Toxic Effect of Organophosphate and Carbamate InsecticidesPhase 1NCT04290039

Sublingual vs IV Atropine Bioavailability Study

A Phase 1 study testing Atropine Sulfate Ophthalmic Solution and Atropine Sulphate Injection in people with Toxic Effect of Organophosphate and Carbamate Insecticides, run by Biomedical Advanced Research and Development Authority at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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 more about this study

Who is it for?: Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for: Toxic Effect of Organophosphate and Carbamate Insecticides
What is being tested?: Atropine Sulfate Ophthalmic Solution and Atropine Sulphate Injection
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 15 participants
Where: 1 siteUnited States
Study dates: 4 Jan 2020to 8 Feb 2020
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 55 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

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

Who cannot join

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.

Show all 17Show fewer

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.

Trial locations and contacts

1 site in 1 country.

United States1 site

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

Other trials in United States

About this study

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

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: Toxic Effect of Organophosphate and Carbamate Insecticides
Being tested: Atropine Sulfate Ophthalmic Solution, Atropine Sulphate Injection

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Atropine Sulfate Ophthalmic SolutionDrug
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 Sulphate InjectionDrug
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).

Study groups in NCT04290039
Study group	Role	What they receive
Low Dose Sublingual	Active comparator	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. Receives: Drug: Atropine Sulfate Ophthalmic Solution
High Dose Sublingual	Active comparator	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. Receives: Drug: Atropine Sulfate Ophthalmic Solution
Intravenous (IV)	Active comparator	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. Receives: Drug: Atropine Sulphate Injection

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Pre-dose through 8 hours post-dose at Days 1, 8 and 15

Secondary outcomes (5)

Treatment-Emergent Adverse Events
Number of patients with treatment-emergent adverse events
Measured: Day 1 through Day 21
Treatment-Emergent Serious Adverse Events
Number of patients with treatment-emergent serious adverse events
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Pre-dose through 1 hour post-dose at Days 1, 8 and 15

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

4 Jan 20208 Feb 2020

First posted28 Feb 2020
Study start4 Jan 2020
Primary completion2 Feb 2020
Study completion8 Feb 2020

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Toxic Effect of Organophosphate and Carbamate InsecticidesStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Enrolment: 15 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04290039
Sponsor's protocol ID: BP-C-19010
Status last verified: Jun 2023
First submitted: 27 Jan 2020
Last updated: 22 Jun 2023
Results posted: Yes, on ClinicalTrials.gov
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

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 at a glance

From the registry record, last updated by the sponsor on 22 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT04290039
Acronym / sponsor ID: BP-C-19010
Conditions: Toxic Effect of Organophosphate and Carbamate Insecticides
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 15 participants (actual)
Lead sponsor: Biomedical Advanced Research and Development AuthorityUS federal agency
Collaborators: Rho, Inc.
Study start: 4 Jan 2020 (actual)
Primary completion: 2 Feb 2020 (actual)
Study completion: 8 Feb 2020 (actual)
First posted: 28 Feb 2020 (actual)
Results: Posted 11 Aug 2021

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Number of arms: 3

Arm	Type	Receives
Low Dose Sublingual	Active comparator	Drug: Atropine Sulfate Ophthalmic SolutionAtropine 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.
High Dose Sublingual	Active comparator	Drug: Atropine Sulfate Ophthalmic SolutionAtropine 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.
Intravenous (IV)	Active comparator	Drug: Atropine Sulphate InjectionAtropine 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.

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (7 listed)

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.

Key exclusion criteria (17 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Atropine Sulfate Ophthalmic SolutionAtropine 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.	Drug	High Dose Sublingual, Low Dose Sublingual
Atropine Sulphate InjectionAtropine 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).	Drug	Intravenous (IV)

Primary outcome

Area Under the Curve to From Time Zero to Infinity (AUC_∞)
Time frame: 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.
Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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.
Clearance (CL/F)
Time frame: 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.

