Placebo-Controlled Evaluation of Intranasal Dexmedetomidine for Postoperative Analgesia Following Bunionectomy Surgery

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Evaluation of the Efficacy and Safety of Intranasal Dexmedetomidine for Postoperative Analgesia Following Bunionectomy

Conditions
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Pain, Post-operative

Intervention / Treatment
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* Drug: Intranasal Dexmedetomidine
* Drug: Intranasal Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DEX-IN 50mcg<br>DEX-IN (Intranasal dexmedetomidine) 50mcg every 6 hours for 48 hours. | Drug: Intranasal Dexmedetomidine<br> <br> * Other names: DEX-IN;|
| Placebo Comparator: IN Placebo<br>IN Placebo every 6 hours for 48 hours. | Drug: Intranasal Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 48 Hours | 
| 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. | 6 hours | 
| Number of Subjects With Significant Pain Improvement Following the First Study Dose. |  | 6 hours | 
| Use of Rescue Medication (Oral Opioids) | Number of subjects requiring rescue medication (Oral opioids) within 48 hours after first study dose | 48 hours | 
| 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. | 48 hours | 
| Number of Subjects With Complete Protection From PONV |  | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bunion, Bunionectomy, Pain, Analgesia, dexmedetomidine, intranasal