Administration of Intranasal Midazolam for Anxiety in Palliative Care (AIM Care)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Anxiety; Acute Anxiety
• Intervention / Treatment: Drug: Placebo Nasal Spray 0 mg/spray; Drug: Midazolam Nasal Spray 0.45 mg/spray; Drug: Midazolam Nasal Spray 0.9 mg/spray

Detailed Description

30 patients (10 patients per study arm) will be enrolled. All patients hospitalized at the three 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. 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 adverse drug 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. Two of the secondary outcomes ('Time to first requested additional dose' and 'Cumulative number of doses over 24 hours') 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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Manuel Haschke, MD; Phone Number: +41 (0)31 632 67 93; Email: manuel.haschke@insel.ch
• Study Contact Backup: Name: Ursina Wernli, MSc; Email: ursina.wernli@students.unibe.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital, Universitätsspital Bern
    • Contact: Manuel Haschke, MD; Phone Number: +41 (0)31 632 67 93; Email: manuel.haschke@insel.ch
    • Principal Investigator: Manuel Haschke
  • Bern, Switzerland
    • Universitäres Zentrum für Palliative Care (UZP)
    • Contact: Steffen Eychmüller, MD; Phone Number: +41 (0)31 632 51 07; Email: steffen.eychmueller@insel.ch
  • Zürich, Switzerland, 8037
    • Zentrum für Palliative Care, Stadtspital Zürich
    • Contact: Andreas Major, MD; Phone Number: +41 (0)44 417 29 26; Email: andreas.major@stadtspital.ch
  • Zürich, Switzerland, 8091
    • Kompetenzzentrum Palliative Care, Universitätsspital Zürich
    • Contact: Caroline Hertler, MD; Phone Number: +41 (0)44 255 29 34; Email: caroline.hertler@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• 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
• Intake of grapefruit or its juice
• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Total dose of midazolam = 0 mg (no active compound)	Drug: 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
Active Comparator: Standard of Care (SOC); Total dose of midazolam = 0.9 mg	Drug: 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
Active Comparator: Double Dose of Standard of Care (2xSOC); Total dose of midazolam = 1.8 mg	Drug: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in anxiety levels, measured by Visual Analogue Scale (VAS)	Patient-reported levels of anxiety, measured by VAS (0-100 mm, from left 'no anxiety at all' to right 'worst possible anxiety') at baseline (0 minutes) and 30 minutes after study drug or placebo administration.	t [0 minutes, 30 minutes]
Change from baseline in anxiety levels, measured by Numerical Rating Scale (NRS)	Patient-reported levels of anxiety, measured by NRS (0-10, 0 = 'no anxiety at all' to 10 = 'worst possible anxiety') at baseline (0 minutes) and 30 minutes after study drug or placebo administration.	t [0 minutes, 30 minutes]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sedation	Richmond Agitation Sedation Scale Palliative Version (RASS-PAL) The RASS-PAL ranges from +4 (combative) to -5 (not rousable), where a higher score (below 0) is associated with agitation and a lower score (below 0) is associated with sedation. A score of 0 (alert and calm) is considered the most balanced state.	t [0 minutes, 30 minutes]
Oxygen saturation SaO2 (percent %)	Oxygen saturation	t [0 minutes, 30 minutes]
Heart rate (bpm)		t [0 minutes, 30 minutes]
Cortisol levels in oral fluid		t [0 minutes, 30 minutes]
Time to first requested additional dose	30 minutes after the intervention, additional doses may be administered as-needed. The time point until the first additional dose starting 30 minutes after the intervention is assessed. The time point can occur anywhere between 30 minutes and 24 hours after the intervention.	t [starting assessment 30 minutes after intervention up to 24 hours after intervention]
Cumulative number of doses over 24 hours	As additional doses may be administered after 30 minutes after the intervention, every additional requested dose is assessed and the total number of doses over 24 hours after the intervention is calculated.	t [starting assessment 30 minutes after intervention up to 24 hours after intervention]
Number of patients with adverse drug events (ADEs)		t [starting assessment 30 minutes after intervention up to 24 hours after intervention]
Peak plasma concentration (Cmax)	Pharmacokinetic parameter obtained by non-compartmental analysis (NCA) or compartmental analysis (CA) in a pre-defined eligible subset of patients (i.e., patients with a central or peripheral venous access). There will be 10 measurement points: at baseline (0 minutes, i.e., before intervention) and at t [2.5, 5, 10, 15, 30, 60, 120, 180, 240 minutes].	t [0 minutes up to 240 minutes after intervention]
Time to reach the peak plasma concentration (Tmax)	Pharmacokinetic parameter obtained by non-compartmental analysis (NCA) or compartmental analysis (CA) in a pre-defined eligible subset of patients (i.e., patients with a central or peripheral venous access). There will be 10 measurement points: at baseline (0 minutes, i.e., before intervention) and at t [2.5, 5, 10, 15, 30, 60, 120, 180, 240 minutes].	t [0 minutes up to 240 minutes after intervention]
Elimination half-life (t1/2)	Pharmacokinetic parameter obtained by non-compartmental analysis (NCA) or compartmental analysis (CA) in a pre-defined eligible subset of patients (i.e., patients with a central or peripheral venous access). There will be 10 measurement points: at baseline (0 minutes, i.e., before intervention) and at t [2.5, 5, 10, 15, 30, 60, 120, 180, 240 minutes].	t [0 minutes up to 240 minutes after intervention]
Area under the curve (AUC0-Τ, AUC0-∞)	Pharmacokinetic parameter obtained by non-compartmental analysis (NCA) or compartmental analysis (CA) in a pre-defined eligible subset of patients (i.e., patients with a central or peripheral venous access). There will be 10 measurement points: at baseline (0 minutes, i.e., before intervention) and at t [2.5, 5, 10, 15, 30, 60, 120, 180, 240 minutes].	t [0 minutes up to 240 minutes after intervention]

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: University Hospital, Basel, Switzerland; University Hospital, Zürich; Stadtspital Zürich
• Investigators: Study Chair: Carla Meyer-Massetti, PhD, Inselspital, Universitätsspital Bern

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): October 31, 2024

Study Registration Dates

• First Submitted: March 6, 2024
• First Submitted That Met QC Criteria: March 18, 2024
• First Posted (Actual): March 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Anxiety; Palliative Care; Midazolam; Nasal Spray; Acute anxiety
• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: AIM Care Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No