Pain, Post-operative
Conditions
Keywords
Bunion, Bunionectomy, Pain, Analgesia, dexmedetomidine, intranasal
Brief summary
The primary objective of this study is to evaluate the analgesic efficacy, on Post-Operative Day (POD) 1, of DEX-IN compared with placebo, using the summed pain intensity difference over the first 48 hours (SPID48) in subjects with acute moderate to severe pain following unilateral bunionectomy.
Interventions
DRUGIntranasal Dexmedetomidine
DRUGIntranasal Placebo
Sponsors
Lotus Clinical Research, LLC
Baudax Bio
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 70 Years
Healthy volunteers
No
Inclusion criteria
* Voluntarily provide written informed consent. * Male or female between 18 and 70 years of age, inclusive. * Be scheduled to undergo a primary unilateral first metatarsal bunionectomy repair * Be American Society of Anesthesiology (ASA) physical class 1 or 2. * Female subject are eligible only if all the following apply: * Not pregnant; * Not lactating; * Not planning to become pregnant during the study; * Be surgically sterile; or at least two year post menopausal; or have a monogamous partner who is surgically sterile; or is practicing double-barrier contraception; or practicing abstinence; or using an insertable, injectable, transdermal, or combination oral contraceptive. * Male subjects must be surgically sterile or commit to the use of a reliable method of birth control * Have a body mass index ≤35 kg/m2 * Be able to understand the study procedures, comply with all study procedures, and agree to participate in the study program.
Exclusion criteria
* Have a known allergy to dexmedetomidine or any excipient in DEX-IN/placebo or to any peri- or postoperative medications used in this study. * Have a clinically significant abnormal clinical laboratory test value. * Have history of or positive test results for HIV, or hepatitis B or C. * Have a history or clinical manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, psychiatric, or other condition that would preclude participation in the study. * Have a history of migraine or frequent headaches, seizures, or are currently taking anticonvulsants. * Have another painful physical condition that may confound the assessments of post operative pain. * Have a history of syncope or other syncopal attacks. * Have evidence of a clinically significant 12 lead ECG abnormality. * Have a history of alcohol abuse (regularly drinks \> 4 units of alcohol per day; 8 oz. beer, 3 oz. wine, 1 oz. spirits) or prescription/illicit drug abuse.. * Have positive results on the urine drug screen or alcohol breath test indicative of illicit drug or alcohol abuse. * Have a history or evidence of orthostatic hypotension. * Have a resting heart rate of \<50 beats per minutes or systolic blood pressure \<100mmHg. * Have been receiving or have received chronic opioid therapy defined as greater than 15 morphine equivalents units per day for greater than 3 out of 7 days per week over a one-month period within 12 months. * Use concurrent therapy that could interfere with the evaluation of efficacy or safety, such as any drugs which in the investigator's opinion may exert significant analgesic properties or act synergistically with DEX-IN. * Unable to discontinue medications, that have not been at a stable dose for at least 14 days prior to the scheduled bunionectomy procedure, within 5 half lives of the specific prior medication (or, if half life is not known, within 48 hours) before dosing. * Have utilized any intranasal medications within the preceding 10 days. * Have signs or a history of significant rhinitis or rhinorrhea (constant or chronic), nasal polyps, mucosal lesions of the nostril, postnasal drip of any etiology (constant or chronic), nasal ulcers, septal perforation or deviation, any nasal surgery, anosmia, nasal piercings, or frequent nosebleeds or other nasal pathology, that is sufficient to interfere with IN drug delivery. * Have had an upper respiratory tract infection within 14 days of screening. * Have utilized corticosteroids, either systemically, inhalational either intranasally or oral, or by intra-articular injection, within 14 days prior to the study. * Have received any investigational product within 30 days before dosing with study medication. * Have previously received DEX-IN in clinical trials, or had bunionectomy in the last 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summed Pain Intensity Difference Over the First 48 Hours (SPID48). | 48 hours | Pain intensity was recorded using a Numeric Pain Rating Scale (Range 0-10) where 0 equates to no pain (better), and 10 equates to the worst pain imaginable (worse). Pain intensity scores were to be recorded at the following time points: 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours post Dose 1. Thereafter pain assessments were to be recorded every 2 hours until 48 hours post Dose 1. Pain intensity differences from baseline were calculated at each time point and a time weighted summed pain intensity difference (SPID) was then calculated. Time weighted SPID calculations were computed by multiplying a weight factor to each score prior to summation. The weight factor at each time point was the time elapsed since the previous observation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SPID at Various Other Time Points | Up to 48 Hours | Pain intensity was recorded using a Numeric Pain Rating Scale (Range 0-10) where 0 equates to no pain (better), and 10 equates to the worst pain imaginable (worse). Pain intensity scores were to be recorded at the following time points: 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours post Dose 1. Thereafter pain assessments were to be recorded every 2 hours until 48 hours post Dose 1. Pain intensity differences from baseline were calculated at each time point and a time weighted summed pain intensity difference (SPID) was then calculated. Time weighted SPID calculations were computed by multiplying a weight factor to each score prior to summation. The weight factor at each time point was the time elapsed since the previous observation. |
