Comparative Bioavailability of Midazolam 7.5 mg/1.5 mL Oromucosal Solution (Buccolam®) Versus 10 mg/2 mL Solution for Injection (Hypnovel®) in Healthy Subjects.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Laboratorios Lesvi S.L.

Participant type

Healthy volunteers

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Not possible to specify

Trial duration

16 Aug 2023 → 22 Sep 2023

Decision date (initial)

2023-06-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Laboratorios Lesvi S.L.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Bioequivalence

To investigate the pharmacokinetics of a single dose of midazolam oromucosal solution (Buccolam®) compared to midazolam solution for intramuscular injection (Hypnovel®) in healthy volunteers under fasting conditions.

Secondary objectives 3

1. To assess the safety and tolerability of midazolam oromucosal solution compared to midazolam intramuscular injection in healthy volunteers in fasting conditions.
2. To investigate the effect of age on the pharmacokinetics of midazolam.
3. To investigate the effect of body mass index (BMI) on the pharmacokinetics of midazolam.

Conditions and MedDRA coding

No medical condition.

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Free written informed consent prior to any procedure required by the study.
2. Male or female subject ≥18 years at the time of signing the informed consent.
3. Body mass index (BMI) of 18.5 to 35.0 kg/m2, inclusive, and body weight ≥50 kg.
4. No clinically relevant diseases captured in medical history.
5. No clinically relevant abnormalities on physical examination.
6. No clinically relevant abnormalities on vital signs.
7. No clinically relevant abnormalities on 12-lead ECG.
8. No clinically relevant abnormalities on clinical laboratory tests.
9. Negative test results for anti-Human Immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab), Hepatitis B surface antigen (HBsAg) and anti-Hepatitis C virus antibodies (anti-HCVAb).
10. Non-smoker or ex-smoker (i.e., someone who abstained from using tobacco- or nicotine-containing products for at least 3 months prior to Screening).
11. Willingness to accept and comply with all study procedures and restrictions.
12. A female subject is eligible if she meets one of the following criteria: a) is of non-childbearing potential; or b) is of childbearing potential and agrees to use an accepted contraceptive method from at least 4 weeks prior to admission to the first study period until the end of study.

Exclusion criteria 32

1. Known hypersensitivity / allergy reaction to the study drug substance or any of the excipients.
2. Known severe hypersensitivity reaction to any other drug.
3. Any medical condition (e.g., gastrointestinal, renal or hepatic, including peptic ulcer, inflammatory bowel disease or pancreatitis) or surgical condition (e.g., cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion) or subject safety.
4. History of cardiovascular or respiratory disease.
5. History of renal or hepatic impairment.
6. History of severe respiratory insufficiency.
7. History of sleep apnea syndrome.
8. History of myasthenia gravis.
9. Current or recurrent abnormality in the oral cavity/mucosa.
10. Difficult airway, congenital mouth and tongue enlargement, and mandibular dysplasia.
11. History of alcohol or drug abuse.
12. Serum transaminases ALT or AST above the upper limit of the normal range.
13. Estimated renal creatinine clearance (CLCR) below the lower limit of normal range (i.e., 90-120 mL/min/1.73 m2 for males and 80-110 mL/min/1.73 m2 for females) for subjects with age up to 59 years, or below 80 mL/min/1.73 m2 for males and below 70 mL/min/1.73 m2 for females with age of 60 years or above, based on creatinine clearance calculation by the Cockcroft-Gault formula and normalized to an average surface area of 1.73 m2.
14. Positive result in drugs-of-abuse or ethanol tests.
15. Use of a depot injection or an implant of any drug (except for contraceptives) within the previous 6 months.
16. Average weekly alcohol consumption of >14 units for males and >7 units for females within the previous 6 months.
17. Average daily consumption of methylxanthines-containing beverages or food (e.g., coffee, tea, cola, sodas, chocolate) equivalent to >500 mg of methylxanthines.
18. Participation in any clinical trial within the previous 2 months.
19. Participation in more than 2 clinical trials within the previous 12 months.
20. Blood donation or significant blood loss (≥ 450 mL) due to any reason or had plasmapheresis within the previous 2 months.
21. Difficulty in fasting or any dietary restriction such as lactose intolerance, vegan, low-fat, low sodium, etc., that may interfere with the diet served during the study.
22. Veins unsuitable for intravenous puncture on either arm.
23. If woman, positive pregnancy test in serum.
24. If woman, she is breast-feeding.
25. Any other condition that the Investigator considers to render the subject unsuitable for the study.
26. Any recent disease or condition or treatment that, according to the Investigator, would put the subject at undue risk due to study participation or occurred at a timeframe in which may interfere with the pharmacokinetics of study drug.
27. Use of prescription or nonprescription medicinal products, vitamins, food supplements or herbal supplements (including St John’s Wort) within the previous 2 weeks prior to admission to Period 1 or during the washout period prior to Period 2, unless in the Investigator’s opinion the medication does not interfere with the pharmacokinetics of study drug or compromise subject safety.
28. Use of CYP3A4 or CYP3A5-inhibitor (antiproteases, ketoconazole, itraconazole, erythromycin and clarithromycin) or inducer drugs (e.g., rifampicin, phenobarbital, carbamazepine) within the previous 4 weeks prior to admission to Period 1 or during the washout period prior to Period 2.
29. Consumption of pineapple, Seville oranges, pomelo, pomegranate, starfruit or grapefruit products (fresh, canned, or frozen) within the previous week.
30. Positive result in drugs-of-abuse or ethanol tests.
31. If woman, positive pregnancy test in urine.
32. Any other condition that the investigator considers to render the subject unsuitable for the study period.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Cmax and AUC0-t of midazolam and 1-OH-midazolam will be the primary pharmacokinetic parameters.

Secondary endpoints 3

1. tmax, t1/2,AUC0-∞, %AUCextrap and λz of midazolam and 1-OH-midazolam will be the secondary pharmacokinetic parameters.
2. Occurrence of treatment-emergent adverse events (TEAEs), including clinically relevant abnormalities from clinical laboratory tests and vital signs.
3. Correlation of Cmax and AUC0–t of midazolam and 1-OH-midazolam as dependent variables with age and BMI as independent variables.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Laboratorios Lesvi S.L.

Sponsor organisation

Laboratorios Lesvi S.L.

Address

Avinguda De Barcelona 69, Poligono Industrialde La Fuensanta Poligono Industrialde La Fuensanta

City

Sant Joan Despi

Postcode

08970

Country

Spain

Scientific contact point

Organisation

Laboratorios Lesvi S.L.

Contact name

Clinical Research Department

Public contact point

Organisation

Laboratorios Lesvi S.L.

Contact name

Clinical Research Department

Third parties 4

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications