Toxic Effect of Organophosphate and Carbamate Insecticides
Conditions
Brief summary
This randomized, three-sequence, three-period, phase 1 study is designed to assess the bioavailability and pharmacokinetics (PK) of sublingually administered atropine sulfate ophthalmic solution 1% USP (at 0.5 mg and 1.0 mg; test) compared to atropine sulfate injection administered IV (1.0 mg; reference).
Detailed description
This is a randomized, three-sequence, three-period crossover study to assess the bioavailability and PK of a single dose of atropine administered sublingually in healthy adult volunteers. At least 15 healthy male and female volunteers will be enrolled to obtain approximately 12 evaluable subjects in the per protocol population. Eligible subjects will be randomized at a 1:1:1 ratio to receive one of three treatment dosing sequences (A, B, or C). Subjects assigned to treatment dosing sequence A will receive a low dose sublingually at Visit 1; Day 1 (Period 1), a high dose sublingually at Visit 2; Day 8 (Period 2) and an IV dose at Visit 3; Day 15 (Period 3). Subjects assigned to treatment dosing sequence B will receive a high dose sublingually at Visit 1; Day 1 (Period 1), an IV dose at Visit 2; Day 8 (Period 2) and a low dose sublingually at Visit 3; Day 15 (Period 3). Subjects assigned to treatment dosing sequence C will receive an IV dose at Visit 1; Day 1 (Period 1), a low dose sublingually at Visit 2; Day 8 (Period 2), and a high dose sublingually at Visit 3; Day 15 (Period 3).
Interventions
DRUGAtropine Sulfate Ophthalmic Solution
Atropine sulfate ophthalmic solution, USP 1% is a sterile topical anti-muscarinic indicated for cyclopegia, mydriasis, and penalization of the healthy eye in the treatment of amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains active ingredient: atropine sulfate 10 mg equivalent to 8.3 mg of atropine. Inactive ingredients include benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection, USP.
DRUGAtropine Sulphate Injection
Atropine sulfate injection, USP, 8mg/20mL (0.4 mg per mL) is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; sodium chloride 9 mg; and may contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8).
Sponsors
Rho, Inc.
Biomedical Advanced Research and Development Authority
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male and nonpregnant female volunteers between the ages of 18 and 55 years at time of randomization 2. Willing and able to provide written informed consent 3. Females who are of childbearing potential and are sexually active with a male partner must have used an acceptable method of birth control for at least 2 months prior to Screening, and must agree to continue using an acceptable method of birth control from Screening to Follow-up (Day 21). A female of childbearing potential is defined as postonset menarche and premenopausal female capable of becoming pregnant. This does not include females who meet any of the following conditions: menopausal \> 2 years, tubal ligation \> 1 year, bilateral salpingo-oophorectomy, or hysterectomy. Adequate contraception is defined as a contraceptive method with a failure rate of less than 1% per year when used consistently and correctly and when applicable, in accordance with the product label. Examples include oral contraceptives, injectable progestogen, implants of etonogestrel or levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device or intrauterine system, or male partner sterilization at least 6 months prior to the female subject's Screening Visit. 4. In the judgment of the investigator, the subject is in good health, based on review of medical history and the results of screening evaluation (including vital signs, physical examination, 12-lead ECG, and routine clinical laboratory testing, performed no more than 14 days prior to randomization into the study) 5. Able to comply with the dosing instructions and available to complete the study Schedule of Events
Exclusion criteria
1. Females who have a positive pregnancy test or who are breastfeeding 2. Subjects with thyroid disease as evidenced by a thyroid-stimulating hormone (TSH) \< 0.9 × lower limit of normal (LLN) or \> 1.2 × upper limit of normal (ULN) at screening. (This test will not be repeated prior to subsequent dosing.) 3. Subjects with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or serum creatinine \> 1.5 × ULN at screening. (These tests will not be repeated prior to subsequent dosing.) 4. Have known human immunodeficiency virus (HIV), or acute or chronic hepatitis B or hepatitis C infection based on medical history; or test positive for any of these at Screening. Subjects who have been effectively treated for hepatitis C, as evidenced by a negative hepatitis C ribonucleic acid (RNA) confirmation test and who no longer require antiviral therapy, are eligible for participation. (Screening tests will not be repeated prior to subsequent dosing.) 