| Time to Perceptible and Meaningful Pain Relief | 6 hours | Kaplan-Meier analysis of time to perceptible and meaningful pain relief for 50th percentile of subjects. Time to perceptible pain relief and time to meaningful pain relief were measured using the double-stopwatch method. The first stopwatch was given to each subject with the instructions to stop the watch when they first perceive pain relief to occur (time to perceptible relief). Once the first watch was stopped, the second stopwatch was given to the subject with the instructions to stop the watch when they are first experiencing meaningful pain relief (time to meaningful relief). A shorter time to pain relief is better. |
| Number of Subjects With Significant Pain Improvement Following the First Study Dose. | 6 hours | — |
| Use of Rescue Medication (Oral Opioids) | 48 hours | Number of subjects requiring rescue medication (Oral opioids) within 48 hours after first study dose |
| Time to First Rescue Medication Use | 48 hours | Kaplan Meier analysis of time to first use of rescue analgesia 50th percentile of subjects. Rescue analgesia (oral oxycodone) was available to subjects with inadequately controlled pain. All doses of rescue analgesia administered were recorded and the time from the first study dose to first rescue analgesia in each subject was evaluated. A longer time to first rescue is better. |
| Number of Subjects With Complete Protection From PONV | 24 hours | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DEX-IN 50mcg DEX-IN (Intranasal dexmedetomidine) 50mcg every 6 hours for 48 hours.
Intranasal Dexmedetomidine | 84 |
| IN Placebo IN Placebo every 6 hours for 48 hours.
Intranasal Placebo | 84 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lack of Efficacy | 3 | 3 |
Baseline characteristics
| Characteristic | DEX-IN 50mcg | IN Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 82 Participants | 81 Participants | 163 Participants |
| Age, Continuous | 43.9 years STANDARD_DEVIATION 12.37 | 44.0 years STANDARD_DEVIATION 13.08 | 44.0 years STANDARD_DEVIATION 12.69 |
| Baseline pain intensity score (NPRS) | 6.4 units on a scale STANDARD_DEVIATION 1.42 | 6.7 units on a scale STANDARD_DEVIATION 1.9 | 6.5 units on a scale STANDARD_DEVIATION 1.68 |
| Body Mass Index (BMI) | 26.6 kg/m^2 STANDARD_DEVIATION 4.31 | 27.4 kg/m^2 STANDARD_DEVIATION 4.08 | 27.0 kg/m^2 STANDARD_DEVIATION 4.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants | 39 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 45 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 21 Participants | 41 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 59 Participants | 56 Participants | 115 Participants |
| Region of Enrollment United States | 84 participants | 84 participants | 168 participants |
| Sex: Female, Male Female | 79 Participants | 75 Participants | 154 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 84 | 36 / 84 |
| serious Total, serious adverse events | 1 / 84 | 0 / 84 |
Outcome results
Primary
Summed Pain Intensity Difference Over the First 48 Hours (SPID48).
Pain intensity was recorded using a Numeric Pain Rating Scale (Range 0-10) where 0 equates to no pain (better), and 10 equates to the worst pain imaginable (worse). Pain intensity scores were to be recorded at the following time points: 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours post Dose 1. Thereafter pain assessments were to be recorded every 2 hours until 48 hours post Dose 1. Pain intensity differences from baseline were calculated at each time point and a time weighted summed pain intensity difference (SPID) was then calculated. Time weighted SPID calculations were computed by multiplying a weight factor to each score prior to summation. The weight factor at each time point was the time elapsed since the previous observation.
Time frame: 48 hours
Population: mITT population, including all randomized subjects who received at least one study dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DEX-IN 50mcg | Summed Pain Intensity Difference Over the First 48 Hours (SPID48). | -2328.2 units on a scale | Standard Deviation 5746.724 |
| IN Placebo | Summed Pain Intensity Difference Over the First 48 Hours (SPID48). | -548.90 units on a scale | Standard Deviation 5819.373 |
p-value: 0.018ANCOVA
Secondary
Number of Subjects With Complete Protection From PONV
Time frame: 24 hours
Population: mITT population, including all randomized subjects who received at least one study dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DEX-IN 50mcg | Number of Subjects With Complete Protection From PONV | 72 participants |
| IN Placebo | Number of Subjects With Complete Protection From PONV | 70 participants |
p-value: 0.7718Cochran-Mantel-Haenszel
Secondary
Number of Subjects With Significant Pain Improvement Following the First Study Dose.
