Trial Outcomes & Findings for Sublingual vs IV Atropine Bioavailability Study (NCT NCT04290039)

NCT ID: NCT04290039

Last Updated: 2023-06-22

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 15 participants
• Primary outcome timeframe: Pre-dose through 8 hours post-dose at Days 1, 8 and 15
• Results posted on: 2023-06-22

Participant Flow

Participant milestones

Measure	Sequence A: Low Dose Sublingual - High Dose Sublingual - IV Subjects assigned to treatment dosing sequence A will receive a low dose sublingually at Visit 1; Day 1 (Period 1), a high dose sublingually at Visit 2; Day 8 (Period 2) and an IV dose at Visit 3; Day 15 (Period 3).	Sequence B: High Dose Sublingual - IV - Low Dose Sublingual Subjects assigned to treatment dosing sequence B will receive a high dose sublingually at Visit 1; Day 1 (Period 1), an IV dose at Visit 2; Day 8 (Period 2) and a low dose sublingually at Visit 3; Day 15 (Period 3).	Sequence C: IV - Low Dose Sublingual - High Dose Sublingual Subjects assigned to treatment dosing sequence C will receive an IV dose at Visit 1; Day 1 (Period 1), a low dose sublingually at Visit 2; Day 8 (Period 2), and a high dose sublingually at Visit 3; Day 15 (Period 3).
Period 1 (Visit 1; Day 1) STARTED	5	5	5
Period 1 (Visit 1; Day 1) COMPLETED	5	5	5
Period 1 (Visit 1; Day 1) NOT COMPLETED	0	0	0
Period 2 (Visit 2; Day 8) STARTED	5	5	5
Period 2 (Visit 2; Day 8) COMPLETED	5	5	5
Period 2 (Visit 2; Day 8) NOT COMPLETED	0	0	0
Period 3 (Visit 3; Day 15) STARTED	5	4	5
Period 3 (Visit 3; Day 15) COMPLETED	5	4	5
Period 3 (Visit 3; Day 15) NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Sublingual vs IV Atropine Bioavailability Study

Baseline characteristics by cohort

Measure	A: Low Dose Sublingual - High Dose Sublingual - IV n=5 Participants 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).	B: High Dose Sublingual - IV - Low Dose Sublingual n=5 Participants 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).	C: Intravenous (IV)-Low Dose Sublingual-High Dose Sublingual n=5 Participants 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).	Total n=15 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	5 Participants n=5 Participants	5 Participants n=7 Participants	5 Participants n=5 Participants	15 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Continuous	37.2 years STANDARD_DEVIATION 7.46 • n=5 Participants	29.2 years STANDARD_DEVIATION 5.76 • n=7 Participants	35.0 years STANDARD_DEVIATION 3.87 • n=5 Participants	33.8 years STANDARD_DEVIATION 6.47 • n=4 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	8 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	13 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	8 Participants n=4 Participants
Race (NIH/OMB) White	1 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Region of Enrollment United States	5 participants n=5 Participants	5 participants n=7 Participants	5 participants n=5 Participants	15 participants n=4 Participants
Body Mass Index	24.76 kg/m^2 n=5 Participants	25.16 kg/m^2 n=7 Participants	34.13 kg/m^2 n=5 Participants	29.55 kg/m^2 n=4 Participants
Screening Xerostomia Assessment - Difficulty Swallowing (0-10)	0 Scores on a scale STANDARD_DEVIATION 0 • n=5 Participants	0 Scores on a scale STANDARD_DEVIATION 0 • n=7 Participants	0 Scores on a scale STANDARD_DEVIATION 0 • n=5 Participants	0 Scores on a scale STANDARD_DEVIATION 0 • n=4 Participants
Screening Xerostomia Assessment - Dryness of Lips (0-10)	0.4 Scores on a scale STANDARD_DEVIATION 0.55 • n=5 Participants	1.6 Scores on a scale STANDARD_DEVIATION 2.07 • n=7 Participants	0.2 Scores on a scale STANDARD_DEVIATION 0.45 • n=5 Participants	0.7 Scores on a scale STANDARD_DEVIATION 1.33 • n=4 Participants
Screening Xerostomia Assessment - Dryness of Tongue (0-10)	0 Scores on a scale STANDARD_DEVIATION 0 • n=5 Participants	0 Scores on a scale STANDARD_DEVIATION 0 • n=7 Participants	0 Scores on a scale STANDARD_DEVIATION 0 • n=5 Participants	0 Scores on a scale STANDARD_DEVIATION 0 • n=4 Participants

PRIMARY outcome

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

Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable period.

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.

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=11 Participants 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.	High Dose Sublingual n=14 Participants 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.
Area Under the Curve to From Time Zero to Infinity (AUC_∞)	816.465 min*ng/mL Geometric Coefficient of Variation 22.0	286.396 min*ng/mL Geometric Coefficient of Variation 26.6	493.808 min*ng/mL Geometric Coefficient of Variation 27.3

PRIMARY outcome

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

Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable period.

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.

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=14 Participants 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.	High Dose Sublingual n=15 Participants 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.
Area Under the Curve From Time Zero to Last Quantifiable Timepoint (AUC_t)	717.665 min*ng/mL Geometric Coefficient of Variation 23.2	218.195 min*ng/mL Geometric Coefficient of Variation 20.2	408.061 min*ng/mL Geometric Coefficient of Variation 23.9

PRIMARY outcome

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

Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable period.

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.

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=14 Participants 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.	High Dose Sublingual n=15 Participants 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.
Maximum Concentration (C_max)	18.247 ng/mL Geometric Coefficient of Variation 66.9	0.883 ng/mL Geometric Coefficient of Variation 27.2	1.639 ng/mL Geometric Coefficient of Variation 30.5

PRIMARY outcome

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

Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable periods for extravascular (sublingual) routes of administration. Note: t\_max was not applicable to intravenous dosing.