5 secondary outcomes

Treatment-Emergent Adverse Events
Time frame: Day 1 through Day 21
Treatment-Emergent Serious Adverse Events
Time frame: Day 1 through Day 21
Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness
Time frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15
Xerostomia Assessment - Dryness of Lips
Time frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15
Xerostomia Assessment - Dryness of Tongue
Time frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15

Results and safety

Results posted to the registry on 11 Aug 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Sequence A: Low Dose Sublingual - High Dose Sublingual - IV	5	5
Sequence B: High Dose Sublingual - IV - Low Dose Sublingual	5	5
Sequence C: IV - Low Dose Sublingual - High Dose Sublingual	5	5

Primary outcome: Area Under the Curve to From Time Zero to Infinity (AUC_∞)

Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15. Geometric mean (Geometric Coefficient of Variation). Unit: min*ng/mL

Measure	Low Dose Sublingual n = 11	High Dose Sublingual n = 14	Intravenous n = 14
Value	286.396 (26.6)	493.808 (27.3)	816.465 (22.0)

Low Dose Sublingual vs High Dose Sublingual: Geometric ratio of least-square means: 0.579 (90% CI 0.5265 to 0.6360), Mixed Models Analysis
Low Dose Sublingual vs Intravenous: Geometric ratio of least-square means: 0.349 (90% CI 0.3171 to 0.3839), Mixed Models Analysis
High Dose Sublingual vs Intravenous: Geometric ratio of least-square means: 0.603 (90% CI 0.5524 to 0.6582), Mixed Models Analysis

Population analysed: 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.

Primary outcome: Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t)

Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15. Geometric mean (Geometric Coefficient of Variation). Unit: min*ng/mL

Measure	Low Dose Sublingual n = 14	High Dose Sublingual n = 15	Intravenous n = 14
Value	218.195 (20.2)	408.061 (23.9)	717.665 (23.2)

Low Dose Sublingual vs High Dose Sublingual: Geometric ratio of least-square means: 0.546 (90% CI 0.4971 to 0.6004), Mixed Models Analysis
Low Dose Sublingual vs Intravenous: Geometric ratio of least-square means: 0.306 (90% CI 0.2788 to 0.3367), Mixed Models Analysis
High Dose Sublingual vs Intravenous: Geometric ratio of least-square means: 0.561 (90% CI 0.5104 to 0.6164), Mixed Models Analysis

Population analysed: 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.

Primary outcome: Maximum Concentration (C_max)

Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15. Geometric mean (Geometric Coefficient of Variation). Unit: ng/mL

Measure	Low Dose Sublingual n = 14	High Dose Sublingual n = 15	Intravenous n = 14
Value	0.883 (27.2)	1.639 (30.5)	18.247 (66.9)

Low Dose Sublingual vs High Dose Sublingual: Geometric ratio of least-square means: 0.549 (90% CI 0.4273 to 0.7118), Mixed Models Analysis
Low Dose Sublingual vs Intravenous: Geometric ratio of least-square means: 0.049 (90% CI 0.0381 to 0.0641), Mixed Models Analysis
High Dose Sublingual vs Intravenous: Geometric ratio of least-square means: 0.090 (90% CI 0.0695 to 0.1167), Mixed Models Analysis

Population analysed: 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.

Primary outcome: Time to Maximum Concentration (t_max)

Time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15. Mean (Standard Deviation). Unit: Minutes

Measure	Low Dose Sublingual n = 14	High Dose Sublingual n = 15	Intravenous n = 0
Value	125.4 (69.81)	107.1 (47.78)	–

Population analysed: 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.

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: 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).. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Low Dose Sublingual	0 of 14 (0%)	1 of 14 (7.1%)	0 of 14
High Dose Sublingual	0 of 15 (0%)	1 of 15 (6.7%)	0 of 15
Intravenous	0 of 14 (0%)	4 of 14 (28.6%)	0 of 14

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 22 Jun 2023.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 20159382Rajpal 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.
Background: PubMed 11250628Pai 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.
Individual participant dataSharing planned: No

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Michael Schwartz, MD MPH study chair

Department of Health and Human Services

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Aug 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Area Under the Curve to From Time Zero to Infinity (AUC_∞) (time frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04290039, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jun 2023.