |
| D000588 | Amines |
| ANCOVA |
| 0.0120 |
| LS Mean Difference |
| 12.14 |
| Standard Error of the Mean |
| 5.297 |
| 1-Sided |
| 90 |
| 5.31 |
TOTPAR24 was analyzed using an ANCOVA model with treatment group as a fixed effect and baseline PI-NPRS as a covariate. The upper limit of one-sided 90% CI was +∞ |
| Superiority |
| Median time to FPR-C (hours)- for severe baseline categorical pain intensity score |
|
|
| Median time to MPR (hours)- for severe baseline categorical pain intensity score |
|
|
|
| 1 |
|
| 1.25 |
|
| 1.75 |
|
| 2.25 |
|
| 3.25 |
|
| 4.25 |
|
| 5.25 |
|
| 6.25 |
|
| 7.25 |
|
| 8.25 |
|
| 9.25 |
|
| 10.25 |
|
| 11.25 |
|
| 12.25 |
|
| 14.25 |
|
| 16.25 |
|
| 18.25 |
|
| 20.25 |
|
| 22.25 |
|
| 24.25 |
|
|
| 1 |
|
| 1.25 |
|
| 1.75 |
|
| 2.25 |
|
| 3.25 |
|
| 4.25 |
|
| 5.25 |
|
| 6.25 |
|
| 7.25 |
|
| 8.25 |
|
| 9.25 |
|
| 10.25 |
|
| 11.25 |
|
| 12.25 |
|
| 14.25 |
|
| 16.25 |
|
| 18.25 |
|
| 20.25 |
|
| 22.25 |
|
| 24.25 |
|
|
| 1 |
|
| 1.25 |
|
| 1.75 |
|
| 2.25 |
|
| 3.25 |
|
| 4.25 |
|
| 5.25 |
|
| 6.25 |
|
| 7.25 |
|
| 8.25 |
|
| 9.25 |
|
| 10.25 |
|
| 11.25 |
|
| 12.25 |
|
| 14.25 |
|
| 16.25 |
|
| 18.25 |
|
| 20.25 |
|
| 22.25 |
|
| 24.25 |
|
| Median time to treatment failure for severe baseline categorical pain intensity score |
|
|