CompletedNCT04290039Updated Jun 22, 2023Results posted

Sublingual vs IV Atropine Bioavailability Study

A Phase 1 interventional study of Atropine Sulfate Ophthalmic Solution and Atropine Sulphate Injection in Toxic Effect of Organophosphate and Carbamate Insecticides, sponsored by Biomedical Advanced Research and Development Authority. Completed at 1 site in United States. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-06-22.

Sponsored by Biomedical Advanced Research and Development Authority · Phase 1, Interventional, and Treatment

Phase: Phase 1
Study type: Interventional
Enrollment: 15
Allocation: Randomized
Ages: 18 Years to 55 Years
Sex: All

Study 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).

Read the 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).

Conditions studied

Toxic Effect of Organophosphate and Carbamate Insecticides

Who can participate

Ages eligible: 18 Years to 55 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Inclusion criteria

Healthy male and nonpregnant female volunteers between the ages of 18 and 55 years at time of randomization
Willing and able to provide written informed consent
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.
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)
Able to comply with the dosing instructions and available to complete the study Schedule of Events

Exclusion criteria

Exclusion Criteria:

Females who have a positive pregnancy test or who are breastfeeding
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.)
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.)
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.)
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.
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.
Subjects with glaucoma and/or history of ocular surgery (including Lasik), ocular trauma, or congenital ocular disorder
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
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
Subjects with a history of partial organic pyloric stenosis, chronic constipation, or other gastrointestinal motility issue
Subjects with a history of xerostomia due to an underlying disease or previous radiation therapy to the head and neck
Males with history of symptomatic prostatic hypertrophy; males or females with a history of hesitancy or retention
Subjects with a blood pressure > 140/90 mm Hg taken after the subject has been seated and resting for at least five minutes
Subjects with a history or current diagnosis of myasthenia gravis
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.)
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.

Study design

Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover assignment
Masking: None (open label)
Enrollment: 15 participants (actual)

Study arms

Active comparator
Low Dose Sublingual
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. Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in dropper bottles containing 2 mL. Each bottle will only be used to administer a single dose, to a single subject.
Drug: Atropine Sulfate Ophthalmic Solution
Active comparator
High Dose Sublingual
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. Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in dropper bottles containing 2 mL. Each bottle will only be used to administer a single dose, to a single subject.
Drug: Atropine Sulfate Ophthalmic Solution
Active comparator
Intravenous (IV)
Atropine sulfate injection is indicated for temporary blockade of severe or life-threatening muscarinic effects, e.g., as an antisialagogue, an antivagal agent, an antidote for organophosphorus, carbamate, or muscarinic mushroom poisoning, and to treat symptomatic bradycardia. 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). Atropine sulfate injection will be supplied in multidose vials containing 20 mL. Each vial will only be used to administer a single dose, to a single subject.
Drug: Atropine Sulphate Injection

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).

What researchers measure

Primary outcomes

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
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
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
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
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
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
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

Secondary outcomes

Treatment-Emergent Adverse Events
Number of patients with treatment-emergent adverse events
Time frame: Day 1 through Day 21
Treatment-Emergent Serious Adverse Events
Number of patients with treatment-emergent serious adverse events
Time frame: Day 1 through Day 21
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
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
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

Results

Posted Aug 11, 2021

Participant flow

Period 1 (Visit 1; Day 1)

Participant flow — Period 1 (Visit 1; Day 1)
Milestone	Sequence A: Low Dose Sublingual - High Dose Sublingual - IV	Sequence B: High Dose Sublingual - IV - Low Dose Sublingual	Sequence C: IV - Low Dose Sublingual - High Dose Sublingual
Started	5	5	5
Completed	5	5	5
Not completed	0	0	0

Period 2 (Visit 2; Day 8)

Participant flow — Period 2 (Visit 2; Day 8)
Milestone	Sequence A: Low Dose Sublingual - High Dose Sublingual - IV	Sequence B: High Dose Sublingual - IV - Low Dose Sublingual	Sequence C: IV - Low Dose Sublingual - High Dose Sublingual
Started	5	5	5
Completed	5	5	5
Not completed	0	0	0

Period 3 (Visit 3; Day 15)

Participant flow — Period 3 (Visit 3; Day 15)
Milestone	Sequence A: Low Dose Sublingual - High Dose Sublingual - IV	Sequence B: High Dose Sublingual - IV - Low Dose Sublingual	Sequence C: IV - Low Dose Sublingual - High Dose Sublingual
Started	5	4	5
Completed	5	4	5
Not completed	0	0	0

Outcome measures

PrimaryArea 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
Reported as:: Geometric mean · min*ng/mL

Area Under the Curve to From Time Zero to Infinity (AUC_∞)
min*ng/mL	Low Dose Sublingual	High Dose Sublingual	Intravenous
Area Under the Curve to From Time Zero to Infinity (AUC_∞)	286.396 ± 26.6	493.808 ± 27.3	816.465 ± 22.0

Statistical analysis

Low Dose Sublingual vs High Dose Sublingual · Mixed Models Analysis · Geometric ratio of least-square means: 0.579 · 90% CI 0.5265 to 0.6360Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.
Low Dose Sublingual vs Intravenous · Mixed Models Analysis · Geometric ratio of least-square means: 0.349 · 90% CI 0.3171 to 0.3839Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.
High Dose Sublingual vs Intravenous · Mixed Models Analysis · Geometric ratio of least-square means: 0.603 · 90% CI 0.5524 to 0.6582Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.

