Experimental Pain Study to Assess Local Anesthetic Efficacy and Safety of CTY-5339 Anesthetic Spray in Normal Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to determine if the topical application to cheek tissue of the combination of benzocaine and tetracaine has a longer duration of local anesthetic activity than benzocaine alone.

Detailed Description
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In a blinded study, either benzocaine alone of the combination of benzocaine and tetracaine will be sprayed onto the cheek mucosal tissue. Onset and duration of local anesthesia will be evaluated over a one hour period using pin prick and QST heat stimulation. Subjects will receive both treatments in a cross-over design with each session separated by 5-7 days. A total of 76 subjects (normal volunteers) will be evaluated.

Official Title
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A Double-blind, Partial Cross-over, Incomplete Factorial Study to Assess the Local Anesthetic Efficacy and Safety of CTY-5339 Anesthetic Spray (CTY-5339-A) When Applied to the Cheek Mucosal Tissue in Normal Volunteers

Conditions
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Anesthesia

Intervention / Treatment
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* Combination Product: One spray CTY-5339-A
* Drug: One spray CTY-5339-CB
* Combination Product: Two sprays CTY-5339-A
* Drug: One spray CTY-5339-CB in combination with one spray CTY-5339-P (vehicle control: placebo)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between 18-75 years of age with a Body Mass Index (BMI) ≤32; Subjects are ASA Category I or II and are in normal physical health as judged by physical and laboratory examinations; Subjects with normal appearance of the oral mucosal tissues; Subjects must agree to refrain from ingesting any systemic or topical analgesic medication for 3 days or 5 half-lives of the drug prior to and during the study period and alcohol for 1 day prior to and during the study period; Subjects must agree to refrain from using mouth rinses, cough drops or throat lozenges on the day of each test session; Female subjects must be physically incapable of childbearing potential (postmenopausal for more than 1 year or surgically sterile) or practicing an acceptable method of contraception (hormonal, barrier with spermicide, intrauterine device, vasectomized or same sex partner, or abstinence). Subjects 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 Baseline of both sessions, all females of childbearing potential must have a negative urine pregnancy test and not be breastfeeding; Negative urine drug screen for drugs of abuse at Screening and at Baseline for each Study Session. A positive drug screen result may be permitted if the subject has been on a stable dose of an allowed medication for >30 days; The subject is capable of reading, comprehending, and signing the informed consent form. Exclusion Criteria: Subjects with a history of any significant hepatic, renal, endocrine, cardiac, neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic disorders, including glaucoma, diabetes, emphysema, and chronic bronchitis; Subjects with a history of any type of cancer other than skin related cancers; Subjects with conditions that affect the absorption, metabolism, or passage of drugs out of the body, (e.g., sprue, celiac disease, Crohn's disease, colitis, or liver, kidney, or thyroid conditions); Subjects with any history of alcohol or substance abuse (including a positive drug screen test); Subjects that currently have or have a history of uncontrolled hypertension; Subjects with a known hypersensitivity to any local anesthetic drug; Subjects with a hematocrit level significantly below the normal range on the screening laboratory examination (as judged by the PI); Subjects with any clinically significant abnormal lab result (as judged by the PI); Subjects with any condition or history felt by the Investigator to place the subject at increased risk; Subjects who have smoked or chewed tobacco-containing substances within 6 months prior to the start of the study; Subjects judged by the Investigator to be unable or unwilling to comply with the requirements of the protocol; Subjects who have used an investigational drug within 30 days prior to entering the study; Subjects who have donated blood within 3 months prior to the start of the study; Subjects who have previously participated in the trial; Subjects who are members of the study site staff directly involved with the study or a relative of the Sponsor or other personnel involved with the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: One spray CTY-5339-A, then one spray CTY-5339-CB<br>A single spray of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) tested over a 60 minute session. | Combination Product: One spray CTY-5339-A<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 28 mg) and 2.0% Tetracaine Hydrochloride (USP = 4 mg). Administered in a single anesthetic spray.<br>* Other names: benzocaine and tetracaine;Drug: One spray CTY-5339-CB<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredient: 14.0% Benzocaine (USP = 28 mg). Administered in a single anesthetic spray.<br>* Other names: 14.0% benzocaine;|
