Toxic Effect of Organophosphate and Carbamate Insecticides Clinical Trial
Official title:
A Randomized, Three-Sequence, Three-Period Crossover Study to Assess the Bioavailability and Pharmacokinetics of a Single Dose of Atropine Administered Sublingually in Healthy Adult Volunteers
| Verified date | June 2023 |
| Source | Biomedical Advanced Research and Development Authority |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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).
| Status | Completed |
| Enrollment | 15 |
| Est. completion date | February 8, 2020 |
| Est. primary completion date | February 2, 2020 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | 18 Years to 55 Years |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| United States | High Point Clinical Trials Center | High Point | North Carolina |
| Lead Sponsor | Collaborator |
|---|---|
| Biomedical Advanced Research and Development Authority | Rho, Inc. |
United States,
Pai S, Ghezzi EM, Ship JA. Development of a Visual Analogue Scale questionnaire for subjective assessment of salivary dysfunction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Mar;91(3):311-6. doi: 10.1067/moe.2001.111551. — View Citation
Rajpal S, Ali R, Bhatnagar A, Bhandari SK, Mittal G. Clinical and bioavailability studies of sublingually administered atropine sulfate. Am J Emerg Med. 2010 Feb;28(2):143-50. doi: 10.1016/j.ajem.2008.10.025. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Area Under the Curve to From Time Zero to Infinity (AUC_8) | 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_8 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. |
Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | |
| 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. |
Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | |
| 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. |
Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | |
| 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. |
Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | |
| 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. |
Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | |
| 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. |
Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | |
| 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. |
Pre-dose through 8 hours post-dose at Days 1, 8 and 15 | |
| Secondary | Treatment-Emergent Adverse Events | Number of patients with treatment-emergent adverse events | Day 1 through Day 21 | |
| Secondary | Treatment-Emergent Serious Adverse Events | Number of patients with treatment-emergent serious adverse events | Day 1 through Day 21 | |
| 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. |
Pre-dose through 1 hour post-dose at Days 1, 8 and 15 | |
| 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. |
Pre-dose through 1 hour post-dose at Days 1, 8 and 15 | |
| 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. |
Pre-dose through 1 hour post-dose at Days 1, 8 and 15 |