PERISAFE: Safety of Ibuprofen After Major Orthopaedic Surgeries

Sponsor

Naestved Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05575700

Collaborator

(none)

2,904

Enrollment

Locations

Arms

Anticipated Duration (Months)

242

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Pain, Acute Hip Arthropathy Knee Arthropathy Safety Issues Analgesia Analgesic Adverse Reaction Postoperative Pain Postoperative Complications	Drug: Ibuprofen Drug: Placebo	Phase 4

Detailed Description

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 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:

One-year follow-up on the composite primary outcome.
Subgroup analysis on predictors of chronic pain and opioid consumption at 90-days, and one-year after surgery.
Coherence of preoperative use of diuretics, ACE-inhibitors or Angiotensin-II-antagonists and postoperative risk of renal failure.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2904 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

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

Primary Purpose:

Treatment

Official Title:

Safety of Ibuprofen After Major Orthopaedic Surgeries. The PERISAFE Randomized Clinical Multicentre Trial

Anticipated Study Start Date :

Apr 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Jul 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ibuprofen Participants received ibuprofen 400 mg tablet administered orally three times daily, with eight hour intervals, for eight days after surgery.	Drug: Ibuprofen 400 mg tablet three times daily
Placebo Comparator: Placebo Participants received identical placebo tablet administered orally three times daily, with eight hour intervals, for eight days after surgery.	Drug: Placebo tablet three times daily

Arm

Intervention/Treatment

Experimental: Ibuprofen

Participants received ibuprofen 400 mg tablet administered orally three times daily, with eight hour intervals, for eight days after surgery.

Drug: Ibuprofen

400 mg tablet three times daily

Placebo Comparator: Placebo

Participants received identical placebo tablet administered orally three times daily, with eight hour intervals, for eight days after surgery.

Drug: Placebo

tablet three times daily

Outcome Measures

Primary Outcome Measures

A composite outcome 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. [Postoperative day 0 to 90.]
Proportion of patients with one or more severe adverse events defined in the composite outcome 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.

Secondary Outcome Measures

Hospital free days within 90 days postoperatively. [Postoperative day 0 to 90.]
Days outside the hospital within 90 days postoperatively.
A composite outcome of ibuprofen related adverse events based on an eight-day postoperative diary: dyspepsia, diarrhoea. [Postoperative day 0 to 7.]
Proportion of patients with one or more adverse events of ibuprofen during intervention period, defined as dyspepsia or diarrhoea.
A composite outcome of opioid related adverse events based on an eight-day postoperative diary: nausea, vomiting, constipation, dizziness, confusion, sedation, headache. [Postoperative day 0 to 7.]
Proportion of patients with one or more adverse events of opioid during intervention period, defined as nausea, vomiting, constipation, dizziness, confusion, sedation, or headache.
Health related quality of life questionnaire (EQ-5D-5L) after 90 days [Postoperative day 90.]
Evaluation of health related quality of life via EuroQol five-dimensions 5 point Likert-type scale (EQ-5D-5L) questionnaire, incl. the Euro Visual analogue scales (VAS) from 0-100. 100=the best health you can imagine, 0= the worst health you can imagine. The questionnaire of health related quality of life includes: mobility, self-care, usual activities, pain or discomfort, anxiety or depression from a scale of no problems, to slight, moderate, severe problems or unable condition.

Other Outcome Measures

Proportion of individual serious adverse events in the composite primary outcome. [Postoperative day 0 to 90.]
Proportion of individual elements of the primary composite outcome: death, acute myocardial infarction, stroke, pulmonary embolism, deep venous thrombosis, renal failure, major bleeding, re-operation, gastrointestinal ulcer, or readmission.
Proportion of individual adverse events of ibuprofen and opioid in the composite secondary outcomes. [Postoperative day 0 to 7.]
Proportion of individual elements of secondary outcome of adverse events of ibuprofen and opioid: dyspepsia, diarrhoea, nausea, vomiting, constipation, dizziness, confusion, sedation, headache.
Postoperative pain levels, analgesic treatment, and opioid consumption based on an eight-day postoperative diary. [Postoperative day 0 to 7.]
Pain levels will be measured by Numeric Rating Scale (NRS) from 0-10 (no pain = 0, worst pain = 10). Analgesic treatment including opioid consumption will be indicated in total daily doses in mg.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Private Hospital Gildhøj	Brøndby	Denmark	2605
2	Bispebjerg Hospital	Copenhagen NV	Denmark	2400
3	Aalborg University Hospital	Farsø	Denmark	9640
4	Aalborg University Hospital	Frederikshavn	Denmark	9900
5	Gentofte Hospital	Hellerup	Denmark	2900
6	Nordsjællands Hospital Hillerød	Hillerød	Denmark	3400
7	Zealand University Hospital	Køge	Denmark	4600
8	Næstved Hospital	Næstved	Denmark	4700
9	Odense University Hospital	Odense	Denmark	3900
10	Silkeborg Regional Hospital	Silkeborg	Denmark	8600
11	Svendborg Hospital	Svendborg	Denmark	5700
12	Vejle Sygehus	Vejle	Denmark	7100