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.

Outcome measures

Measure	Intravenous 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.	Low Dose Sublingual n=14 Participants 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.	High Dose Sublingual n=15 Participants 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.
Time to Maximum Concentration (t_max)	—	125.4 Minutes Standard Deviation 69.81	107.1 Minutes Standard Deviation 47.78

PRIMARY outcome

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

Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable period.

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.

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=11 Participants 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.	High Dose Sublingual n=14 Participants 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.
Terminal Elimination Half-Life (t_1/2)	179.327 Minutes Standard Deviation 60.412	176.187 Minutes Standard Deviation 75.0887	171.258 Minutes Standard Deviation 49.9828

PRIMARY outcome

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

Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable periods for extravascular (sublingual) routes of administration. Note: V\_d/F is not applicable to intravenous dosing.

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.

Outcome measures

Measure	Intravenous 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.	Low Dose Sublingual n=11 Participants 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.	High Dose Sublingual n=14 Participants 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.
Volume of Distribution (V_d/F)	—	423.71 L Standard Deviation 119.774	496.70 L Standard Deviation 138.811

PRIMARY outcome

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

Population: The PK analysis population includes all subjects who were randomized, received at least 1 study drug dose, and have PK samples collected for the applicable periods for extravascular (sublingual) routes of administration. Note: CL/F is not applicable to intravenous dosing.

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.

Outcome measures

Measure	Intravenous 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.	Low Dose Sublingual n=11 Participants 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.	High Dose Sublingual n=14 Participants 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.
Clearance (CL/F)	—	1800.800 mL/min Standard Deviation 473.3604	2098.806 mL/min Standard Deviation 632.8211

SECONDARY outcome

Timeframe: Day 1 through Day 21

Population: The Safety population includes all subjects who were randomized and received at least 1 study drug dose.

Number of patients with treatment-emergent adverse events

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=14 Participants 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.	High Dose Sublingual n=15 Participants 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.
Treatment-Emergent Adverse Events	4 Participants	1 Participants	1 Participants

SECONDARY outcome

Timeframe: Day 1 through Day 21

Population: The Safety population includes all subjects who were randomized and received at least 1 study drug dose.

Number of patients with treatment-emergent serious adverse events

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=14 Participants 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.	High Dose Sublingual n=15 Participants 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.
Treatment-Emergent Serious Adverse Events	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Pre-dose through 1 hour post-dose at Days 1, 8 and 15

Population: The Safety population includes all subjects who were randomized and received at least 1 study drug dose.

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.

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=14 Participants 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.	High Dose Sublingual n=15 Participants 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.
Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness	2.0 Scores on a scale Standard Deviation 2.77	0.3 Scores on a scale Standard Deviation 1.07	0.3 Scores on a scale Standard Deviation 0.82

SECONDARY outcome

Timeframe: Pre-dose through 1 hour post-dose at Days 1, 8 and 15

Population: The Safety population includes all subjects who were randomized and received at least 1 study drug dose.

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.

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=14 Participants 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.	High Dose Sublingual n=15 Participants 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.
Xerostomia Assessment - Dryness of Lips	2.9 Maximum Score Standard Deviation 2.88	1.1 Maximum Score Standard Deviation 1.38	1.5 Maximum Score Standard Deviation 1.85

SECONDARY outcome

Timeframe: Pre-dose through 1 hour post-dose at Days 1, 8 and 15

Subject reported xerostomia scores were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 10, 20, 30, 40, 50, and 60 minutes. Scores were assessed by questionnaire (0-10 point scale, with 0 being not dry at all and 10 being very dry) previously validated for measurement of salivary gland dysfunction.

The maximum xerostomia score representing dryness of tongue was calculated for each subject and dose. Maximum xerostomia scores were summarized by study dosage as the mean and standard deviation.

Outcome measures

Measure	Intravenous n=14 Participants 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.	Low Dose Sublingual n=14 Participants 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.	High Dose Sublingual n=15 Participants 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.
Xerostomia Assessment - Dryness of Tongue	2.1 Maximum Score Standard Deviation 2.67	0.3 Maximum Score Standard Deviation 0.61	0.3 Maximum Score Standard Deviation 0.46

Adverse Events

Low Dose Sublingual

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

High Dose Sublingual

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Intravenous

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Low Dose Sublingual n=14 participants at risk 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.	High Dose Sublingual n=15 participants at risk 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.	Intravenous n=14 participants at risk 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.
Gastrointestinal disorders Abdominal Pain - Lower	7.1% 1/14 • Number of events 1 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	0.00% 0/15 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	0.00% 0/14 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.
Infections and infestations Upper Respiratory Tract Infection	0.00% 0/14 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	6.7% 1/15 • Number of events 1 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	0.00% 0/14 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.
Nervous system disorders Somnolence	0.00% 0/14 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	0.00% 0/15 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	14.3% 2/14 • Number of events 2 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.
Nervous system disorders Dizziness	0.00% 0/14 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	0.00% 0/15 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	7.1% 1/14 • Number of events 1 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.
Nervous system disorders Headache	0.00% 0/14 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	0.00% 0/15 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	7.1% 1/14 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.
Vascular disorders Flushing	0.00% 0/14 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	0.00% 0/15 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.	7.1% 1/14 • Number of events 1 • 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). Events grade 1 or higher were be recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the NCI-CTCAE Version 5.0.

Additional Information

Brenda Wolling, Regulatory SME

BARDA

Phone: (202) 692-4763

Email: Brenda.Wolling@hhs.gov

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place