A Randomized, Multi-Center Study Comparing Fentanyl Citrate Nasal Spray and Placebo for Postoperative Pain Management in Orthopedic Surgery Patients

The primary objective of this study is to evaluate the **efficacy** of Fentanyl Nasal Spray, in conjunction with an applicator, compared to a placebo for managing postoperative pain. This assessment is clinically relevant as it aims to determine the potential of Fentanyl Nasal Spray to provide effective pain relief following orthopedic surgery, which serves as a model for postoperative pain. The study will utilize existing literature to extrapolate the analgesic effectiveness of nasal fentanyl from nociceptive pain to visceral pain, such as that caused by abdominal surgery.

The secondary objectives include assessing the tolerability and side effects of prolonged postoperative administration of Fentanyl Nasal Spray compared to the standard of care, which involves morphine administered via intravenous patient-controlled analgesia (PCA). Additionally, the study will evaluate the usability of the administration control device associated with the Fentanyl Nasal Spray.

The clinical trial focuses on evaluating the efficacy of **Fentanyl Nasal Spray** for managing **postoperative pain** following orthopedic surgery. The study population comprises both male and female patients aged 18 years and older. Participants are required to have an intended stay in a Post Anesthesia Care Unit or recovery room for at least 120 minutes post-surgery, which includes procedures such as knee joint endoprosthesis surgery or isolated fractures treated by open reduction and internal fixation. The trial includes individuals with an American Society of Anesthesiology physical status of I, II, or III, who are expected to experience acute moderate or severe pain necessitating parenteral opioids for at least 24 hours post-surgery. Participants must be capable of handling the administration control device and willing to engage in all study aspects, as indicated by signed informed consent. The sponsor has not provided information regarding the total number of participants. The trial does not involve a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted.

The clinical trial is designed as a **randomized**, parallel-group, multi-center study to evaluate the efficacy of **Fentanyl Nasal Spray** compared to a placebo nasal spray for the management of **postoperative pain**. The trial will also include a prolonged open treatment phase lasting up to 120 hours postoperatively, compared with intravenous patient-controlled analgesia using **morphine**. The study will involve adult patients aged 18 years and older who are expected to experience moderate to severe pain following orthopedic surgery, necessitating parenteral opioids for at least 24 hours post-surgery. The trial will be conducted over an estimated duration from April 2024 to December 2025.

Participants will be randomly assigned to receive either the **Fentanyl Nasal Spray**, the placebo nasal spray, or intravenous **morphine**. The trial will be **double-blind**, ensuring that neither the participants nor the investigators know which treatment is being administered, thereby minimizing bias. The primary endpoint is the survival distribution from the start of treatment until trial termination due to inadequate analgesia within the first 24 hours. Secondary endpoints include pain intensity ratings at specified intervals, usability assessments, and global efficacy ratings by both patients and investigators.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including the patient's ability to handle the administration control device and their willingness to participate. Follow-up visits will occur at pre-defined intervals to monitor pain intensity and treatment efficacy. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of the treatment's effectiveness and any adverse events. The expected length of participant involvement is up to 120 hours postoperatively, with conditions for early termination including inadequate analgesia or any adverse events deemed necessary by the investigator.

The clinical trial involves the administration of **Fentanyl Nasal Spray**, a nasal spray solution containing **fentanyl citrate** as the active substance. This investigational product is designed for **intranasal use** and is intended to manage postoperative pain. The maximum daily dose is 7.2 mg, with a total maximum dose of 43.2 mg over a treatment period of up to 6 days. The administration is facilitated by a device known as DOLONOSE, which serves as a control and application device. Participant compliance is monitored through the use of this device, ensuring accurate dosing and adherence to the treatment protocol.

The study also includes a **Fentanyl Nasal Spray Placebo**, which is a structurally diverse substance used as a comparator in the trial. This placebo is also administered as a nasal spray solution for **intranasal use**. The placebo is designed to mimic the administration of the active treatment without delivering any pharmacologically active ingredients. The maximum daily and total dose for the placebo is 144 U units, with a treatment period limited to 1 day. This placebo serves to assess the efficacy of the active treatment by providing a baseline for comparison.

Additionally, the trial incorporates **Morphin-hameln 100 mg Injektionslösung**, a standard-of-care therapy containing **morphine sulfate pentahydrate**. This solution for injection is administered **intravenously** and serves as a reference product for patient-controlled analgesia. The maximum daily dose is 180 mg, with a total maximum dose of 1080 mg over a treatment period of up to 6 days. This comparator treatment is used to evaluate the effectiveness of the fentanyl nasal spray in comparison to established pain management practices.

The efficacy of the Fentanyl Nasal Spray in managing postoperative pain will be assessed through a randomized, parallel group, multi-center study. The primary endpoint for evaluating efficacy is the **survival distribution** from the start of treatment with the first dose of the study medication until trial termination due to inadequate analgesia within the first 24 hours. Patients who do not terminate the trial will be censored at 24 hours. Secondary endpoints include the sum of ratings of pain intensity on an 11-point numeric rating scale at predefined time points: hours 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 after treatment initiation (TotPaR). Additionally, the sum of pain intensity difference ratings (SPID) will be measured at hours 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, and 120, with the last observation carried forward method used for missing values.

Further secondary endpoints include the percentage of patients terminating the study due to inadequate analgesia or any reason during the 24-hour treatment period, the number of actuations administered, and the number of unsuccessful actuations during the lock-out period. Patient-reported outcomes will be collected using the System Usability Scale (SUS) for usability ratings and a four-point Likert scale for global efficacy ratings. Investigator's global efficacy ratings will also be collected using a similar Likert scale. The ease of care will be evaluated by patients, nursing staff, and physiotherapists. These assessments will provide comprehensive data on the efficacy of the Fentanyl Nasal Spray in comparison to placebo for postoperative pain management.