5. Subjects who took any prescription medications (with the exception of oral contraceptives or hormone replacement therapy) within 30 days of screening. Prior to each dose, the investigator will review prohibited medication use and determine whether the subject should be terminated from further dosing. 6. Subjects who took any over-the-counter medication/vitamins/herbal supplements in the last 72 hours prior to screening. Prior to each dose, the investigator will review prohibited medication use and determine whether the subject should be terminated from further dosing. 7. Subjects with glaucoma and/or history of ocular surgery (including Lasik), ocular trauma, or congenital ocular disorder 8. Subjects with any history of heart disease including but not limited to coronary artery disease, arrhythmia (treated or untreated), congestive heart failure, pacemaker, history of vasovagal syncope, peripheral vascular disease, or claudication 9. Subjects with clinically significant arrhythmias or abnormal conduction; abnormal conduction is defined as a prolonged PR or QRS, or a QTc ≥ 450 msec for males or ≥ 470 msec for females 10. Subjects with a history of partial organic pyloric stenosis, chronic constipation, or other gastrointestinal motility issue 11. Subjects with a history of xerostomia due to an underlying disease or previous radiation therapy to the head and neck 12. Males with history of symptomatic prostatic hypertrophy; males or females with a history of hesitancy or retention 13. Subjects with a blood pressure \> 140/90 mm Hg taken after the subject has been seated and resting for at least five minutes 14. Subjects with a history or current diagnosis of myasthenia gravis 15. Subjects with a history of drug or alcohol abuse in the last two years or evidence of a positive urine drug test at screening. (This screening test will not be repeated prior to subsequent dosing.) 16. Subjects with a known sensitivity or prior adverse reaction to atropine Subjects cannot be rescreened for exclusionary laboratory test results. Potentially exclusionary vital sign results may be repeated once. If a subject's repeat vitals remain exclusionary or the investigator determines that the repeat vital signs could pose a risk to the subject participating in the study, then the subject will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clearance (CL/F) | Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and sublingual dosing period using the noncompartmental method. This outcome is not applicable for the intravenous dosing period. CL/F is summarized by study dosage as the mean and standard deviation for all evaluable participants and expressed as mL/min. |
| Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t) | Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using the noncompartmental method for extravascular (for sublingual doses) or IV infusion routes of administration. AUC\_t is summarized by study dosage as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as min\*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model. |
| Maximum Concentration (C_max) | Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using the noncompartmental method for extravascular (for sublingual doses) or IV infusion routes of administration. C\_max is summarized by study dosage as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model. |
| Time to Maximum Concentration (t_max) | Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and sublingual dosing period using the noncompartmental method. This outcome is not applicable for the intravenous dosing period. t\_max is summarized by study dosage as the mean and standard deviation for all evaluable participants and expressed as minutes. |
| Terminal Elimination Half-Life (t_1/2) | Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using the noncompartmental method for extravascular (for sublingual doses) or IV infusion routes of administration. t\_1/2 is summarized by study dosage as the mean and standard deviation for all evaluable participants and expressed as minutes. |
| Volume of Distribution (V_d/F) | Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and sublingual dosing period using the noncompartmental method. This outcome is not applicable for the intravenous dosing period. V\_d/F is summarized by study dosage as the mean and standard deviation for all evaluable participants and expressed as liters. |
| Area Under the Curve to From Time Zero to Infinity (AUC_∞) | Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using the noncompartmental method for extravascular (for sublingual doses) or IV infusion routes of administration. AUC\_∞ is summarized by study dosage as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as min\*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-Emergent Serious Adverse Events | Day 1 through Day 21 | Number of patients with treatment-emergent serious adverse events |
| Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness | Pre-dose through 1 hour post-dose at Days 1, 8 and 15 | Subject reported xerostomia scores were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 10, 20, 30, 40, 50, and 60 minutes. Scores were assessed by questionnaire (0-10 point scale, with 0 being not difficult at all and 10 being very difficult) previously validated for measurement of salivary gland dysfunction. The maximum xerostomia score representing difficulty swallowing due to mouth dryness was calculated for each subject and dose. Maximum xerostomia scores were summarized by study dosage as the mean and standard deviation. |
| Xerostomia Assessment - Dryness of Lips | Pre-dose through 1 hour post-dose at Days 1, 8 and 15 | Subject reported xerostomia scores were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 10, 20, 30, 40, 50, and 60 minutes. Scores were assessed by questionnaire (0-10 point scale, with 0 being not dry at all and 10 being very dry) previously validated for measurement of salivary gland dysfunction. The maximum xerostomia score representing dryness of lips was calculated for each subject and dose. Maximum xerostomia scores were summarized by study dosage as the mean and standard deviation. |
| Xerostomia Assessment - Dryness of Tongue | Pre-dose through 1 hour post-dose at Days 1, 8 and 15 | Subject reported xerostomia scores were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 10, 20, 30, 40, 50, and 60 minutes. Scores were assessed by questionnaire (0-10 point scale, with 0 being not dry at all and 10 being very dry) previously validated for measurement of salivary gland dysfunction. The maximum xerostomia score representing dryness of tongue was calculated for each subject and dose. Maximum xerostomia scores were summarized by study dosage as the mean and standard deviation. |
| Treatment-Emergent Adverse Events | Day 1 through Day 21 | Number of patients with treatment-emergent adverse events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| A: Low Dose Sublingual - High Dose Sublingual - IV Subjects assigned to treatment dosing sequence A will receive a low dose sublingually at Visit 1; Day 1 (Period 1), a high dose sublingually at Visit 2; Day 8 (Period 2) and an IV dose at Visit 3; Day 15 (Period 3). | 5 |
| B: High Dose Sublingual - IV - Low Dose Sublingual Subjects assigned to treatment dosing sequence B will receive a high dose sublingually at Visit 1; Day 1 (Period 1), an IV dose at Visit 2; Day 8 (Period 2) and a low dose sublingually at Visit 3; Day 15 (Period 3). | 5 |
| C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual Subjects assigned to treatment dosing sequence C will receive an IV dose at Visit 1; Day 1 (Period 1), a low dose sublingually at Visit 2; Day 8 (Period 2), and a high dose sublingually at Visit 3; Day 15 (Period 3). | 5 |
| Total | 15 |
Baseline characteristics
| Characteristic | C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual | Total | A: Low Dose Sublingual - High Dose Sublingual - IV | B: High Dose Sublingual - IV - Low Dose Sublingual |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 15 Participants | 5 Participants | 5 Participants |
| Age, Continuous | 35.0 years STANDARD_DEVIATION 3.87 | 33.8 years STANDARD_DEVIATION 6.47 | 37.2 years STANDARD_DEVIATION 7.46 | 29.2 years STANDARD_DEVIATION 5.76 |
| Body Mass Index | 34.13 kg/m^2 | 29.55 kg/m^2 | 24.76 kg/m^2 | 25.16 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 13 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 8 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 5 participants | 15 participants | 5 participants | 5 participants |
| Screening Xerostomia Assessment - Difficulty Swallowing (0-10) | 0 Scores on a scale STANDARD_DEVIATION 0 | 0 Scores on a scale STANDARD_DEVIATION 0 | 0 Scores on a scale STANDARD_DEVIATION 0 | 0 Scores on a scale STANDARD_DEVIATION 0 |
| Screening Xerostomia Assessment - Dryness of Lips (0-10) | 0.2 Scores on a scale STANDARD_DEVIATION 0.45 | 0.7 Scores on a scale STANDARD_DEVIATION 1.33 | 0.4 Scores on a scale STANDARD_DEVIATION 0.55 | 1.6 Scores on a scale STANDARD_DEVIATION 2.07 |
| Screening Xerostomia Assessment - Dryness of Tongue (0-10) | 0 Scores on a scale STANDARD_DEVIATION 0 | 0 Scores on a scale STANDARD_DEVIATION 0 | 0 Scores on a scale STANDARD_DEVIATION 0 | 0 Scores on a scale STANDARD_DEVIATION 0 |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 5 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 | 0 / 14 |
| other Total, other adverse events | 1 / 14 | 1 / 15 | 4 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 | 0 / 14 |
Outcome results
Primary
Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t)
Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using the noncompartmental method for extravascular (for sublingual doses) or IV infusion routes of administration. AUC\_t is summarized by study dosage as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as min\*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.
Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15
Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t) | 218.195 min*ng/mL | Geometric Coefficient of Variation 20.2 |
| High Dose Sublingual | Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t) | 408.061 min*ng/mL | Geometric Coefficient of Variation 23.9 |
| Intravenous | Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t) | 717.665 min*ng/mL | Geometric Coefficient of Variation 23.2 |
90% CI: [0.4971, 0.6004]Mixed Models Analysis
90% CI: [0.2788, 0.3367]Mixed Models Analysis
90% CI: [0.5104, 0.6164]Mixed Models Analysis
Primary
Area Under the Curve to From Time Zero to Infinity (AUC_∞)
Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using the noncompartmental method for extravascular (for sublingual doses) or IV infusion routes of administration. AUC\_∞ is summarized by study dosage as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as min\*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.
Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15
Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Area Under the Curve to From Time Zero to Infinity (AUC_∞) | 286.396 min*ng/mL | Geometric Coefficient of Variation 26.6 |
| High Dose Sublingual | Area Under the Curve to From Time Zero to Infinity (AUC_∞) | 493.808 min*ng/mL | Geometric Coefficient of Variation 27.3 |
| Intravenous | Area Under the Curve to From Time Zero to Infinity (AUC_∞) | 816.465 min*ng/mL | Geometric Coefficient of Variation 22 |
90% CI: [0.5265, 0.636]Mixed Models Analysis
90% CI: [0.3171, 0.3839]Mixed Models Analysis
90% CI: [0.5524, 0.6582]Mixed Models Analysis
Primary
Clearance (CL/F)
Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and sublingual dosing period using the noncompartmental method. This outcome is not applicable for the intravenous dosing period. CL/F is summarized by study dosage as the mean and standard deviation for all evaluable participants and expressed as mL/min.
Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15
Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable periods for extravascular (sublingual) routes of administration. Note: CL/F is not applicable to intravenous dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Clearance (CL/F) | 1800.800 mL/min | Standard Deviation 473.3604 |
| High Dose Sublingual | Clearance (CL/F) | 2098.806 mL/min | Standard Deviation 632.8211 |
Primary
Maximum Concentration (C_max)
Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using the noncompartmental method for extravascular (for sublingual doses) or IV infusion routes of administration. C\_max is summarized by study dosage as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.
Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15
Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Maximum Concentration (C_max) | 0.883 ng/mL | Geometric Coefficient of Variation 27.2 |
| High Dose Sublingual | Maximum Concentration (C_max) | 1.639 ng/mL | Geometric Coefficient of Variation 30.5 |
| Intravenous | Maximum Concentration (C_max) | 18.247 ng/mL | Geometric Coefficient of Variation 66.9 |
90% CI: [0.4273, 0.7118]Mixed Models Analysis
90% CI: [0.0381, 0.0641]Mixed Models Analysis
90% CI: [0.0695, 0.1167]Mixed Models Analysis
Primary
Terminal Elimination Half-Life (t_1/2)
Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using the noncompartmental method for extravascular (for sublingual doses) or IV infusion routes of administration. t\_1/2 is summarized by study dosage as the mean and standard deviation for all evaluable participants and expressed as minutes.
Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15
Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Terminal Elimination Half-Life (t_1/2) | 176.187 Minutes | Standard Deviation 75.0887 |
| High Dose Sublingual | Terminal Elimination Half-Life (t_1/2) | 171.258 Minutes | Standard Deviation 49.9828 |
| Intravenous | Terminal Elimination Half-Life (t_1/2) | 179.327 Minutes | Standard Deviation 60.412 |
Primary
Time to Maximum Concentration (t_max)
Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and sublingual dosing period using the noncompartmental method. This outcome is not applicable for the intravenous dosing period. t\_max is summarized by study dosage as the mean and standard deviation for all evaluable participants and expressed as minutes.
Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15
Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable periods for extravascular (sublingual) routes of administration. Note: t\_max was not applicable to intravenous dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Time to Maximum Concentration (t_max) | 125.4 Minutes | Standard Deviation 69.81 |
| High Dose Sublingual | Time to Maximum Concentration (t_max) | 107.1 Minutes | Standard Deviation 47.78 |
Primary
Volume of Distribution (V_d/F)
Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 2, 4, 6, 10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 8 hours. PK parameters were estimated for each subject and sublingual dosing period using the noncompartmental method. This outcome is not applicable for the intravenous dosing period. V\_d/F is summarized by study dosage as the mean and standard deviation for all evaluable participants and expressed as liters.
Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15
Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable periods for extravascular (sublingual) routes of administration. Note: V\_d/F is not applicable to intravenous dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Volume of Distribution (V_d/F) | 423.71 L | Standard Deviation 119.774 |
| High Dose Sublingual | Volume of Distribution (V_d/F) | 496.70 L | Standard Deviation 138.811 |
Secondary
Treatment-Emergent Adverse Events
Number of patients with treatment-emergent adverse events
Time frame: Day 1 through Day 21
Population: The Safety population includes all subjects who were randomized and received at least 1 study drug dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose Sublingual | Treatment-Emergent Adverse Events | 1 Participants |
| High Dose Sublingual | Treatment-Emergent Adverse Events | 1 Participants |
| Intravenous | Treatment-Emergent Adverse Events | 4 Participants |
Secondary
Treatment-Emergent Serious Adverse Events
Number of patients with treatment-emergent serious adverse events
Time frame: Day 1 through Day 21
Population: The Safety population includes all subjects who were randomized and received at least 1 study drug dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose Sublingual | Treatment-Emergent Serious Adverse Events | 0 Participants |
| High Dose Sublingual | Treatment-Emergent Serious Adverse Events | 0 Participants |
| Intravenous | Treatment-Emergent Serious Adverse Events | 0 Participants |
Secondary
Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness
Subject reported xerostomia scores were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 10, 20, 30, 40, 50, and 60 minutes. Scores were assessed by questionnaire (0-10 point scale, with 0 being not difficult at all and 10 being very difficult) previously validated for measurement of salivary gland dysfunction. The maximum xerostomia score representing difficulty swallowing due to mouth dryness was calculated for each subject and dose. Maximum xerostomia scores were summarized by study dosage as the mean and standard deviation.
Time frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15
Population: The Safety population includes all subjects who were randomized and received at least 1 study drug dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness | 0.3 Scores on a scale | Standard Deviation 1.07 |
| High Dose Sublingual | Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness | 0.3 Scores on a scale | Standard Deviation 0.82 |
| Intravenous | Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness | 2.0 Scores on a scale | Standard Deviation 2.77 |
Secondary
Xerostomia Assessment - Dryness of Lips
Subject reported xerostomia scores were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 10, 20, 30, 40, 50, and 60 minutes. Scores were assessed by questionnaire (0-10 point scale, with 0 being not dry at all and 10 being very dry) previously validated for measurement of salivary gland dysfunction. The maximum xerostomia score representing dryness of lips was calculated for each subject and dose. Maximum xerostomia scores were summarized by study dosage as the mean and standard deviation.
Time frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15
Population: The Safety population includes all subjects who were randomized and received at least 1 study drug dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Xerostomia Assessment - Dryness of Lips | 1.1 Maximum Score | Standard Deviation 1.38 |
| High Dose Sublingual | Xerostomia Assessment - Dryness of Lips | 1.5 Maximum Score | Standard Deviation 1.85 |
| Intravenous | Xerostomia Assessment - Dryness of Lips | 2.9 Maximum Score | Standard Deviation 2.88 |
Secondary
Xerostomia Assessment - Dryness of Tongue
Subject reported xerostomia scores were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 10, 20, 30, 40, 50, and 60 minutes. Scores were assessed by questionnaire (0-10 point scale, with 0 being not dry at all and 10 being very dry) previously validated for measurement of salivary gland dysfunction. The maximum xerostomia score representing dryness of tongue was calculated for each subject and dose. Maximum xerostomia scores were summarized by study dosage as the mean and standard deviation.
Time frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Sublingual | Xerostomia Assessment - Dryness of Tongue | 0.3 Maximum Score | Standard Deviation 0.61 |
| High Dose Sublingual | Xerostomia Assessment - Dryness of Tongue | 0.3 Maximum Score | Standard Deviation 0.46 |
| Intravenous | Xerostomia Assessment - Dryness of Tongue | 2.1 Maximum Score | Standard Deviation 2.67 |