Pharmacokinetic Comparison of Subcutaneous Versus Intravenous Midazolam Hydrochloride in Terminally Ill Patients Requiring Palliative Care

The primary objective of this study is to estimate the **bioavailability** of subcutaneous (SC) versus intravenous (IV) administration of midazolam in terminally ill patients. This is clinically relevant as it aims to determine the most effective route of administration for midazolam, which is crucial for optimizing symptom management in palliative care settings.

Secondary objectives include:

• Estimating early exposure pharmacokinetic profiles of midazolam and its metabolite following SC versus IV administration in terminally ill patients.
• Assessing the safety and local tolerability of SC and IV midazolam.
• Evaluating the sedative effect of SC and IV midazolam.

The clinical trial involves **terminally ill patients** requiring palliative care, specifically those with indications for parenteral midazolam administration to manage symptoms such as anxiety, restlessness, agitation, and dyspnea. The study population includes both male and female participants aged 18 years and older, with a life expectancy of less than one month. Participants are selected from those receiving palliative care in the palliative care ward at the study site. The trial does not focus on a vulnerable population. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations, such as diet and physical activity, are not specified. The inclusion criteria require that participants are capable of providing informed consent and are deemed eligible by their attending physician for midazolam administration. The trial aims to estimate the bioavailability of subcutaneous versus intravenous administration of midazolam in this patient group.

The clinical trial is designed as a **randomized**, open-label, parallel-group, Phase 2 study to evaluate the **pharmacokinetic** profiles of subcutaneous versus intravenous administration of **midazolam** in adult male and female patients with terminal illness requiring palliative care. The primary objective is to estimate the bioavailability of subcutaneous versus intravenous administration of midazolam in this patient population. The trial is expected to commence recruitment on August 20, 2025, and conclude by August 20, 2027. Participants will be involved in the study for a maximum treatment period of one day, with the possibility of early termination if the attending physician deems it necessary based on the patient's condition or if the patient withdraws consent.

The study will include an initial screening visit to confirm eligibility, which requires participants to be terminally ill with a life expectancy of less than one month, receiving palliative care, and capable of providing informed consent. The inclusion criteria also specify that participants must be 18 years or older and eligible for 1 mg of midazolam administered either subcutaneously or intravenously for symptom management. The primary endpoint is the area under the curve (AUC0-90) of midazolam based on serum samples collected at specified time points post-administration. Secondary endpoints include Tmax, Cmax of midazolam and 1-OH-midazolam, metabolic ratio, and changes in respiratory rate, oxygen saturation, and RASS-PAL score from baseline at various intervals.

Study visits will be structured to include the initial screening, followed by the administration of the investigational product and subsequent monitoring. Blood samples will be collected at 2, 5, 7, 10, 12, 15, 20, 25, 30, 40, 50, 60, 75, and 90 minutes post-administration to assess pharmacokinetic parameters. The end-of-study visit will occur after the final data collection point, ensuring all necessary information is gathered for analysis. Participants may be withdrawn from the study if they experience adverse effects that compromise their safety or if they no longer meet the inclusion criteria. The trial is classified as low-intervention, as it involves a well-known medicinal product used according to national guidelines, with minimal additional risk beyond standard therapy.

The clinical trial involves the administration of **Midazolam B. Braun 1 mg/ml**, a **solution for injection/infusion** containing the active substance **midazolam hydrochloride**. This experimental medication is provided in two different administration routes to evaluate its pharmacokinetic profiles. The first route is **subcutaneous**, where the solution is injected under the skin. The dosage for this administration is set at a maximum of 1 mg per day, with a total treatment period of one day. The pharmaceutical form remains consistent as a solution for injection/infusion, ensuring uniformity in the formulation used across different administration methods.

The second administration route for **Midazolam B. Braun 1 mg/ml** is **intravenous use**, where the solution is directly infused into the bloodstream. Similar to the subcutaneous route, the maximum daily dose is 1 mg, and the treatment period is limited to one day. This route is intended to serve as a comparator to the subcutaneous administration, allowing for a direct comparison of bioavailability between the two methods. Both routes utilize the same pharmaceutical form, ensuring that any differences in pharmacokinetic profiles can be attributed to the route of administration rather than formulation differences.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial is designed to assess the bioavailability of midazolam when administered subcutaneously compared to intravenously in terminally ill patients. The study does not involve any non-experimental treatments such as standard-of-care therapy or placebo, focusing solely on the comparison between the two administration routes of the experimental medication.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the area under the curve (AUC_0-90) of **midazolam** based on serum samples collected at specific time intervals: 2, 5, 7, 10, 12, 15, 20, 25, 30, 40, 50, 60, 75, and 90 minutes post-administration. This will provide a measure of the drug's bioavailability when administered subcutaneously compared to intravenously in terminally ill patients.

Secondary endpoints include the time to maximum concentration (Tmax), maximum concentration (Cmax) of midazolam and its metabolite 1-OH-midazolam, and the AUC_0-90 for 1-OH-midazolam. Additionally, the metabolic ratio of AUC_0-90 (1-OH-midazolam/midazolam) will be evaluated. Patient-reported outcomes such as injection site discomfort (pain, redness, swelling, itching) will also be assessed. Changes in respiratory rate and oxygen saturation from baseline will be measured at 10, 20, 30, 40, 50, 60, 75, and 90 minutes. The Richmond Agitation-Sedation Scale for Palliative Care (RASS-PAL) score will be used to assess changes in sedation levels at the same timepoints. The time and number of repeated administrations of sedative medication within 90 minutes following the study drug injection will also be recorded.