• To determine the onset of action of IN MDZ as compared to IV MDZ.• To determine extend and duration of the sedative effects of 2.5 mg and 5 mg IN MDZ. • To estimate the absolute and relative bioavailability and dose proportionality of single doses…
ID
Source
Brief title
Condition
- Other condition
- Seizures (incl subtypes)
Synonym
Health condition
Introduction of conscious sedation
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacodynamics:
• Peak Saccadic Velocity
• Visual Analogue Scale (Bond and Lader) for sedation
• Observer*s Assessment of Alertness/Sedation Scale
• Simple Reaction Time Task
Pharmacokinetics:
• AUC 0-t: The area under the plasma concentration time curve, from time 0 to
the last measurable concentration, as calculated by the linear trapezoidal
method.
• AUC0-*: The area under the plasma concentration time curve from time 0 to
infinity.
• AUCextrap: Percent of the AUC located from the last quantifiable plasma
concentration to infinity.
• CL: Total systemic clearance.
• V: Volume of distribution.
• F: Bioavailability.
• Cmax: Maximum measured plasma concentration over the time span specified.
• Tmax: Time of the maximum measured plasma concentration.
• t*: The apparent first-order terminal elimination half-life.
• kel: apparent first-order terminal elimination rate constant.
Safety and tolerability:
• Adverse events, vital signs, ECG, blood hematology and chemistry, pulse
oxymetry and ENT-examination.
Secondary outcome
N.A.
Background summary
Benzodiazepines elicit their pharmacological effects through non-selective
modulation of GABAA-receptors. Midazolam (MDZ) is a short-acting
benzodiazepine. MDZ solution for parenteral use has been administered nasally
in studies for epilepsy and conscious sedation in both patients and healthy
volunteers. These studies showed that parenteral solution is less suitable for
nasal administration because of a low pH and too low concentrations, which
necessitates high volumes to be administered leading to nasal run-off. To avoid
swallowing and gastrointestinal absorption of excess fluid reaching the
oropharynx, the maximal volume of nasal application is ideally restricted to
approximately 100 µL, requiring the dose of MDZ to be solubilized within this
volume. Therefore, highly concentrated solutions with a high bioavailability
are essential to achieve clinically relevant serum concentrations. Availability
of nasal MDZ formulations would offer clinical benefits in conscious sedation
and in lay treatment of patients with epileptic seizures, saving important time
until IV access can be established. There appears to be an unmet need for an
adequate MDZ formulation for nasal delivery.
Study objective
• To determine the onset of action of IN MDZ as compared to IV MDZ.
• To determine extend and duration of the sedative effects of 2.5 mg and 5 mg
IN MDZ.
• To estimate the absolute and relative bioavailability and dose
proportionality of single doses of IN MDZ 2.5 and 5 mg.
• To determine the inter-subject variability of IN MDZ pharmacokinetics.
• To evaluate the safety and tolerability of IN MDZ.
• Optional: to determine possible associations between genetic variation and
the observed pharmacokinetic characteristics.
Study design
This study will be a four way cross over, randomized, double blind, double
dummy study in 16 healthy subjects. For each study subject, the whole
study-period, screening and follow-up visit included, will last at least five
weeks and maximally ten weeks.
A randomized, double blind, double dummy study is selected to avoid bias and to
reduce symptoms arising from the subjects* knowledge of treatment. Placebo
administration is selected to obtain reference data and to avoid bias. Male and
female healthy subjects are chosen to enhance the generalization of the study
results. The four-way crossover plan is designed to balance the carry-over
effects of different medication orders and meet the requirement for power with
a relatively small group of subjects.
The administration of a single dose with at least 6 days apart from the next
treatment will minimize the carry-over effects from previous treatments. 6 days
is longer than expected to be needed for MDZ to be virtually absent in plasma,
based on the known T1/2 el.
Intervention
Midazolam nasal spray, injection and placebo.
Study burden and risks
During the screening clinical significant abnormalities might be discovered,
while during the study after the administration of midazolam, respiratory
depression may occurs.