PrimaryArea 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
Reported as:: Geometric mean · min*ng/mL

Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t)
min*ng/mL	Low Dose Sublingual	High Dose Sublingual	Intravenous
Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t)	218.195 ± 20.2	408.061 ± 23.9	717.665 ± 23.2

Statistical analysis

Low Dose Sublingual vs High Dose Sublingual · Mixed Models Analysis · Geometric ratio of least-square means: 0.546 · 90% CI 0.4971 to 0.6004Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.
Low Dose Sublingual vs Intravenous · Mixed Models Analysis · Geometric ratio of least-square means: 0.306 · 90% CI 0.2788 to 0.3367Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.
High Dose Sublingual vs Intravenous · Mixed Models Analysis · Geometric ratio of least-square means: 0.561 · 90% CI 0.5104 to 0.6164Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.

PrimaryMaximum 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
Reported as:: Geometric mean · ng/mL

Maximum Concentration (C_max)
ng/mL	Low Dose Sublingual	High Dose Sublingual	Intravenous
Maximum Concentration (C_max)	0.883 ± 27.2	1.639 ± 30.5	18.247 ± 66.9

Statistical analysis

Low Dose Sublingual vs High Dose Sublingual · Mixed Models Analysis · Geometric ratio of least-square means: 0.549 · 90% CI 0.4273 to 0.7118Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.
Low Dose Sublingual vs Intravenous · Mixed Models Analysis · Geometric ratio of least-square means: 0.049 · 90% CI 0.0381 to 0.0641Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.
High Dose Sublingual vs Intravenous · Mixed Models Analysis · Geometric ratio of least-square means: 0.090 · 90% CI 0.0695 to 0.1167Only subjects who had at least 2 periods where study drug was received with an evaluable PK profile were included in the comparisons.

PrimaryTime 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
Reported as:: Mean · Minutes

Time to Maximum Concentration (t_max)
Minutes	Low Dose Sublingual	High Dose Sublingual	Intravenous
Time to Maximum Concentration (t_max)	125.4 ± 69.81	107.1 ± 47.78	—

PrimaryTerminal 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
Reported as:: Mean · Minutes

Terminal Elimination Half-Life (t_1/2)
Minutes	Low Dose Sublingual	High Dose Sublingual	Intravenous (IV)
Terminal Elimination Half-Life (t_1/2)	176.187 ± 75.0887	171.258 ± 49.9828	179.327 ± 60.412

PrimaryVolume 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
Reported as:: Mean · L

Volume of Distribution (V_d/F)
L	Low Dose Sublingual	High Dose Sublingual	Intravenous
Volume of Distribution (V_d/F)	423.71 ± 119.774	496.70 ± 138.811	—

PrimaryClearance (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
Reported as:: Mean · mL/min

Clearance (CL/F)
mL/min	Low Dose Sublingual	High Dose Sublingual	Intravenous
Clearance (CL/F)	1800.800 ± 473.3604	2098.806 ± 632.8211	—

SecondaryTreatment-Emergent Adverse Events

Number of patients with treatment-emergent adverse events

Time frame:: Day 1 through Day 21
Reported as:: Count of participants · Participants

Treatment-Emergent Adverse Events
Participants	Low Dose Sublingual	High Dose Sublingual	Intravenous
Treatment-Emergent Adverse Events	1	1	4

SecondaryTreatment-Emergent Serious Adverse Events

Number of patients with treatment-emergent serious adverse events

Time frame:: Day 1 through Day 21
Reported as:: Count of participants · Participants

Treatment-Emergent Serious Adverse Events
Participants	Low Dose Sublingual	High Dose Sublingual	Intravenous
Treatment-Emergent Serious Adverse Events	0	0	0

SecondaryXerostomia 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
Reported as:: Mean · Scores on a scale

Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness
Scores on a scale	Low Dose Sublingual	High Dose Sublingual	Intravenous
Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness	0.3 ± 1.07	0.3 ± 0.82	2.0 ± 2.77

SecondaryXerostomia 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
Reported as:: Mean · Maximum Score

Xerostomia Assessment - Dryness of Lips
Maximum Score	Low Dose Sublingual	High Dose Sublingual	Intravenous
Xerostomia Assessment - Dryness of Lips	1.1 ± 1.38	1.5 ± 1.85	2.9 ± 2.88

