Sublingual vs IV Atropine Bioavailability Study

NCT04290039 | Completed Phase 1 Results FDA Drug

• 1 other identifier: BP-C-19010
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Toxic Effect of Organophosphate and Carbamate Insecticides

Outcome Measures

Primary Outcomes (7)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

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

Secondary Outcomes (5)

• Treatment-Emergent Adverse Events

  Day 1 through Day 21

• Treatment-Emergent Serious Adverse Events

  Day 1 through Day 21

• Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness

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

• Xerostomia Assessment - Dryness of Lips

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

• Xerostomia Assessment - Dryness of Tongue

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

Study Arms (3)

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.

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.

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.

Drug: Atropine Sulphate Injection

Interventions

Atropine Sulfate Ophthalmic Solution DRUG

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.

High Dose Sublingual; Low Dose Sublingual

Atropine Sulphate Injection DRUG

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).

Intravenous (IV)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• Females who have a positive pregnancy test or who are breastfeeding
• Subjects with thyroid disease as evidenced by a thyroid-stimulating hormone (TSH) \< 0.9 × lower limit of normal (LLN) or \> 1.2 × upper limit of normal (ULN) at screening. (This test will not be repeated prior to subsequent dosing.)
• Subjects with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or serum creatinine \> 1.5 × ULN at screening. (These tests will not be repeated prior to subsequent dosing.)
• Have known human immunodeficiency virus (HIV), or acute or chronic hepatitis B or hepatitis C infection based on medical history; or test positive for any of these at Screening. Subjects who have been effectively treated for hepatitis C, as evidenced by a negative hepatitis C ribonucleic acid (RNA) confirmation test and who no longer require antiviral therapy, are eligible for participation. (Screening tests will not be repeated prior to subsequent dosing.)
• Subjects who took any prescription medications (with the exception of oral contraceptives or hormone replacement therapy) within 30 days of screening. Prior to each dose, the investigator will review prohibited medication use and determine whether the subject should be terminated from further dosing.
• Subjects who took any over-the-counter medication/vitamins/herbal supplements in the last 72 hours prior to screening. Prior to each dose, the investigator will review prohibited medication use and determine whether the subject should be terminated from further dosing.
• Subjects with glaucoma and/or history of ocular surgery (including Lasik), ocular trauma, or congenital ocular disorder
• Subjects with any history of heart disease including but not limited to coronary artery disease, arrhythmia (treated or untreated), congestive heart failure, pacemaker, history of vasovagal syncope, peripheral vascular disease, or claudication
• Subjects with clinically significant arrhythmias or abnormal conduction; abnormal conduction is defined as a prolonged PR or QRS, or a QTc ≥ 450 msec for males or ≥ 470 msec for females
• Subjects with a history of partial organic pyloric stenosis, chronic constipation, or other gastrointestinal motility issue
• Subjects with a history of xerostomia due to an underlying disease or previous radiation therapy to the head and neck
• Males with history of symptomatic prostatic hypertrophy; males or females with a history of hesitancy or retention
• Subjects with a blood pressure \> 140/90 mm Hg taken after the subject has been seated and resting for at least five minutes
• Subjects with a history or current diagnosis of myasthenia gravis
• Subjects with a history of drug or alcohol abuse in the last two years or evidence of a positive urine drug test at screening. (This screening test will not be repeated prior to subsequent dosing.)

Sponsors & Collaborators

• Biomedical Advanced Research and Development Authority: lead
• Rho, Inc.: collaborator

Study Sites (1)

High Point Clinical Trials Center

High Point, North Carolina, 27265, United States

Location

Related Publications (2)

• 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.

  PMID: 20159382 BACKGROUND

• 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.

  PMID: 11250628 BACKGROUND

MeSH Terms

Interventions

Atropine

Intervention Hierarchy (Ancestors)

Atropine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Organic Chemicals; Belladonna Alkaloids; Solanaceous Alkaloids; Alkaloids; Heterocyclic Compounds; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring

Results Point of Contact

• Title: Brenda Wolling, Regulatory SME
• Organization: BARDA

Brenda.Wolling@hhs.gov

(202) 692-4763

Study Officials

• Michael Schwartz, MD MPH

  Department of Health and Human Services

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 27, 2020
• First Posted: February 28, 2020
• Study Start: January 4, 2020
• Primary Completion: February 2, 2020
• Study Completion: February 8, 2020
• Last Updated: June 22, 2023
• Results First Posted: August 11, 2021

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)