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A Trial of Intranasal Remimazolam Pharmacokinetics, Pharmacodynamics, Safety and Bioavailability

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ClinicalTrials.gov Identifier: NCT03329014
Recruitment Status : Completed
First Posted : November 1, 2017
Last Update Posted : April 4, 2019
Sponsor:
Collaborator:
PRA Health Sciences
Information provided by (Responsible Party):
Paion UK Ltd.

Brief Summary:
A prospective dose escalation, nine period cross-over trial assessing the safety, pharmacokinetics, bioavailability and pharmacodynamics of escalating doses of Remimazolam when administered intranasally as powder and solution in healthy subjects and compared to an intravenous control

Condition or disease Intervention/treatment Phase
Procedural Sedation Drug: Remimazolam Drug: Placebo Phase 1

Detailed Description:
The design will be a randomized, double-blind, comparative, placebo- and active-controlled nine-period crossover study in healthy male volunteers. Subjects will be randomized and will receive each of the 9 treatments which will be separated by a minimum of 48 hours.The first treatment arm will always be the intravenous remimazolam. Eligible subjects will then be randomized to treatment sequence prior to study drug administration in treatment period 2. Each subject will participate in the study for up to 51 days, from Screening until Follow-up.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled 9-period Crossover, Dose-Escalation Study on the Safety, Bioavailability and Pharmacodynamics of Remimazolam Administered Intranasally as Powder and as Solution in Healthy Subjects
Actual Study Start Date : May 15, 2017
Actual Primary Completion Date : June 9, 2017
Actual Study Completion Date : June 14, 2017

Arm Intervention/treatment
Experimental: Intravenous Remimazolam
4 mg intravenous remimazolam as an intravenous control
Drug: Remimazolam
For induction and maintenance of sedation
Other Name: CNS7056

Experimental: 10 mg Powder Remimazolam
Powder containing 10 mg remimazolam for intranasal administration
Drug: Remimazolam
For induction and maintenance of sedation
Other Name: CNS7056

Experimental: 10 mg Solution Remimazolam
Solution containing 10 mg remimazolam for intranasal administration
Drug: Remimazolam
For induction and maintenance of sedation
Other Name: CNS7056

Experimental: 20 mg Powder Remimazolam
Powder containing 20 mg remimazolam for intranasal administration
Drug: Remimazolam
For induction and maintenance of sedation
Other Name: CNS7056

Experimental: 20 mg solution Remimazolam
Solution containing 20 mg remimazolam for intranasal administration
Drug: Remimazolam
For induction and maintenance of sedation
Other Name: CNS7056

Experimental: 40 mg Powder Remimazolam
Powder containing 40 mg remimazolam for intranasal administration
Drug: Remimazolam
For induction and maintenance of sedation
Other Name: CNS7056

Experimental: 40 mg Solution Remimazolam
Solution containing 40 mg remimazolam for intranasal administration
Drug: Remimazolam
For induction and maintenance of sedation
Other Name: CNS7056

Placebo Comparator: Placebo Powder
Powder containing 20 mg placebo for intranasal administration
Drug: Placebo
Control arm

Placebo Comparator: Placebo solution
Solution containing 20 mg placebo for intranasal administration
Drug: Placebo
Control arm




Primary Outcome Measures :
  1. Number of Participants with Treatment-related Adverse Events [ Time Frame: Predose until 180 minutes postdose ]
    Adverse events assessment will include: change in clinical laboratory assessments from baseline, change in vital signs from baseline, change in 12-lead electrocardiograms from baseline, drop in oxygen saturation measured using continuous pulse oximetry, nasal effect using the Nasal Effect Questionnaire (NEQ) and nose and throat examination. Adverse events with a respiratory or cardiovascular focus and adverse events related to effects seen with medications known to be associated with abuse will be analysed separately. The intensity, causality, outcome, seriousness and expectedness of adverse events will be assessed


Secondary Outcome Measures :
  1. Alertness/Drowsiness using a bipolar 100-point Visual Analogue Scale (VAS) [ Time Frame: Predose until 180 minutes postdose ]
    maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose, 5, 10, 30, 60 and 180 minutes post dose

  2. Agitation/Relaxation using a bipolar 100-point Visual Analogue Scale (VAS) [ Time Frame: Predose until 180 minutes postdose ]
    maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose, 5, 10, 30, 60 and 180 minutes post dose

  3. Any Drug Effects using a unipolar 100-point Visual Analogue Scale (VAS) [ Time Frame: Predose until 180 minutes postdose ]
    maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose, 5, 10, 30, 60 and 180 minutes post dose

  4. Memory/Amnestic Effects using the Paired Associates Learning (PALs) test [ Time Frame: Predose until 180 minutes postdose ]
    maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose,10, 30, 60 and 180 minutes post dose

  5. Reaction Time using the Reaction Time Test [ Time Frame: Predose until 180 minutes postdose ]
    maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose, 20, 30, 60, 90, 120, 150 and 180 post dose