SecondaryXerostomia 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
Reported as:: Mean · Maximum Score

Xerostomia Assessment - Dryness of Tongue
Maximum Score	Low Dose Sublingual	High Dose Sublingual	Intravenous
Xerostomia Assessment - Dryness of Tongue	0.3 ± 0.61	0.3 ± 0.46	2.1 ± 2.67

Adverse events

Collected over AEs were collected from the time of consent until completion of the follow-up period after the last administration of study drug Follow-up (Day 21).. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Low Dose Sublingual	0/14 (0%)	0/14 (0%)	1/14 (7.1%)
High Dose Sublingual	0/15 (0%)	0/15 (0%)	1/15 (6.7%)
Intravenous	0/14 (0%)	0/14 (0%)	4/14 (28.6%)

Most frequent other events

Most frequent other events
Event	Low Dose Sublingual	High Dose Sublingual	Intravenous
SomnolenceNervous system disorders	0/14	0/15	2/14
Abdominal Pain - LowerGastrointestinal disorders	1/14	0/15	0/14
DizzinessNervous system disorders	0/14	0/15	1/14
HeadacheNervous system disorders	0/14	0/15	1/14
FlushingVascular disorders	0/14	0/15	1/14
Upper Respiratory Tract InfectionInfections and infestations	0/14	1/15	0/14

Baseline characteristics

Safety population includes all participants who were randomized and received at least 1 study drug dose.

Age, Categorical
Age, Categorical(Participants)	A: Low Dose Sublingual - High Dose Sublingual - IV	B: High Dose Sublingual - IV - Low Dose Sublingual	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual	Total
<=18 years	0	0	0	0
Between 18 and 65 years	5	5	5	15
>=65 years	0	0	0	0

Age, Continuous
Age, Continuous(years)	A: Low Dose Sublingual - High Dose Sublingual - IV	B: High Dose Sublingual - IV - Low Dose Sublingual	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual	Total
Mean	37.2 ± 7.46	29.2 ± 5.76	35.0 ± 3.87	33.8 ± 6.47

Sex: Female, Male
Sex: Female, Male(Participants)	A: Low Dose Sublingual - High Dose Sublingual - IV	B: High Dose Sublingual - IV - Low Dose Sublingual	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual	Total
Female	0	4	3	7
Male	5	1	2	8

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	A: Low Dose Sublingual - High Dose Sublingual - IV	B: High Dose Sublingual - IV - Low Dose Sublingual	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual	Total
Hispanic or Latino	1	0	1	2
Not Hispanic or Latino	4	5	4	13
Unknown or Not Reported	0	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	A: Low Dose Sublingual - High Dose Sublingual - IV	B: High Dose Sublingual - IV - Low Dose Sublingual	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual	Total
American Indian or Alaska Native	0	0	0	0
Asian	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	2	3	3	8
White	1	2	2	5
More than one race	1	0	0	1
Unknown or Not Reported	1	0	0	1

Region of Enrollment
Region of Enrollment(participants)	A: Low Dose Sublingual - High Dose Sublingual - IV	B: High Dose Sublingual - IV - Low Dose Sublingual	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual	Total
United States	5	5	5	15

Body Mass Index
Body Mass Index(kg/m^2)	A: Low Dose Sublingual - High Dose Sublingual - IV	B: High Dose Sublingual - IV - Low Dose Sublingual	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual	Total
Median	24.76 (21.1 to 29.7)	25.16 (21.2 to 35.2)	34.13 (26.8 to 39.0)	29.55 (21.1 to 39.0)

Screening Xerostomia Assessment - Difficulty Swallowing (0-10)
Screening Xerostomia Assessment - Difficulty Swallowing (0-10)(Scores on a scale)	A: Low Dose Sublingual - High Dose Sublingual - IV	B: High Dose Sublingual - IV - Low Dose Sublingual	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual	Total
Mean	0 ± 0	0 ± 0	0 ± 0	0 ± 0

2 further baseline measures are reported on the registry.

Study locations

1 site

High Point Clinical Trials Center
High Point, North Carolina 27265, United States

References and documents

Publications

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. PubMed 20159382 ↗
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. PubMed 11250628 ↗

Study documents

Protocol and statistical analysis plan · Nov 21, 2019
Informed consent form · Dec 19, 2019

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Registry details

Key details

Study ID: NCT04290039
Lead sponsor: Biomedical Advanced Research and Development Authority
Collaborators: Rho, Inc.
Responsible party: Sponsor
First posted: Feb 28, 2020
Start date: Jan 4, 2020
Primary completion: Feb 2, 2020
Completion: Feb 8, 2020
Results posted: Aug 11, 2021
Last update: Jun 22, 2023

Study contacts

Michael Schwartz, MD MPH

study chair · Department of Health and Human Services

Oversight

FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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Sublingual vs IV Atropine Bioavailability Study

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