Administration of Intranasal Midazolam for Anxiety in Palliative Care

Официальное название

Administration of Intranasal Midazolam for Anxiety in Palliative Care - a Double-blind, Randomized, Placebo-controlled Multicenter Exploratory Pilot Study With a Nested Pharmacokinetic Analysis

Обзор

The goal of this double-blind, randomized, placebo-controlled parallel-group multicenter exploratory pilot study (three study arms) is to describe effects and safety of different doses of intranasal midazolam to treat acute anxiety in palliative care patients, while providing pharmacokinetic and pharmacodynamic data.

Подробное описание

36 patients (12 per study arm) will be enrolled. All patients hospitalized at the four study sites, which are prescribed intranasal midazolam in their as-needed drug regimen and who meet inclusion criteria, are eligible. Patients will be asked for consent at the time of prescription of midazolam by the attending physician. Patients who have provided consent and have been randomized to one of the arms will be included (block randomization).

In a nested analysis, pharmacokinetic properties of all three doses will be analyzed in participants with available venous access.

The primary outcome is the change in patient-reported levels of anxiety from baseline. Secondary outcomes include time until first requested additional dose, cumulative number of doses including time points of administration after the first application, oxygen saturation, heart rate, cortisol levels in oral fluid, levels of sedation on the Richmond Agitation Sedation Scale Palliative Version (RASS-PAL), and occurrence of (serious) adverse events.

The primary and secondary outcomes will be assessed at baseline, i.e., immediately before the intervention (0 minutes) and 30 minutes after the intervention. The secondary outcomes 'Time to first requested additional dose' and 'Cumulative number of doses over 24 hours' as well as (serious) adverse events will be assessed starting 30 minutes after the intervention up to 24 hours after the intervention.

In patients included in the nested pharmacokinetic analysis, basic pharmacokinetic parameters will additionally be assessed at 10 time points, starting at baseline (0 minutes) up to 240 minutes after the intervention.

Вмешательства

• Препарат Placebo Nasal Spray 0 mg/spray
  A unit-dose nasal spray will be used for the intervention. 1 spray (= 0.1 μl = 0 mg midazolam/spray) in each nostril, i.e., no active compound
• Препарат Midazolam Nasal Spray 0.45 mg/spray
  A unit-dose nasal spray will be used for the intervention. 1 spray (= 0.1 μl = 0.45 mg midazolam/spray) in each nostril, i.e., total dose of midazolam 0.9 mg
• Препарат Midazolam Nasal Spray 0.9 mg/spray
  A unit-dose nasal spray will be used for the intervention. 1 spray (= 0.1 μl = 0.9 mg midazolam/spray) in each nostril, i.e., total dose of midazolam 1.8 mg

Первичные конечные точки

• Change from baseline in anxiety levels, measured by Visual Analogue Scale (VAS) and quantified by Numerical Rating Scale (NRS) [Срок оценки: t [0 minutes, 30 minutes]]

Вторичные конечные точки (11)

• Sedation [Срок оценки: t [0 minutes, 30 minutes]]
• Oxygen saturation SaO2 (percent %) [Срок оценки: t [0 minutes, 30 minutes]]
• Heart rate (bpm) [Срок оценки: t [0 minutes, 30 minutes]]
• Cortisol levels in oral fluid [Срок оценки: t [0 minutes, 30 minutes]]
• Time to first requested additional dose [Срок оценки: t [starting assessment 30 minutes after intervention up to 24 hours after intervention]]
• Cumulative number of doses over 24 hours [Срок оценки: t [starting assessment 30 minutes after intervention up to 24 hours after intervention]]
• Number of patients with adverse drug events (ADEs) [Срок оценки: t [starting immediately after intervention up to 24 hours after intervention]]
• Peak plasma concentration (Cmax) [Срок оценки: t [0 minutes up to 240 minutes after intervention]]
• Time to reach the peak plasma concentration (Tmax) [Срок оценки: t [0 minutes up to 240 minutes after intervention]]
• Elimination half-life (t1/2) [Срок оценки: t [0 minutes up to 240 minutes after intervention]]
• Area under the curve (AUC0-Τ, AUC0-∞) [Срок оценки: t [0 minutes up to 240 minutes after intervention]]

Критерии участия

Критерии включения

• Adult palliative care patients (≥ 18 years) hospitalized at one of the study sites
• Self-reported acute anxiety with clinical indication for intranasal midazolam administration according to attending physician
• Patient willing and able to provide written informed consent
• Informed consent as documented by signature
• Patient willing and able to complete anxiety assessment
• Additionally for nested pharmacokinetic analysis: Patients with available central or peripheral venous access, i.e., peripheral venous catheter (PVC), central venous catheter (CVC), peripherally inserted central venous catheter (PICC) line, midline catheter, or PORT-A-CATH® (PAC), and patient willing and able to provide blood samples

Критерии исключения

• Intranasal midazolam prescribed for seizures
• Midazolam (any route of administration) prescribed and administered for continuous sedation
• History of allergy or hypersensitivity to midazolam
• History of benzodiazepine-related paradoxical reaction to midazolam
• Acute narrow-angle glaucoma
• Impaired nasal absorption (e.g., nasogastric tube, nasal obstruction, nasal polyps, etc.)
• Intranasal midazolam within 24 h before study enrollment
• Time between informed general consent for study participation through investigators and planned midazolam administration < 24 h
• Co-medication with strong CYP3A4 inducers or inhibitors according to pre-defined list (FDA)
• Recently initiated therapy with strong opioids (i.e., within past 5 days)
• Co-medication with other CNS depressants causing clinically relevant degree of sedation
• Inability to follow the procedures of the study (i.e., provision of Informed Consent, completion of assessment tool, e.g., due to language problems or dementia)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Швейцария · 5 центров

• Palliativzentrum Bethesda Spital — Basel
• Inselspital, Universitätsspital Bern — Bern
• Universitäres Zentrum für Palliative Care (UZP) — Bern
• Zentrum für Palliative Care, Stadtspital Zürich — Zurich
• Kompetenzzentrum Palliative Care, Universitätsspital Zürich — Zurich

Идентификаторы

NCT: NCT06330584 · 2024-00873

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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