  6. Time to Maximum Observed Plasma Concentration (Tmax) [ Time Frame: From first dose of study drug until 240 minutes postdose ]
  7. Maximum Observed Plasma Concentration (Cmax) [ Time Frame: From first dose of study drug until 240 minutes postdose ]
  8. Area Under the Plasma Concentration-time Curve from Zero to the last Measurable Concentration (AUC0-last) [ Time Frame: From first dose of study drug until 240 minutes postdose ]
  9. Area Under the Plasma Concentration-time Curve from Zero to Infinity (AUC0-∞) [ Time Frame: From first dose of study drug until 240 minutes postdose ]
  10. Terminal Elimination Half-life (t1/2) for Remimazolam and its Metabolite (CNS7054) [ Time Frame: From first dose of study drug until 240 minutes postdose ]
  11. Concentration at Time Zero (C0) for Intravenous Remimazolam and its Metabolite (CNS7054) Only [ Time Frame: From first dose of study drug until 240 minutes postdose ]
  12. The Fraction in Percent as a Measurement of the Rate and Extent to Which a Drug Reaches the Site of Action (F%) [ Time Frame: From first dose of study drug until 240 minutes postdose ]
    F% will be calculated for the highest dose level (40 mg) and dose-proportionality will be evaluated across the dose range of 10 - 40 mg for each formulation (powder and solution) as available. Dose proportionality is AUC0-∞ and Cmax based. Bioavailability will be dose adjusted.



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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Willing to participate in the trial, give written informed consent prior to the initiation of any protocol specific procedures, and to comply with the study restrictions.
  2. Able to speak, read and understand English sufficiently to allow completion of all study assessments.
  3. Gender: males
  4. Age: 18 45 years, inclusive, at screening
  5. Weight: 50 to 120 kg, inclusive, at screening
  6. Body mass index: 19.0 to 33.0 kg/m2, inclusive, at screening
  7. Healthy status, defined by the absence of evidence of any clinically significant, active or chronic diseases, in the opinion of the Investigator, following a detailed medical and surgical history, a complete physical examination, and evaluation of vital signs, 12 lead ECG, hematology, blood chemistry, serology, and urinalysis.
  8. Previous experience with intranasal drug application (within the last year)
  9. Ability and willingness to abstain from alcohol, caffeine, and xanthine containing beverages or food (e.g., coffee, tea, cola, chocolate, energy drinks) from 24 hours (1 day) prior to admission to the clinical facility on Day 0 until study discharge.
  10. 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.

Exclusion Criteria:

  1. Use of any intranasally applied medication within two weeks from randomization.
  2. Use of benzodiazepines or other central nervous system (CNS) active drugs within 4 weeks of inclusion.
  3. History of alcohol abuse or drug addiction (except nicotine), as defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision (DSM V TR), or any self reported dependence or "addiction" within the subject's lifetime (except nicotine or caffeine).
  4. Abnormal 12 lead ECG at screening, including:

    1. QTcF ≥ 450 ms
    2. QRS ≥ 110 ms
    3. PR ≥ 220 ms
    4. Second or third degree AV block
  5. Use of any investigational drug or device within 30 days of the first dose of study medication.
  6. History of relevant food allergies.
  7. Any disease which, in the opinion of the Investigator, poses an unacceptable risk to the subjects.
  8. Known allergy, hypersensitivity or prior intolerance to benzodiazepine derivatives or flumazenil, or a medical condition such that these agents are contraindicated.
  9. Strenuous activity, sunbathing, and contact sports within 48 hours (2 days) prior to (first) admission to the clinical facility and for the duration of the study.
  10. History of donation or loss of more than 450 mL of blood or blood products within 60 days prior to dosing in the clinical research center or planned donation before 30 days has elapsed since intake of study drug in the current study.
  11. 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.
  12. Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines [including ecstasy], barbiturates, benzodiazepines, tricyclic antidepressants and alcohol) at screening and at admission to the clinical research center; subjects positive for cannabinoids will be allowed only at the discretion of the Investigator.
  13. Inability to be venipunctured or tolerate venous access as determined by the Investigator.
  14. History of clinically significant, non remote suicidal ideations or suicide attempts based on the C SSRS that, in the opinion of the Investigator, pose an unacceptable risk to the subject for participating in the study.
  15. Had had any major surgery within 4 weeks of study drug administration.
  16. Requires concomitant treatment with any prescription or non prescription medications (with the exception of acetaminophen) or natural health products (herbal remedies), or respiratory depressants, or cannot safely discontinue these medications at least 7 days prior to receiving study drug.
  17. Subject is an employee of the sponsor or research site personnel directly affiliated with this study or their immediate family member defined as a spouse, parent, child or sibling, whether biological or legally adopted.
  18. A subject who, in the opinion of the investigator, is considered unsuitable or unlikely to comply with the study protocol for any reason.

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): NCT03329014


Locations
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United States, Utah
PRA Health Sciences
Salt Lake City, Utah, United States, 84106
Sponsors and Collaborators
Paion UK Ltd.
PRA Health Sciences
Investigators
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Principal Investigator: Shawn Searly, M.D PRA Health Sciences

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Responsible Party: Paion UK Ltd.
ClinicalTrials.gov Identifier: NCT03329014     History of Changes
Other Study ID Numbers: CNS7056-019
First Posted: November 1, 2017    Key Record Dates
Last Update Posted: April 4, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Pharmaceutical Solutions