Pharmacokinetic Profiles of Subcutaneous vs. Intravenous Midazolam in Terminally Ill Patients in Palliative Care (PK-MID-PAL-study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Akershus University Hospital

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-06-13

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

South-Eastern Norway Regional Health Authority

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Bioequivalence, Pharmacokinetic, Therapy

To estimate the bioavailability of SC versus IV administration of midazolam in terminally ill patients

Secondary objectives 3

1. To estimate early exposure pharmacokinetic profiles of midazolam and metabolite following SC versus IV administration of midazolam in terminally ill patients.
2. To assess the safety and local tolerability of SC and IV midazolam.
3. To assess the sedative effect of SC and IV midazolam.

Conditions and MedDRA coding

Terminal illness requiring palliative care, with indications for parenteral midazolam administration for symptom management (e.g., anxiety, restlessness, agitation, and dyspnea).

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Terminally ill patients with a life expectancy of less than one month.
2. Patients receiving palliative care in the palliative care ward at the study site
3. 18 years of age or older, at the time of signing the informed consent
4. Capable of giving signed informed consent as described in Appendix 1 at inclusion, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
5. The attending physician finds the patient eligible for 1 mg of midazolam administered either SC or IV if symptoms commonly treated with parenteral midazolam, such as anxiety, restlessness, agitation, or insomnia, occur

Exclusion criteria 11

1. Known hypersensitivity to midazolam other benzodiazepines, or any of the excipients listed in point 6.1 of the SmPC for midazolam 1 mg/ml (B. Braun) (sodium chloride, hydrochloric acid, or water for injections).
2. Received midazolam within the past 24 hours before study drug injection.
3. No development of symptoms requiring midazolam within 5 days from inclusion.
4. RASS PAL score of +3 or higher at the time of intervention, or if the next of kin, treating physician, or study personnel determine at that time that conducting serum measurements would pose a burden, even if consent has not been withdrawn.
5. Intake of strong CYP3A4 inducers/inhibitors, as defined by the FDA (U.S. Food and Drug Administration, 2023), within the last 7 days or during the 90-minute intervention period..
6. Hemoglobin < 9.0 g/dL.
7. Acute respiratory depression, defined as a respiratory rate < 8 breaths per minute at the time of intervention
8. Withdrawal of consent between inclusion and intervention, or at any other time
9. Inability to establish venous access for blood sampling and/or IV injection
10. Strong indication for a dose of midazolam other than 1 mg, as judged by the attending physician
11. Clear indication for administration of either IV or SC injection (by consensus of two senior consultants in palliative medicine).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. AUC0-90 of midazolam based on serum samples collected at 2, 5, 7, 10, 12, 15, 20, 25, 30, 40, 50, 60, 75, and 90 minutes post-administration.

Secondary endpoints 8

1. Tmax, Cmax of midazolam and 1-OH-midazolam
2. AUC0-90 for 1-OH-midazolam
3. Metabolic ratio: AUC0-90 (1-OH-midazolam / midazolam).
4. Injection site discomfort (pain, redness, swelling, itching).
5. Change in respiratory rate from baseline at 10, 20, 30, 40, 50, 60, 75, and 90 minutes
6. Change in oxygen saturation from baseline at 10, 20, 30, 40, 50, 60, 75, and 90 minutes
7. Change in RASS-PAL score from baseline at 10, 20, 30, 40, 50, 60, 75, and 90 minutes
8. Time and number of repeated administrations of sedative medication within 90 minutes following study drug injection

Investigational products

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

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Akershus University Hospital

Sponsor organisation

Akershus University Hospital

Address

Sykehusveien 27

City

Lorenskog

Postcode

1478

Country

Norway

Scientific contact point

Organisation

Akershus University Hospital

Contact name

Olav Fredheim (Principal Investigator)

Public contact point

Organisation

Akershus University Hospital

Contact name

Olav Fredheim (Principal Investigator)

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

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

Documents 6 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