Safety of ibuprofen after major orthopaedic surgeries - the PERISAFE randomized clinical multicentre trial

The primary objective of this study is to evaluate the **beneficial and harmful effects** of an eight-day postoperative treatment with **ibuprofen**, a non-selective non-steroidal anti-inflammatory drug (NSAID), following elective hip and knee arthroplasties. This assessment is clinically relevant as it aims to determine the safety profile of ibuprofen, which is widely used as a non-opioid analgesic, in managing acute postoperative pain after major orthopaedic surgeries. Understanding the safety of ibuprofen in this context is crucial for optimizing pain management strategies and minimizing potential adverse effects in patients undergoing these common surgical procedures.

The clinical trial involves participants undergoing **hip and knee arthroplasties** and experiencing **acute postoperative pain**. The study population includes both male and female subjects aged 18 years and older. Participants are generally in good health, as they are scheduled for planned primary hip or knee arthroplasty, including hemiarthroplasty. The trial does not focus on a vulnerable population. The selection criteria require participants to have a planned perioperative pain treatment with NSAIDs, as decided by the clinical doctor. Women of childbearing potential must have a negative urine Human Chorionic Gonadotropin (hCG) pregnancy test and use contraception. Written informed consent is mandatory for participation. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **safety** and efficacy of **ibuprofen** in managing acute postoperative pain following elective hip and knee arthroplasties. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or placebo, thus minimizing bias. The trial is expected to run from April 2023 to December 2026, with participant involvement lasting approximately 90 days postoperatively. The primary objective is to assess the beneficial and harmful effects of an eight-day postoperative treatment with ibuprofen, a non-selective NSAID, which is commonly used as a non-opioid analgesic.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being scheduled for planned primary hip or knee arthroplasty, age of 18 years or older, and a negative urine Human Chorionic Gonadotropin (hCG) pregnancy test for women of childbearing potential. Written informed consent is also required. Follow-up visits will monitor the participants' health status and any adverse events, with the primary endpoint being a composite outcome of serious complications such as death, myocardial infarction, stroke, and others within 90 days postoperatively. Secondary endpoints include hospital-free days, adverse events related to ibuprofen and opioids, and health-related quality of life assessments via the EQ-5D-5L questionnaire at 90 days and one year postoperatively.

The end-of-study visit will conclude the participant's involvement, assessing the long-term outcomes and any lingering effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial employs a low-intervention approach, justified by the routine postoperative use of ibuprofen in the target population, ensuring that the study aligns with standard clinical practices while providing valuable insights into the drug's safety profile in this context.

The clinical trial involves the administration of **Ibuprofen 400 mg, tabletten**, which is a **coated tablet** formulation. The active substance in this medication is **ibuprofen**, a non-selective non-steroidal anti-inflammatory drug (NSAID) commonly used for its analgesic and anti-inflammatory properties. The ibuprofen tablets are administered orally, with a maximum daily dose of 1200 mg and a total maximum dose of 9200 mg over the course of the treatment. The treatment period is set for eight days, following major orthopedic surgeries such as elective hip and knee arthroplasties. The pharmaceutical product is manufactured by GENRX B.V. and is authorized in the Netherlands under the marketing authorization number RVG 18544. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes the use of an **Identical capsule** as a comparator treatment. This capsule serves as a placebo to evaluate the effects of ibuprofen against a non-active substance. The Identical capsule is designed to match the appearance of the ibuprofen tablets to maintain blinding in the study. The route of administration for the Identical capsule is oral, similar to the ibuprofen tablets. The use of a placebo is critical in assessing the true efficacy and safety profile of the experimental medication by providing a baseline for comparison. Compliance with the administration of the Identical capsule will be similarly monitored to ensure the integrity of the trial results.

Efficacy in the clinical trial titled "Safety of ibuprofen after major orthopaedic surgeries - the PERISAFE randomized clinical multicentre trial" will be assessed using both primary and secondary endpoints. The primary endpoint is a composite outcome that includes the occurrence of either death, acute myocardial infarction, stroke, pulmonary embolism, deep venous thrombosis, renal failure, major bleeding, re-operation, gastrointestinal ulcer, or readmission within 90 days postoperatively. This endpoint will provide a comprehensive measure of the safety and efficacy of ibuprofen in the postoperative setting.

Secondary endpoints include the number of hospital-free days within 90 days postoperatively, and a composite outcome of **ibuprofen**-related adverse events based on an eight-day postoperative diary, which will track symptoms such as pain or discomfort from the epigastrium, reflux, and diarrhea. Additionally, a composite outcome of opioid-related adverse events will be assessed, including nausea, vomiting, constipation, sedation, headache, mood changes, and mouth dryness. Health-related quality of life will be evaluated using the EQ-5D-5L questionnaire at 90 days and one year postoperatively. These secondary endpoints will help to further elucidate the impact of ibuprofen on patient recovery and quality of life following surgery.