Time frame: 6 hours
Population: mITT population, including all randomized subjects who received at least one study dose
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DEX-IN 50mcg | Number of Subjects With Significant Pain Improvement Following the First Study Dose. | ≥30% reduction in pain | 26 participants |
| DEX-IN 50mcg | Number of Subjects With Significant Pain Improvement Following the First Study Dose. | ≥50% reduction in pain | 9 participants |
| IN Placebo | Number of Subjects With Significant Pain Improvement Following the First Study Dose. | ≥30% reduction in pain | 15 participants |
| IN Placebo | Number of Subjects With Significant Pain Improvement Following the First Study Dose. | ≥50% reduction in pain | 2 participants |
p-value: <0.05Cochran-Mantel-Haenszel
Secondary
SPID at Various Other Time Points
Pain intensity was recorded using a Numeric Pain Rating Scale (Range 0-10) where 0 equates to no pain (better), and 10 equates to the worst pain imaginable (worse). Pain intensity scores were to be recorded at the following time points: 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours post Dose 1. Thereafter pain assessments were to be recorded every 2 hours until 48 hours post Dose 1. Pain intensity differences from baseline were calculated at each time point and a time weighted summed pain intensity difference (SPID) was then calculated. Time weighted SPID calculations were computed by multiplying a weight factor to each score prior to summation. The weight factor at each time point was the time elapsed since the previous observation.
Time frame: Up to 48 Hours
Population: mITT population, including all randomized subjects who received at least one study dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DEX-IN 50mcg | SPID at Various Other Time Points | SPID 0-6 | -346.57 units on a scale | Standard Deviation 579.0378 |
| DEX-IN 50mcg | SPID at Various Other Time Points | SPID 0-12 | -568.89 units on a scale | Standard Deviation 1213.41 |
| DEX-IN 50mcg | SPID at Various Other Time Points | SPID 0-24 | -1043.2 units on a scale | Standard Deviation 2553.89 |
| IN Placebo | SPID at Various Other Time Points | SPID 0-6 | -120.46 units on a scale | Standard Deviation 590.7313 |
| IN Placebo | SPID at Various Other Time Points | SPID 0-12 | -151.93 units on a scale | Standard Deviation 1263.656 |
| IN Placebo | SPID at Various Other Time Points | SPID 0-24 | -239.07 units on a scale | Standard Deviation 2717.394 |
p-value: <0.05ANCOVA
Secondary
Time to First Rescue Medication Use
Kaplan Meier analysis of time to first use of rescue analgesia 50th percentile of subjects. Rescue analgesia (oral oxycodone) was available to subjects with inadequately controlled pain. All doses of rescue analgesia administered were recorded and the time from the first study dose to first rescue analgesia in each subject was evaluated. A longer time to first rescue is better.
Time frame: 48 hours
Population: mITT population, including all randomized subjects who received at least one study dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DEX-IN 50mcg | Time to First Rescue Medication Use | 4.94 hours |
| IN Placebo | Time to First Rescue Medication Use | 2.68 hours |
p-value: 0.0009Log Rank
Secondary
Time to Perceptible and Meaningful Pain Relief
Kaplan-Meier analysis of time to perceptible and meaningful pain relief for 50th percentile of subjects. Time to perceptible pain relief and time to meaningful pain relief were measured using the double-stopwatch method. The first stopwatch was given to each subject with the instructions to stop the watch when they first perceive pain relief to occur (time to perceptible relief). Once the first watch was stopped, the second stopwatch was given to the subject with the instructions to stop the watch when they are first experiencing meaningful pain relief (time to meaningful relief). A shorter time to pain relief is better.
Time frame: 6 hours
Population: mITT population, including all randomized subjects who received at least one study dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DEX-IN 50mcg | Time to Perceptible and Meaningful Pain Relief | Time to perceptible pain relief | 18.39 minutes |
| DEX-IN 50mcg | Time to Perceptible and Meaningful Pain Relief | Time to meaningful pain relief | 79.32 minutes |
| IN Placebo | Time to Perceptible and Meaningful Pain Relief | Time to perceptible pain relief | 33.0 minutes |
| IN Placebo | Time to Perceptible and Meaningful Pain Relief | Time to meaningful pain relief | NA minutes |
p-value: <0.05Log Rank
Secondary
Use of Rescue Medication (Oral Opioids)
Number of subjects requiring rescue medication (Oral opioids) within 48 hours after first study dose
Time frame: 48 hours
Population: mITT population, including all randomized subjects who received at least one study dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DEX-IN 50mcg | Use of Rescue Medication (Oral Opioids) | 66 participants |
| IN Placebo | Use of Rescue Medication (Oral Opioids) | 76 participants |