| Experimental: 2 sprays CTY-5339-A, then 1 spray CTY-5339-CB +1 spray placebo<br>Two sprays of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) and a single spray of vehicle control (CTY-5339-P) (sprayed outside the circumscribed area to avoid dilution of active drug) tested over a 60 minute session. | Combination Product: Two sprays CTY-5339-A<br>* Metered spray bottle with ≈400 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 56 mg total) and 2.0% Tetracaine Hydrochloride (USP = 8 mg total). Administered in two anesthetic sprays.<br>* Other names: benzocaine and tetracaine;Drug: One spray CTY-5339-CB in combination with one spray CTY-5339-P (vehicle control: placebo)<br>* A single spray of CTY-5339-CB in a metered spray bottle with ≈200 uL total spray volume, containing the active ingredient: 14.0% Benzocaine (USP = 28 mg). This was administered in combination with a single spray of CTY-5339-P (acting as vehicle control placebo with no active ingredient) in a metered spray bottle with ≈200 uL total spray volume. This combination was used to maintain double-blind conditions. The vehicle control was sprayed outside the circumscribed area to avoid dilution of active drug.<br>* Other names: 14.0% benzocaine and Control;|
| Experimental: One spray of CTY-5339-CB, then one spray CTY-5339-A<br>A single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a single spray of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session. | Combination Product: One spray CTY-5339-A<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 28 mg) and 2.0% Tetracaine Hydrochloride (USP = 4 mg). Administered in a single anesthetic spray.<br>* Other names: benzocaine and tetracaine;Drug: One spray CTY-5339-CB<br>* Metered spray bottle with ≈200 uL total spray volume. Contains the active ingredient: 14.0% Benzocaine (USP = 28 mg). Administered in a single anesthetic spray.<br>* Other names: 14.0% benzocaine;|
| Experimental: 1 spray CTY-5339-CB +1 spray placebo, then 2 sprays CTY-5339-A<br>A single spray of CTY-5339-CB Anesthetic Spray (14.0% benzocaine) and a single spray of vehicle control (CTY-5339-P) (sprayed outside the circumscribed area to avoid dilution of active drug) tested over a 60 minute session, followed by a 4-14 day washout period, followed by a two sprays of CTY-5339-A Anesthetic Spray (14.0% benzocaine and 2.0% tetracaine HCl) tested over a 60 minute session. | Combination Product: Two sprays CTY-5339-A<br>* Metered spray bottle with ≈400 uL total spray volume. Contains the active ingredients: 14.0% Benzocaine (USP = 56 mg total) and 2.0% Tetracaine Hydrochloride (USP = 8 mg total). Administered in two anesthetic sprays.<br>* Other names: benzocaine and tetracaine;Drug: One spray CTY-5339-CB in combination with one spray CTY-5339-P (vehicle control: placebo)<br>* A single spray of CTY-5339-CB in a metered spray bottle with ≈200 uL total spray volume, containing the active ingredient: 14.0% Benzocaine (USP = 28 mg). This was administered in combination with a single spray of CTY-5339-P (acting as vehicle control placebo with no active ingredient) in a metered spray bottle with ≈200 uL total spray volume. This combination was used to maintain double-blind conditions. The vehicle control was sprayed outside the circumscribed area to avoid dilution of active drug.<br>* Other names: 14.0% benzocaine and Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Anesthesia as Measured by Pin Prick Test (PPT) for One Spray CTY-5339-A Compared to One Spray CTY-5339-CB | Evaluations were completed at 1-minute intervals for the first 5 minutes to capture onset of anesthesia. Starting at 5 minutes after drug administration, the PPT was done at 5 minute intervals up to the one hour time point. If there was no indication of anesthesia by 10 minutes, the subject was considered a treatment failure and the assessment of PPT was discontinued. In addition, once onset of anesthesia had occurred, if there was no longer any anesthesia at two consecutive evaluation time points from 10 minutes onward, the assessment of PPT was discontinued. The PPT was assessed using a 90-mm, 26-gauge pencil-point spinal needle. At screening, 3 pin pricks were performed on each cheek. Pin pricks were assessed using a 0 (no pain) to 10 (severe pain) Numerical Rating Scale (NRS). In order to be eligible for the study, for each cheek, subjects must have had a minimum score of 3 for the last 2 pin pricks, and one of those scores had to be 4 or higher. | Change in pain assessment from baseline (time of application) up to one hour post-application | 
