Sublingual Atropine Bioequivalence by Route of Administration (SABER) (SABER)

A Two-Period, Two-Sequence, Two-Treatment, Single-Dose Crossover Study of Atropine Sulfate Ophthalmic Solution (1%) Administered Sublingually vs Atropine Sulfate Administered Intramuscularly for Bioequivalence Determination

A randomized, two-period, two-sequence, crossover study to assess the bioequivalence, bioavailability, and pharmacokinetics (PK) of a single dose of atropine administered sublingually (SL) or intramuscularly (IM) in healthy adult volunteers.

Study Overview

• Status: Not yet recruiting
• Conditions: Atropine Bioequivalence
• Intervention / Treatment: Drug: Atropine Sulfate Ophthalmic Solution USP, 1%; Drug: Atropine Sulfate Injection, USP 8 mg/20 mL (0.4 mg/mL)

Detailed Description

This is a randomized, two-period, two-sequence, crossover study to assess the bioequivalence, bioavailability, and pharmacokinetics (PK) of a single dose of atropine administered SL or IM in healthy adult volunteers. Approximately 46 healthy male and non-pregnant female volunteers will be enrolled to obtain approximately 36 evaluable participants in the per protocol population. Additional participants may be randomized if participants are withdrawn prior to receiving one or both doses of study drug. Eligible participants will be randomized at a 1:1 ratio to receive one of two treatment dosing sequences (A [Visit 1 SL, Visit 2 IM] or B [Visit 1 IM, Visit 2 SL]).

Volunteers will be screened for study participation from Days -14 to -3. After Screening on Day 1, eligible participants will be enrolled and will be randomized to receive dosing sequences A or B. Once randomized, each participant will receive 2 doses of atropine separated by a wash out period of 6 ±1 days. During Visit 1 (Day 1) and Visit 2 (Day 8), participants will be administered SL or IM atropine, according to their randomly assigned dosing sequence. At each dosing visit, blood samples for PK will be collected at time 0 (pre-dose) and at 13 time points post-dose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes and 2, 2.5, 4, 6, and 8 hours after dosing. Participants will be discharged from the clinic after the 8-hour blood sample collection. Participants will be followed for approximately 6 days after their last dose.

• Study Type: Interventional
• Enrollment (Estimated): 46
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Mazen Zari; Phone Number: 913-825-4400; Email: mzari@jcct.com
• Study Contact Backup: Name: Carlos A Fierro, MD; Phone Number: 913-825-4400; Email: cfierro@jcct.com

Study Locations

• United States
  • Kansas
    • Lenexa, Kansas, United States, 66219
      • Johnson County Clin-Trials (JCCT)
      • Contact: Mazen Zari; Phone Number: 913-825-4400; Email: mzari@jcct.com
      • Contact: Carlos A Fierro, MD; Phone Number: 913-825-4400; Email: cfierro@jcct.com
      • Principal Investigator: Carlos A Fierro, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy male and non-pregnant female volunteers between the ages of 18 and 65 years, inclusive, at time of consent.
2. Willing and able to provide written informed consent.

3. Females who are of childbearing potential and are sexually active with a male partner must have used an adequate method of birth control for at least 2 months prior to Screening and must agree to continue using an adequate method of birth control from Screening through Follow-up (Day 15).

   1. A female of childbearing potential is defined as a post onset of 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.
   2. 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 participant's Screening Visit.
4. In the judgment of the investigator, the participant is in good health, based on review of medical history and the results of Screening evaluation (including vital signs, physical examination, 12-lead electrocardiogram [ECG], and Screening laboratory assessments, performed no more than 14 days prior to randomization into the study).
5. Able to comply with the dosing instructions and available to complete the study Schedule of Assessments.

Exclusion Criteria:

1. Females who have a positive pregnancy test or who are breastfeeding.
2. Participants 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 Screening test will not be repeated prior to subsequent dosing).
3. Participants with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or serum creatinine >1.5 × ULN at Screening. (These Screening tests will not be repeated prior to subsequent dosing.)
4. Have known human immunodeficiency virus (HIV), or acute or chronic hepatitis B or hepatitis C infection based on medical history; or test positive for any of these at Screening. Participants who have been effectively treated for hepatitis C, as evidenced by a negative hepatitis C RNA confirmation test and who no longer require antiviral therapy, are eligible for participation. (These Screening tests will not be repeated prior to subsequent dosing.)
5. Participants 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 participant should be terminated from further dosing.
6. Participants 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 participant should be terminated from further dosing.
7. Participants who are current smokers or are currently using any oral nicotine/oral tobacco product (e.g. snuff, chew, lozenges, nicotine gum, pouches) or electronic cigarette or vaping device (e.g., e-cigarette, mod, vape pen, JUUL, e-cigar, e-hookah, e-pipe, vape pods) or have used any of these products within 6 months prior to Screening.
8. Participants with glaucoma and/or history of ocular surgery (including LasikTM), ocular trauma, or congenital ocular disorder.
9. Participants with any history of heart disease, including but not limited to hypertension, coronary artery disease, arrhythmia (treated or untreated), congestive heart failure, pacemaker, history of vasovagal syncope, any supraventricular tachycardia, peripheral vascular disease, or claudication.
10. Participants 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.
11. Participants with a history of partial organic pyloric stenosis, chronic constipation, gastroparesis, or other gastrointestinal motility issues.
12. Participants with a history of xerostomia due to an underlying disease or previous radiation therapy to the head and neck.
13. Males with history of symptomatic prostatic hypertrophy; males or females with a history of urinary hesitancy or retention.
14. Participants with a blood pressure >140/90 mm Hg taken after the participant has been seated and resting for at least five minutes.
15. Participants with a history or current diagnosis of myasthenia gravis.
16. Participants who have donated blood within 8 weeks of Screening or intend to donate blood during the study period.
17. Participants 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.)
18. Participants with a known sensitivity or prior adverse reaction to atropine.
19. Participants who have consumed alcohol within 24 hours prior to each Pre-dose Visit. (This will be assessed only at Visit 1 [Pre-dose] and Visit 2 [Pre-dose].)
20. Participants with any other condition that, in the opinion of the investigator, would pose a health risk to the participant if enrolled, would interfere with SL or IM administration of study drug, or would otherwise interfere with interpretation of study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sublingual; 1 mg (100 µL of a 1% w/v solution), administered SL by pipette with at least a 30 second dwell time without swallowing.	Drug: Atropine Sulfate Ophthalmic Solution USP, 1%; Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch & Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.
Active Comparator: Intramuscular; Multidose vial presentation, 1 mg (2.5 ml) administered by IM injection into the mid-anterolateral thigh.	Drug: Atropine Sulfate Injection, USP 8 mg/20 mL (0.4 mg/mL); Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi 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; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The bioequivalence of atropine sulfate administered SL versus administered IM as measured by area under the analyte concentration versus time curve to infinity (AUCinf).	Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and route using noncompartmental analysis (NCA) methods. AUCinf is summarized by route of administration 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. Bioequivalence will be considered met if the 90% CI of the ratio for AUCinf lies within 80.00 to 125.00%.	Pre-dose through 8 hours post-dose at Days 1 and 8
The bioequivalence of atropine sulfate administered SL versus administered IM as measured by area under the analyte concentration versus time curve to time of last quantifiable data point (AUCt).	Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and route using noncompartmental analysis (NCA) methods. AUCt is summarized by route of administration 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. Bioequivalence will be considered met if the 90% CI of the ratio for AUCt lies within 80.00 to 125.00%.	Pre-dose through 8 hours post-dose at Days 1 and 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The relative bioavailability of atropine sulfate administered SL versus IM as measured by area under the analyte concentration versus time curve to time 45, 60, 90, 120, 150, and 240 minutes (AUC45, AUC60, AUC90, AUC120, AUC150, and AUC240, respectively)	Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods. AUC45, AUC60, AUC90, AUC120, AUC150, and AUC240 are summarized by route of administration as the geometric mean and coefficient of variation for the geometric mean for all evaluable participants expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.	Pre-dose through 8 hours post-dose at Days 1 and 8
The relative bioavailability of atropine sulfate administered SL versus IM as measured by maximum measured plasma concentration (Cmax)	Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods. C_max is summarized by route of administration as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.	Pre-dose through 8 hours post-dose at Days 1 and 8
The relative bioavailability of atropine sulfate administered SL versus IM as measured by time to Cmax (tmax)	Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods. t_max is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as minutes.	Pre-dose through 8 hours post-dose at Days 1 and 8
The relative bioavailability of atropine sulfate administered SL versus IM as measured by apparent terminal elimination half-life (t1/2)	Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods. t_1/2 is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as minutes.	Pre-dose through 8 hours post-dose at Days 1 and 8
The relative bioavailability of atropine sulfate administered SL versus IM as measured by terminal elimination rate constant (λz)	Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods. λz is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as 1/sec.	Pre-dose through 8 hours post-dose at Days 1 and 8
The relative bioavailability of atropine sulfate administered SL versus IM as measured by volume of distribution (Vd/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 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods. V_d/F is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as liters.	Pre-dose through 8 hours post-dose at Days 1 and 8
The relative bioavailability of atropine sulfate administered SL versus IM as measured by total body 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 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods. CL/F is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as mL/min.	Pre-dose through 8 hours post-dose at Days 1 and 8
The relative bioavailability of atropine sulfate administered SL versus IM as measured by absorption rate constant (Ka)	Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods. Ka is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed 1/sec.	Pre-dose through 8 hours post-dose at Days 1 and 8

Collaborators and Investigators

• Sponsor: Biomedical Advanced Research and Development Authority
• Collaborators: Rho Federal Systems Division, Inc.; Allucent
• Investigators: Study Chair: Derek Eisnor, MD, Biomedical Advanced Research and Development Authority; Study Chair: Michael Schwartz, MD, Biomedical Advanced Research and Development Authority

Study record dates

Study Major Dates

• Study Start (Estimated): April 15, 2024
• Primary Completion (Estimated): May 24, 2024
• Study Completion (Estimated): May 24, 2024

Study Registration Dates

• First Submitted: April 11, 2024
• First Submitted That Met QC Criteria: April 11, 2024
• First Posted (Estimated): April 15, 2024

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 11, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Physiological Effects of Drugs; Peripheral Nervous System Agents; Pharmaceutical Solutions; Anti-Asthmatic Agents; Anti-Arrhythmia Agents; Bronchodilator Agents; Autonomic Agents; Respiratory System Agents; Neurotransmitter Agents; Atropine; Molecular Mechanisms of Pharmacological Action; Adjuvants, Anesthesia; Muscarinic Antagonists; Mydriatics; Parasympatholytics; Ophthalmic Solutions; Cholinergic Agents; Cholinergic Antagonists
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Adjuvants, Anesthesia; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Pharmaceutical Solutions; Mydriatics; Ophthalmic Solutions; Atropine
• Other Study ID Numbers: BP-C-24-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No