Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Sublingual vs IV Atropine Bioavailability Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04290039
Recruitment Status : Completed
First Posted : February 28, 2020
Last Update Posted : February 28, 2020
Sponsor:
Collaborator:
Rho, Inc.
Information provided by (Responsible Party):
Biomedical Advanced Research and Development Authority

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).

Condition or disease Intervention/treatment Phase
Toxic Effect of Organophosphate and Carbamate Insecticides Drug: Atropine Sulfate Ophthalmic Solution Drug: Atropine Sulphate Injection Phase 1

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).

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Three-Sequence, Three-Period Crossover Study to Assess the Bioavailability and Pharmacokinetics of a Single Dose of Atropine Administered Sublingually in Healthy Adult Volunteers
Actual Study Start Date : January 4, 2020
Actual Primary Completion Date : February 2, 2020
Actual Study Completion Date : February 8, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Sequence A - 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.

Drug: 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.

Active Comparator: Sequence B - 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.

Drug: 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.

Active Comparator: Sequence C - 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.

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).




Primary Outcome Measures :
  1. Bioavailability (AUC∞) [ Time Frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15 ]
    To assess in vivo bioequivalence of atropine sulfate administered sublingually versus intravenously by measurement of sequential plasma concentrations for determination of the area under the analyte concentration versus time curve to infinity (AUC∞).

  2. Bioavailability (AUCt) [ Time Frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15 ]
    To assess in vivo bioequivalence of atropine sulfate administered sublingually versus intravenously by measurement of sequential plasma concentrations for determination of area under the analyte concentration versus time curve to time of last quantifiable data point (AUCt).

  3. Cmax [ Time Frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15 ]
    To assess in vivo bioequivalence of atropine sulfate administered sublingually versus intravenously by measurement of sequential plasma concentrations for determination of the maximum measured plasma concentration (Cmax).

  4. Tmax [ Time Frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15 ]
    To assess in vivo bioequivalence of atropine sulfate administered sublingually versus intravenously by measurement of sequential plasma concentrations for determination of time to Cmax (tmax).

  5. Terminal Elimination Half-Life [ Time Frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15 ]
    To assess in vivo bioequivalence of atropine sulfate administered sublingually versus intravenously by measurement of sequential plasma concentrations for determination of apparent terminal elimination half-life (t½).

  6. Volume of Distribution [ Time Frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15 ]
    To assess in vivo bioequivalence of atropine sulfate administered sublingually versus intravenously by measurement of sequential plasma concentrations for determination of apparent total body clearance after extracascular administration (CL/F).

  7. Clearance [ Time Frame: Pre-dose through 8 hours post-dose at Days 1, 8 and 15 ]
    To assess in vivo bioequivalence of atropine sulfate administered sublingually versus intravenously by measurement of sequential plasma concentrations for determination of apparent total volume of distribution after extravascular administration (Vd/F).


Secondary Outcome Measures :
  1. Treatment-Emergent Adverse Events [ Time Frame: Day 1 through Day 21 ]
    Number of patients with treatment-emergent Adverse Events

  2. Treatment-Emergent Serious Adverse Events [ Time Frame: Day 1 through Day 21 ]
    Number of patients with treatment-emergent Serious Adverse Events

  3. Xerostomia Assessment - Difficulty Swallowing Due to Mouth Dryness [ Time Frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15 ]
    The average xerostomia score of difficulty swallowing due to mouth dryness, assessed by questionnaire (0-10 point scale) previously validated for measurement of salivary gland dysfunction

  4. Xerostomia Assessment - Dryness of Lips [ Time Frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15 ]
    The average xerostomia score of dryness of lips, assessed by questionnaire (0-10 point scale) previously validated for measurement of salivary gland dysfunction

  5. Xerostomia Assessment - Dryness of Tongue [ Time Frame: Pre-dose through 1 hour post-dose at Days 1, 8 and 15 ]
    The average xerostomia score of dryness of tongue, assessed by questionnaire (0-10 point scale) previously validated for measurement of salivary gland dysfunction



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04290039


Locations
Layout table for location information
United States, North Carolina
High Point Clinical Trials Center
High Point, North Carolina, United States, 27265
Sponsors and Collaborators
Biomedical Advanced Research and Development Authority
Rho, Inc.
Investigators
Layout table for investigator information
Study Chair: Michael Schwartz, MD MPH Department of Health and Human Services
Publications:
Layout table for additonal information
Responsible Party: Biomedical Advanced Research and Development Authority
ClinicalTrials.gov Identifier: NCT04290039    
Other Study ID Numbers: BP-C-19010
First Posted: February 28, 2020    Key Record Dates
Last Update Posted: February 28, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Atropine
Ophthalmic Solutions
Pharmaceutical Solutions
Adjuvants, Anesthesia
Anti-Arrhythmia Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Mydriatics
Parasympatholytics
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action