| Duration of Anesthesia as Measured by Heat Sensation Threshold (QST Heat) for One Spray CTY-5339-A Compared to One Spray CTY-5339-CB | Starting at 5 minutes after drug administration, the QST was done at 5 minute intervals up to the one hour time point. If there was no indication of anesthesia by 10 minutes, the subject was considered a treatment failure and the assessment of PPT was discontinued. In addition, once onset of anesthesia had occurred, if there was no longer any anesthesia at two consecutive evaluation time points from 10 minutes onward, the assessment of QST was discontinued. The heat stimuli were delivered in 3 repetitions, with inter-stimulus intervals of 30s. The basal thermode temperature was set at a comfortable 35ºC. The rate at which the thermode heated up was set at 0.5ºC/s, while the rate at which it cooled down was set at 8ºC/s. The maximum thermode temperature was set at 51ºC. Heat sensation threshold was defined as the temperature at which the subjects first felt tingling, warmth, heat, or pain. | Change in temperature from baseline (time of application) up to one hour post-application | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Anesthesia as Measured by Pin Prick Test (PPT) for Two Sprays CTY-5339-A Compared to One Spray CTY-5339-CB in Combination With One Spray CTY-5339-P (Placebo) | Assessments will be made over a period of one hour, with assessments at 1 minute intervals for the first 5 minutes and then every 5 minutes after that. Duration of effect was defined as the time (in minutes) from onset to treatment failure (i.e., for PPT, an assessment of Same/More pain, and for QST, the average heat temperature was greater than the average heat temperature at Baseline (non-treated cheek), up to the 60-minute time point (at two consecutive time points). | Time of application up to one hour post-application | 
| Duration of Anesthesia as Measured by QST Heat for Two Sprays CTY-5339-A Compared to One Spray CTY-5339-CB in Combination With One Spray CTY-5339-P (Placebo) | Assessments will be made over a period of one hour, with assessments at 1 minute intervals for the first 5 minutes and then every 5 minutes after that. Duration of effect was defined as the time (in minutes) from onset to treatment failure (i.e., for PPT, an assessment of Same/More pain, and for QST, the average heat temperature was greater than the average heat temperature at Baseline (non-treated cheek), up to the 60-minute time point (at two consecutive time points). | Time of application up to one hour post-application | 
| Duration of Anesthesia as Measured by PPT for One Spray CTY-5339-A Compared to Two Sprays CTY-5339-A | Assessments will be made over a period of one hour, with assessments at 1 minute intervals for the first 5 minutes and then every 5 minutes after that. | Time of application up to one hour post-application | 
| Duration of Anesthesia as Measured by QST Heat for One Spray CTY-5339-A Compared to Two Sprays CTY-5339-A | Assessments will be made over a period of one hour, with assessments at 1 minute intervals for the first 5 minutes and then every 5 minutes after that. | Time of application up to one hour post-application | 
| Onset of Anesthesia for PPT | Assessments will be made over a period of one hour, with assessments at 1 minute intervals for the first 5 minutes and then every 5 minutes after that. | Time of application up to one hour post-application | 
| Onset of Anesthesia for QST Heat | Assessments will be made over a period of one hour, with assessments at 1 minute intervals for the first 5 minutes and then every 5 minutes after that. | Time of application up to one hour post-application | 
| Percentage of Responders for PPT at Each Time Point | Assessments will be made over a period of one hour, with assessments at 1 minute intervals for the first 5 minutes and then every 5 minutes after that. | Time of application up to one hour post-application | 
| Percentage of Responders for QST Heat at Each Time Point | Assessments will be made over a period of one hour, with assessments at 1 minute intervals for the first 5 minutes and then every 5 minutes after that. | Time of application up to one hour post-application |