Evaluation of Intranasal Sufentanil and Intravenous Morphine for Analgesia in Pediatric Sickle Cell Vaso-occlusive Crisis: A Randomized Controlled Trial

The primary objective of this study is to demonstrate the superiority of a procedure involving the **intranasal (IN) administration of sufentanil** followed by intravenous (IV) administration of morphine, compared to a placebo with IV morphine, in terms of analgesic efficacy at 30 minutes in children with sickle cell disease (SCD) experiencing a severe vaso-occlusive crisis (VOC) in the pediatric emergency department (ED). This is clinically relevant as it aims to provide a more effective pain management strategy for a condition that is often challenging to treat, potentially improving patient outcomes and reducing the burden on healthcare resources.

Secondary objectives include: - Demonstrating the superiority of the IN Sufentanil + IV morphine procedure over the placebo in terms of analgesic efficacy at various time points (10, 20, 40, 50, and 60 minutes) and for moderate pain relief at 10, 20, 30, 40, 50, and 60 minutes. - Assessing the ability of the procedure to decrease the delay before relief, the delay before administration of other opioid analgesics, and the duration of the ED visit. - Evaluating the reduction in morphine consumption levels. - Demonstrating the safety of the procedure by ensuring no increase in hemodynamic and non-hemodynamic side effects of opiates. - Evaluating the safety of the procedure in children aged 0-18 years. - Demonstrating improvements in the management of a VOC episode and a decrease in the proportion of VOC complications. - Assessing improvements in parent and child satisfaction with the quality of analgesia and management during the emergency room stay.

The clinical trial involves a study population of children under the age of 18, both **male** and **female**, who are experiencing a **vaso-occlusive crisis** due to sickle cell disease. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on specific criteria, including a diagnosis of sickle cell disease, a weight of more than 10 kilograms, and registration with a social security scheme or State Medical Aid. The trial does not focus on any particular lifestyle considerations such as diet or physical activity. The study does not involve a vulnerable population, and informed consent from the holders of parental authority is required for participation. The trial aims to assess the efficacy of a treatment protocol involving the administration of sufentanil and morphine in managing severe pain associated with vaso-occlusive crises in the pediatric emergency department setting.

The clinical trial is designed to evaluate the efficacy of **intranasal sufentanil** followed by intravenous **morphine hydrochloride** in managing severe vaso-occlusive crisis pain in pediatric patients with sickle cell disease. This is a randomized, double-blind, placebo-controlled trial. The trial aims to demonstrate the superiority of the active treatment over placebo in providing effective analgesia within 30 minutes of administration. The study is expected to commence on January 30, 2025, and conclude by July 30, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age under 18 years, weight over 10 kg, and a confirmed diagnosis of sickle cell disease. Informed consent from the holder(s) of parental authority is required. The randomization visit will occur when the participant presents to the emergency department with a vaso-occlusive crisis characterized by severe pain, as determined by specific pain scales. The primary endpoint is the proportion of children experiencing pain relief at 30 minutes post-intranasal spray, assessed using the EVENDOL scale for children under 8 years and the Numeric Pain Rating Scale (NRS-11) for those aged 8 to less than 18 years.

Follow-up visits will assess secondary endpoints, including pain relief at various time points, time to relief, morphine consumption, and adverse events such as hypotension and respiratory distress. The end-of-study visit will evaluate overall satisfaction with pain management and any hospital admissions or complications. Participant involvement is expected to last until the end of the study period, with early termination possible if adverse events occur or if the participant withdraws consent. The trial's methodology ensures rigorous assessment of the treatment's efficacy and safety, contributing valuable data to the management of sickle cell disease-related pain crises in pediatric patients.

The clinical trial involves the administration of **Sufentanil**, marketed as "Sufentanil Mylan 50 microgrammes/ml solution injectable," which is utilized as the experimental medication. This pharmaceutical is presented in the form of a **solution for injection**. The active substance, **sufentanil**, is of chemical origin. The administration route for this medication is **nasal use**, with a maximum daily dose of 50 micrograms and a total dose not exceeding 50 micrograms. The treatment period is limited to one day. The trial aims to assess the efficacy of intranasal sufentanil in providing analgesia for severe sickle cell vaso-occlusive pain crisis in a pediatric emergency department setting.

In addition to the experimental treatment, the trial employs **Morphine Hydrochloride** as a standard-of-care therapy. This medication is provided as a **solution for injection** and is administered intravenously. The active substance, **morphine hydrochloride**, is also of chemical origin. The dosing regimen allows for a maximum daily and total dose of 1.5 mg/kg, with the treatment period restricted to one day. This standard-of-care therapy is administered as soon as possible following the intranasal administration of the experimental medication or placebo.

The trial also includes a placebo control, which is represented by "Chlorure de Sodium 0,9 % Lavoisier, solution pour perfusion." This placebo is a **solution for infusion** containing **sodium chloride** as the active substance, which is chemically derived. The placebo is administered via **nasal use**, with a maximum daily and total dose of 1 ml. The treatment period for the placebo is similarly limited to one day. The placebo is used to compare the efficacy of the experimental treatment against a non-active control in the context of the trial's objectives.

The efficacy of the clinical trial titled "Intranasal Sufentanil for Analgesia of Severe Sickle Cell Vaso-occlusive Pain Crisis in the Pediatric Emergency Department: a Double Blind Randomized versus placebo Controlled Trial (INVOPE)" will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of children relieved at 30 minutes after the intranasal (IN) spray. Pain relief will be evaluated using the EVENDOL Scale for children under 8 years and the Numeric Pain Rating Scale (NRS-11) for children aged 8 to less than 18 years. Relief is defined as an EVENDOL score of ≤ 5/15 or an NRS-11 score of ≤ 3/10.

Secondary endpoints include the proportion of children relieved at various time points (10, 20, 40, 50, and 60 minutes) after the IN spray, and the proportion of children with moderate pain at these same intervals. Additional measures include the time from triage to relief, venous access, and intravenous (IV) morphine initiation, as well as morphine consumption at 60, 120, and 240 minutes post-IN injection. Safety parameters such as rates of hypotension, hypoxia, and other adverse events will be monitored until 4 hours after the IN injection. The trial will also assess hospital admission rates, length of stay, and satisfaction with analgesia and management during the emergency room stay, using patient and parent-reported outcomes for children over and under 8 years, respectively.