Absolute Oral Bioavailability of Remimazolam

A Randomized, Open-label, Single-dose, 2-way Crossover Study to Compare the Relative Bioavailability of Orally Administered Remimazolam to an Intravenous Formulation in Healthy Volunteers

A randomized, open-label, single-dose, 2-way crossover study to compare the relative bioavailability of orally administered remimazolam to an intravenous formulation in healthy volunteers

Study Overview

• Status: Completed
• Conditions: Bioavailability
• Intervention / Treatment: Drug: Remimazolam

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • PRA Health Sciences (PRA) - Early Development Services (EDS)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Willing to participate in the study, willing to give written informed consent prior to the initiation of any protocol-specific procedures, and willing to comply with the study restrictions.
2. Had to be able to speak, read, and understand English sufficiently to allow completion of all study assessments.
3. Gender : males and/or females
4. Age : 18 - 55 years, inclusive
5. Body mass index (BMI) : 18.0 - 32.0 kg/m2
6. Weight : ≥50 kg
7. Healthy status was defined by the absence of evidence of any clinically significant, in the opinion of the Investigator, active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, clinical chemistry, serology, and urinalysis.
8. Ability and willingness to abstain from alcohol, caffeine, and xanthine-containing beverages or food (eg, coffee, tea, cola, chocolate, energy drinks) from 48 hours (2 days) prior to admission to the clinical facility on Day -1 until study discharge.
9. All values for hematology and for clinical chemistry tests of blood and urine within the normal range or showing no clinically relevant deviations as judged by the Investigator.
10. Females of childbearing potential and males and their female partner(s) of childbearing potential had to agree to use 2 forms of contraception, 1 of which had to be a barrier method, during the study and for 90 days after the last drug administration. Acceptable barrier forms of contraception were condom and diaphragm. Acceptable non-barrier forms of contraception for this study were an intrauterine device (IUD) and/or spermicide.
11. For females: a negative pregnancy test at Screening and Day -1.
12. Postmenopausal females: defined as 12 months with no menses prior to Screening and a serum follicle stimulating hormone (FSH) >40 IU/L at Screening.
13. All non-regular medication (including over-the-counter [OTC] medication, health supplements, and herbal remedies such as St. John's Wort extract) must have been stopped at least 14 days prior to admission to the clinical research center. An exception was made for paracetamol (acetaminophen), which was allowed up to admission to the clinical research center.

Exclusion Criteria:

1. Women who were pregnant or lactating.
2. Males with female partners who were pregnant or lactating.
3. Use of any investigational drug or device within 30 days of the first dose of study medication.
4. Any disease which, in the opinion of the Investigator, posed an unacceptable risk to the subjects.
5. Known allergy, hypersensitivity or prior intolerance to benzodiazepine derivates or flumazenil, or a medical condition such that these agents were contraindicated.
6. The use of tobacco products within 60 days prior to the first drug administration.
7. Routine or chronic use of more than 3 grams of acetaminophen daily.
8. Strenuous activity, sunbathing and contact sports within 48 hours (2 days) prior to admission to the clinical facility and for the duration of the study.
9. History of donation of more than 450 mL of blood within 60 days prior to dosing in the clinical research center or planned donation before 30 days had elapsed since intake of study drug.
10. Plasma or platelet donation within 7 days of dosing and throughout the entire study.
11. History of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol). Alcohol consumption was prohibited from 48 hours prior to admission to the clinical facility and throughout the entire study until discharge.
12. Positive screening test for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies, or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies.
13. Positive results for drugs of abuse, including cotinine, in the urine at Screening or Day -1.
14. Positive results for alcohol abuse, as determined by alcohol breath test, at Screening or Day -1.
15. Inability to be venipunctured or tolerate venous access as determined by the Investigator or designee.
16. History of clinically significant, recent/current and nonremote suicidal ideations or suicide attempts that, in the opinion of the Investigator, posed an unacceptable risk to the subject for participating in the study.
17. Any major surgery within 4 weeks of study drug administration. NOTE: Any parameter/test could be repeated at the Investigator's discretion during Screening and/or on Day -1.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IV remimazolam; IV remimazolam administration of 0.025 mg/kg body weight	Drug: Remimazolam; Other Names: CNS7056
Experimental: Oral remimazolam; Oral remimazolam Administration of 0.14 mg/kg Body weight	Drug: Remimazolam; Other Names: CNS7056

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute oral bioavailability of remimazolam	Single-dose bioavailability of an oral formulation of remimazolam relative to an IV formulation of remimazolam in healthy male and female subjects	Day 1 (pre-dode) to Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma concentration (Cmax)	Maximum observed plasma concentration	Day 1 (pre-dode) to Day 3
Time to Maximum Plasma concentration (Tmax)	Time to attain maximum observed plasma concentration	Day 1 (pre-dode) to Day 3
Area under the plasma concentration-time curve (AUC0-t)	Area under the plasma concentration-time curve from time 0 up to the time of the last measurable concentration	Day 1 (pre-dode) to Day 3
Elimination half-life (T1/2)	Terminal elimination half-life	Day 1 (pre-dode) to Day 3
Clearance (CL/F)	Apparent oral clearance	Day 1 (pre-dode) to Day 3
Volume of Distribution (Vz/F)	Apparent volume of distribution at terminal phase	Day 1 (pre-dode) to Day 3
Incidences of Treatment-emergent adverse events	Incidences of Treatment-emergent adverse events	Day 1 (pre-dode) to Day 3

Collaborators and Investigators

• Sponsor: Paion UK Ltd.
• Collaborators: PRA Health Sciences

Publications and helpful links

General Publications

• Pesic M, Stohr T, Ossig J, Borkett K, Donsbach M, Dao VA, Webster L, Schippers F. Remimazolam Has Low Oral Bioavailability and No Potential for Misuse in Drug-Facilitated Sexual Assaults, with or Without Alcohol: Results from Two Randomised Clinical Trials. Drugs R D. 2020 Sep;20(3):267-277. doi: 10.1007/s40268-020-00317-0.

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2015
• Primary Completion (Actual): November 20, 2015
• Study Completion (Actual): November 20, 2015

Study Registration Dates

• First Submitted: September 27, 2019
• First Submitted That Met QC Criteria: October 1, 2019
• First Posted (Actual): October 2, 2019

Study Record Updates

• Last Update Posted (Actual): October 2, 2019
• Last Update Submitted That Met QC Criteria: October 1, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Other Study ID Numbers: CNS7056-016

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