Safety of an eight-day treatment with ibuprofen after primary hip and knee arthroplasties.

Hip and knee arthroplasty surgeries are some of the most frequently performed planned procedures in the western world. Multimodal analgesic treatment is the leading analgesic treatment principle, with NSAIDs as an essential part. Ibuprofen, the most frequently prescribed NSAID, is effective in reducing acute postoperative pain. However, ibuprofen may be associated with various serious adverse events, including death, cardiovascular morbidity, gastrointestinal ulcer, and renal impairment. The balance between beneficial and harmful effects of a short-term postoperative treatment with ibuprofen after elective hip and knee arthroplasty is unknown.

Objectives: to assess the adverse events of an eight-day treatment of postoperative pain with ibuprofen in patients undergoing elective primary hip or knee arthroplasty.

Intervention: the participants will be randomized in two groups: a) oral ibuprofen 400 mg 3 times daily for eight days. b) identical oral placebo 3 times daily for eight days.

Design and trial size: PERISAFE is a randomized, placebo-controlled multicentre trial with centralized computer-generated allocation sequence and allocation concealment with unknown block size. Patients, investigators, assessors, caregivers, data-managers, writers of the manuscript, and statisticians will be blinded. A total of 2904 eligible patients are needed to detect or discard an effect corresponding to a relative risk reduction of 1/3 with an acceptable risk of type I error of 5 % and of type II error of 20 %, and a proportion of the composite outcome of serious adverse events of 8% in the experimental group.

Sub-studies:

• Serious adverse events relating to the renal system
• Serious adverse events relating to the cardiovascular system
• Serious adverse events relating to the gastrointestinal system, including major bleeding
• Persistent pain and opioid consumption at 90 days and one year postoperatively. Predictive co-factors include preoperative analgesic treatment, type of anesthesia, gender, age, ASA-classification, diabetes, and type of surgery
• Bayesian re-analysis of the primary and secondary outcomes up to 90 days postoperatively. Further details will appear in the statistical analysis plan
• Health-related quality of life via EQ-5D-5L questionnaire 90-days and one year postoperatively

Inclusion Criteria:

• Patients scheduled for elective primary hip and knee arthroplasty.
• Age ≥ 18 years.
• Planned postoperative treatment with NSAID.
• Negative pregnancy test for women in the fertile age.
• Informed consent.

Exclusion Criteria:

• Unable to understand or speak Danish.
• Allergy to or contraindications against ibuprofen.

Data will be published anonymised according to ICMJEs (International Committee of Medical Journal Editors) guidelines

Nine month after the trial has ended, and the primary results article has been published

The study protocol and statistical analysis plan will be available after they have been published. Study protocol will be available at PERISAFE website.

We will make anonymized data available to other researchers' trough public database such as Zenodo open data repository (CERN), or another equivalent database. Furthermore, researchers wishing to access data from the PERISAFE trial should contact omat@regionsjaelland.dk in the first instance.

The study medication will be masked by the pharmacy. The experimental medicine will be packed and labelled by Region Hovedstadens Pharmacy in accordance with the Good Manufacturing Practice regulations. The sponsor has a set of sealed, opaque envelopes with the participants' allocation, and these will only be revealed for the investigators when the data has been analysed and abstracts and conclusions covering the different possibilities for interpreting the trial results, have been agreed upon by the steering committee