Sublingual vs IV Atropine Bioavailability Study

NCT ID: NCT04290039

Last Updated: 2023-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-04
• Study Completion Date: 2020-02-08

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).

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low Dose Sublingual

Atropine sulfate ophthalmic solution, USP 1% is a sterile topical anti-muscarinic indicated for cyclopegia, mydriasis, and penalization of the healthy eye in the treatment of amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains active ingredient: atropine sulfate 10 mg equivalent to 8.3 mg of atropine. Inactive ingredients include benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection, USP. Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in dropper bottles containing 2 mL.

Each bottle will only be used to administer a single dose, to a single subject.

Group Type: ACTIVE_COMPARATOR

Atropine Sulfate Ophthalmic Solution

Intervention Type: 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

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.

Group Type: ACTIVE_COMPARATOR

Atropine Sulfate Ophthalmic Solution

Intervention Type: 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.

Intravenous (IV)

Atropine sulfate injection is indicated for temporary blockade of severe or life-threatening muscarinic effects, e.g., as an antisialagogue, an antivagal agent, an antidote for organophosphorus, carbamate, or muscarinic mushroom poisoning, and to treat symptomatic bradycardia.

Atropine sulfate injection, USP,8mg/20mL (0.4 mg per mL) is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; sodium chloride 9 mg; and may contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8).

Atropine sulfate injection will be supplied in multidose vials containing 20 mL.

Each vial will only be used to administer a single dose, to a single subject.

Group Type: ACTIVE_COMPARATOR

Atropine Sulphate Injection

Intervention Type: 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).

Interventions

Atropine Sulfate Ophthalmic Solution

Atropine sulfate ophthalmic solution, USP 1% is a sterile topical anti-muscarinic indicated for cyclopegia, mydriasis, and penalization of the healthy eye in the treatment of amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains active ingredient: atropine sulfate 10 mg equivalent to 8.3 mg of atropine. Inactive ingredients include benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection, USP.

Intervention Type: DRUG

Atropine Sulphate Injection

Atropine sulfate injection, USP, 8mg/20mL (0.4 mg per mL) is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; sodium chloride 9 mg; and may contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8).

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Healthy male and nonpregnant female volunteers between the ages of 18 and 55 years at time of randomization

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 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.

4. 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)

5. Able to comply with the dosing instructions and available to complete the study Schedule of Events

Exclusion Criteria

1. Females who have a positive pregnancy test or who are breastfeeding

2. 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.)

3. 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.)

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. 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.)

5. 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.

6. 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.

7. Subjects with glaucoma and/or history of ocular surgery (including Lasik), ocular trauma, or congenital ocular disorder

8. 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

9. 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

10. Subjects with a history of partial organic pyloric stenosis, chronic constipation, or other gastrointestinal motility issue

11. Subjects with a history of xerostomia due to an underlying disease or previous radiation therapy to the head and neck

12. Males with history of symptomatic prostatic hypertrophy; males or females with a history of hesitancy or retention

13. Subjects with a blood pressure > 140/90 mm Hg taken after the subject has been seated and resting for at least five minutes

14. Subjects with a history or current diagnosis of myasthenia gravis

15. 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.)

16. 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Rho, Inc.

INDUSTRY

Sponsor Role: collaborator

Biomedical Advanced Research and Development Authority

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Schwartz, MD MPH

Role: STUDY_CHAIR

Department of Health and Human Services

Locations

High Point Clinical Trials Center

High Point, North Carolina, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 20159382 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11250628 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

BP-C-19010

Identifier Type: -

Identifier Source: org_study_id