Amersfoortseweg 6
3951 LB Maarn
NL
Amersfoortseweg 6
3951 LB Maarn
NL
Listed location countries
Age
Inclusion criteria
1. Males and females aged 18-55 years (both inclusive).
2. Females with reproductive potential should agree to remain abstinent or use (and have her partner use) acceptable methods of birth control throughout the study.
3. Voluntary provision of written informed consent prior to any study procedure, indicative of understanding the purpose of the study and willing to participate in the study and comply with the study procedures and restrictions.
Exclusion criteria
1. Subject is unhealthy according to medical history, physical examination, ECG, blood pressure and heart rate, and laboratory profile of blood and urine. A volunteer with a clinical abnormality may be included only if the investigator or his designee considers that the abnormality will not introduce additional risk factor for the subject's health, or interfere with the study objectives.
2. Presence or history of clinical significant psychiatric diseases, as judged by the investigator.
3. Any clinically relevant acute or chronic diseases which according to the investigator could interfere with the subject*s safety during the trial, or expose them to undue risk, or which could interfere with the study objectives.
4. Presence or history of clinical significant diseases of the renal, hepatic, gastrointestinal, cardiovascular, musculoskeletal system or presence of history of clinical significant immunological, endocrine, metabolic diseases, or other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs, as judged by the investigator.
5. Presence or history of clinically significant allergy or known hypersensitivity to any component of the investigational product.
6. Clinically significant upper respiratory infection, common cold or flu -like symptoms and/or rhinitis, as judged by the investigator.
7. Presence or history of clinically significant nasal abnormalities (e.g. polyps or other physical abnormalities), as judged by the investigator.
8. Recent (< 4 weeks) nose bleeds.
9. History of clinically significant nasal surgery that could affect the nasal absorption of midazolam or would result in a reduced tolerability of midazolam, as judged by the investigator.
10. Has a Body Mass Index (BMI) < 18 or > 33 kg/m2.
11. Has positive serology for HIV, hepatitis B (surface antigen), and/or hepatitis C antibodies.
12. Has planned medical treatments (including dental care) between screening and follow-up visit.
13. Use of prescribed medication or over-the-counter (OTC) medication within two weeks prior to dosing, except for paracetamol (up to 1.5 g per day).
14. Enrolment in any investigational study or intake of an investigational drug within 3 months prior to the start of the study or more than 4 times a year.
15. Current regular user of any illicit drugs or history of drug or alcohol abuse and history of any drug use taken intransally (e.g. cocaine). Subjects who have a positive drug screen, or have a positive alcohol breath test at screening will be excluded.
16. Donation of blood/plasma outside limits of Sanquin Blood Supply Foundation guidelines.
17. Unlikely to co-operate in the study, and/or has poor compliance anticipated by the investigator. Or not consistently reachable in case of emergency.
18. Daily consumption of xanthine-containing products more than 8 units. Unwilling or unable to refrain from consumption of xanthine-containing foods or drinks from 1 days prior to admission and during the stay in the research unit. One caffeine unit is contained in the following items: one cup of coffee, two cans of cola, one glass of tea, * cup of energy drink (e.g. Red Bull) or three chocolate bars.
19. Unwilling or unable to refrain from intensive physical exercise from screening until the follow-up visit.
20. Unwilling or unable to refrain from products containing alcohol from 1 days before admission and during the stay in the research unit.
21. Unwilling or unable to refrain from products containing grapefruit and star fruit, from 2 days before admission and during the stay in the research unit.
22. Unwilling or unable to refrain from smoking during admission and the stay in the research unit.
23. Males who are unwilling to abstain from having unprotected sexual intercourse or donating sperm during the study and for 3 months after study.
24. Male*s partner is planning pregnancy within 3 month of last dosing.
25. Is unsuitable, in the opinion of the investigator, to participate in the study for any other reason.
26. Unwilling to refrain from consuming St. Johns Wort, an herbal remedy, from screening until their last assessment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023425-38-NL |
| CCMO | NL34435.058.10 |