Fentanyl or esketamine for traumatic pain trial

The primary objective of the study is to determine whether **intranasal (IN) fentanyl**, **intravenous (IV) esketamine**, and **intranasal esketamine** are non-inferior to **intravenous fentanyl** for analgesia in acute traumatic pain in the prehospital environment. This is clinically relevant as it seeks to establish alternative routes and agents for effective pain management in emergency settings, potentially offering more flexible and rapid administration options.

Secondary objectives include:

• Determining whether, compared to IV fentanyl, IN fentanyl, IV esketamine, and IN esketamine provide similar patient satisfaction considering analgesia.
• Assessing whether, compared to IV fentanyl, IN fentanyl, IV esketamine, and IN esketamine are equally safe.

The clinical trial focuses on evaluating the efficacy of different analgesic methods for **acute traumatic pain** in a prehospital setting. The study population includes both male and female participants aged 18 years and older. Participants are required to have experienced trauma-induced pain on the same day and need strong opioid or esketamine administration for pain relief, as determined by prehospital personnel. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to be transported to a hospital following the administration of the analgesic treatment. No specific lifestyle considerations such as diet or physical activity are highlighted for this study.

The clinical trial is designed to evaluate the efficacy and safety of **fentanyl** and **esketamine** for the management of acute traumatic pain in a prehospital setting. This study employs a randomized, double-blind, controlled trial design to ensure the reliability and validity of the results. The trial is expected to span from September 2023 to March 2025, with participant involvement lasting up to the point of hospital arrival, depending on the treatment response and safety assessments.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (≥18 years), recent trauma, and the necessity for strong analgesics. Following the inclusion visit, participants will receive one of the study medications: intranasal **fentanyl**, intravenous **esketamine**, or intranasal **esketamine**. The primary endpoint is the change in the Numeric Rating Scale (NRS) score from baseline to 10 minutes post-administration. Secondary endpoints include NRS score changes at 20 minutes and upon hospital arrival, as well as the need for additional medication or unblinding due to treatment failure.

Participants are expected to remain in the study until they reach the hospital, with the possibility of early termination if adverse events occur or if unblinding is necessary due to treatment failure. The trial aims to determine the non-inferiority of the study medications compared to intravenous **fentanyl**. The study's rigorous design and comprehensive endpoints will provide valuable insights into the analgesic efficacy and safety of these medications in acute traumatic pain management.

The clinical trial involves the administration of several treatments to evaluate their efficacy in managing acute traumatic pain. **Esketamine** is utilized in two forms: Esketiv 25 mg/ml, a solution for injection, and Esketamine for intranasal use. Esketiv 25 mg/ml is administered intravenously with a maximum daily dose of 0.4 mg/kg. The intranasal form of Esketamine is administered with a maximum daily dose of 0.8 mg/kg. Both forms are chemical in origin and are used to assess their analgesic properties compared to other treatments.

**Fentanyl Citrate** is another key treatment in this trial, available as Fentanyl hameln 50 microgram/ml, a solution for injection, and as an intranasal formulation. The intravenous form is administered with a maximum daily dose of 2.0 µg/kg, while the intranasal form is also dosed at 2.0 µg/kg. Fentanyl Citrate is a chemical substance used for its potent analgesic effects.

**Diclofenac Sodium** is included in the trial in two forms: Diclofenac Na CF 25 mg/ml, a solution for injection, and Diclofenacnatrium Aurobindo 50 mg, a gastro-resistant tablet. The injectable form is administered intramuscularly with a maximum daily dose of 75 mg, while the oral tablet form is dosed at 50 mg. Diclofenac Sodium serves as an NSAID and analgesic, providing a comparator for the experimental treatments.

**Midazolam Hydrochloride** is administered as Midazolam Aurobindo 5 mg/ml, a solution for injection/infusion, with a maximum daily dose of 1 mg. This treatment is delivered intravenously and is used for its sedative properties, complementing the analgesic treatments in the trial.

**Paracetamol** is provided in two forms: Paracetamol Sanias 500 mg tablets and Paracetamol B. Braun 10 mg/ml, a solution for infusion. The oral tablets are administered with a maximum daily dose of 1000 mg, while the intravenous infusion is also dosed at 1000 mg. Paracetamol is used as an analgesic to support pain management in the trial.

**Sodium Chloride** is used as a saline solution in the trial, available as Natriumchloride 0.9% solution for injection and another intranasal formulation. The intravenous form is administered with a maximum daily dose of 20 ml, while the intranasal form is dosed at 4 ml. Sodium Chloride serves as an auxiliary treatment, providing a control for the experimental medications.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure accurate assessment of the treatments' efficacy and safety. The trial aims to determine the non-inferiority of intranasal fentanyl, intravenous esketamine, and intranasal esketamine compared to intravenous fentanyl in the prehospital management of acute traumatic pain.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the difference in the Numeric Rating Scale (NRS) score between baseline and 10 minutes after the administration of the study medication. Secondary endpoints include the difference in NRS score between baseline and 20 minutes after the first dose, as well as upon arrival at the hospital. Additionally, the relative change in NRS score at these time points will be evaluated. Other secondary endpoints include the number of subjects requiring a second dose of the study medication, the number of subjects requiring unblinding due to treatment failure, the number of subjects experiencing adverse events, and patient satisfaction with prehospital analgesia.

The NRS is a validated scale used to measure pain intensity, where patients rate their pain on a scale from 0 (no pain) to 10 (worst possible pain). Efficacy assessments will be conducted at specified time points: 10 minutes and 20 minutes after the first dose of the study medication, and upon arrival at the hospital. The collection and analysis of these efficacy parameters will be performed in accordance with the trial protocol to ensure the reliability and validity of the results.