Administration of Intranasal Midazolam for Anxiety in Palliative Care - a Double-blind, Randomized, Placebo-controlled Multicenter Exploratory Pilot Study With a Nested Pharmacokinetic Analysis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 36
- 试验地点
- 5
- 主要终点
- Change from baseline in anxiety levels, measured by Visual Analogue Scale (VAS) and quantified by Numerical Rating Scale (NRS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
All study personnel except the personnel at the facility preparing the investigational medicinal product (IMP) (Hospital Pharmacy, University Hospital Basel), and all patients will be blinded to the assigned treatment. Allocation will be concealed using sequentially coded drug packs (using consecutive patient identification numbers from 1 to 36) containing the IMP that are otherwise identical. Each drug pack will contain two nasal sprays of identical appearance. Patients and all trial personnel involved in recruitment and care of patients, trial assessment, monitoring, and analyses will be blinded to the assigned trial arm. Blinding will be upheld until the last patient (36 patients, i.e., 12 per study arm) has completed the pilot study and data entry into the trial database has been completed.
To safeguard blinding, placebo formulation will be produced with the same pH as the active study drug formulations to mimic nasal irritation induced by verum sprays.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
Placebo
Total dose of midazolam = 0 mg (no active compound)
干预措施: Placebo Nasal Spray 0 mg/spray (Drug)
Standard of Care (SOC)
Total dose of midazolam = 0.9 mg
干预措施: Midazolam Nasal Spray 0.45 mg/spray (Drug)
Double Dose of Standard of Care (2xSOC)
Total dose of midazolam = 1.8 mg
干预措施: Midazolam Nasal Spray 0.9 mg/spray (Drug)
结局指标
主要结局
Change from baseline in anxiety levels, measured by Visual Analogue Scale (VAS) and quantified by Numerical Rating Scale (NRS)
时间窗: t [0 minutes, 30 minutes]
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. The VAS response will be quantified measuring the distance in mm from zero to the position of the VAS response on a ruler (=100 mm, separated by 1 mm intervals), with 0 mm representing absence of anxiety, and 100 mm representing maximal possible anxiety.
次要结局
- Sedation(t [0 minutes, 30 minutes])
- Oxygen saturation SaO2 (percent %)(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(t [starting assessment 30 minutes after intervention up to 24 hours after intervention])
- Cumulative number of doses over 24 hours(t [starting assessment 30 minutes after intervention up to 24 hours after intervention])
- Number of patients with adverse drug events (ADEs)(t [starting immediately after intervention up to 24 hours after intervention])
- Peak plasma concentration (Cmax)(t [0 minutes up to 240 minutes after intervention])
- Time to reach the peak plasma concentration (Tmax)(t [0 minutes up to 240 minutes after intervention])
- Elimination half-life (t1/2)(t [0 minutes up to 240 minutes after intervention])
- Area under the curve (AUC0-Τ, AUC0-∞)(t [0 minutes up to 240 minutes after intervention])