Pain, AcutePhase 4PERISAFENCT05575700
Safety of Ibuprofen After Major Orthopaedic Surgeries
A Phase 4 study testing Ibuprofen in people with Pain, Acute and Hip Arthropathy, run by Naestved Hospital at 11 sites in Denmark.
Trial summary
Safety of an eight-day treatment with ibuprofen after primary hip and knee arthroplasties. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pain, Acute, Hip Arthropathy, Knee Arthropathy
- What is being tested?
- Ibuprofen
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 2,904 participants
- Where
- 11 sitesDenmark
- Study dates
- 17 Apr 2023to 19 Aug 2025
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- Unable to understand or speak Danish.
- Allergy to or contraindications against ibuprofen.
Trial locations and contacts
11 sites in 1 country.
11 sites in 1 country
Denmark11 sites
Private Hospital Gildhøj
Brøndby, 2605
Bispebjerg Hospital
Copenhagen NV, 2400
Aalborg University Hospital
Farsø, 9640
Gentofte Hospital
Hellerup, 2900
Nordsjællands Hospital Hillerød
Hillerød, 3400
Zealand University Hospital
Køge, 4600
Næstved Hospital
Næstved, 4700
Odense University Hospital
Odense, 3900
Silkeborg Regional Hospital
Silkeborg, 8600
Svendborg Hospital
Svendborg, 5700
Vejle Sygehus
Vejle, 7100
About this study
Official title: Safety of Ibuprofen After Major Orthopaedic Surgeries. The PERISAFE Randomized Clinical Multicentre Trial
Safety of an eight-day treatment with ibuprofen after primary hip and knee arthroplasties.
Read the 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 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
- Conditions
- Pain, Acute, Hip Arthropathy, Knee Arthropathy, Safety Issues, Analgesia, Analgesic Adverse Reaction
- Being tested
- Ibuprofen, Placebo
- Keywords
- PERISAFE, Hip Arthroplasty, Knee Arthroplasty, Postoperative pain, Analgesia, Safety, Non-steroidal Anti-inflammatory drugs
- Medical subject headings
- Acute Pain, Agnosia, Pain, Postoperative, Postoperative Complications
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IbuprofenDrug
400 mg tablet three times daily
PlaceboDrug
tablet three times daily
| Study group | Role | What they receive |
|---|---|---|
| Ibuprofen | Experimental | Participants received ibuprofen 400 mg tablet administered orally three times daily, with eight hour intervals, for eight days after surgery. Receives: Drug: Ibuprofen |
| Placebo | Placebo comparator | Participants received identical placebo tablet administered orally three times daily, with eight hour intervals, for eight days after surgery. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
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.
Measured: Postoperative day 0 to 90.
Secondary outcomes (4)
Hospital free days within 90 days postoperatively.
Days outside the hospital within 90 days postoperatively.
Measured: Postoperative day 0 to 90.
A composite outcome of ibuprofen related adverse events based on an eight-day postoperative diary: dyspepsia, diarrhoea.
Proportion of patients with one or more adverse events of ibuprofen during intervention period, defined as dyspepsia or diarrhoea.
Measured: Postoperative day 0 to 8.
A composite outcome of opioid related adverse events based on an eight-day postoperative diary: nausea, vomiting, constipation, dizziness, confusion, sedation, headache.
Proportion of patients with one or more adverse events of opioid during intervention period, defined as nausea, vomiting, constipation, dizziness, confusion, sedation, or headache.
Measured: Postoperative day 0 to 8.
Health related quality of life questionnaire (EQ-5D-5L) after 90 days
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.
Measured: Postoperative day 90.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Oct 2022
- Study start17 Apr 2023
- Primary completion19 Aug 2025
- Study completion19 Aug 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Pain, AcuteStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 2,904 participants (actual)
Sponsor and investigators
- Lead sponsor
- Naestved Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ole Mathiesen, Professor, Study chair, Zealand University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05575700
- Sponsor's protocol ID
- 001CCWL2022
- Acronym
- PERISAFE
- Status last verified
- Dec 2025
- First submitted
- 7 Oct 2022
- Last updated
- 19 Dec 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be published anonymised according to ICMJEs (International Committee of Medical Journal Editors) guidelines
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety of Ibuprofen After Major Orthopaedic Surgeries. The PERISAFE Randomized Clinical Multicentre Trial
- ClinicalTrials.gov ID
- NCT05575700
- Acronym / sponsor ID
- PERISAFE / 001CCWL2022
- Conditions
- Pain, Acute, Hip Arthropathy, Knee Arthropathy, Safety Issues, Analgesia, Analgesic Adverse Reaction
- Keywords
- PERISAFE, Hip Arthroplasty, Knee Arthroplasty, Postoperative pain, Analgesia, Safety, Non-steroidal Anti-inflammatory drugs
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2,904 participants (actual)
- Lead sponsor
- Naestved HospitalUniversity, hospital or other
- Study start
- 17 Apr 2023 (actual)
- Primary completion
- 19 Aug 2025 (actual)
- Study completion
- 19 Aug 2025 (actual)
- First posted
- 12 Oct 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Safety of an eight-day treatment with ibuprofen after primary hip and knee arthroplasties.
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 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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ibuprofen | Experimental | Drug: IbuprofenParticipants received ibuprofen 400 mg tablet administered orally three times daily, with eight hour intervals, for eight days after surgery. |
| Placebo | Placebo comparator | Drug: PlaceboParticipants received identical placebo tablet administered orally three times daily, with eight hour intervals, for eight days after surgery. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (2 listed)
- Unable to understand or speak Danish.
- Allergy to or contraindications against ibuprofen.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ibuprofen400 mg tablet three times daily | Drug | Ibuprofen |
| Placebotablet three times daily | Drug | Placebo |
Primary outcome
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.
Time frame: 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.
4 secondary outcomes
Hospital free days within 90 days postoperatively.
Time frame: Postoperative day 0 to 90.
A composite outcome of ibuprofen related adverse events based on an eight-day postoperative diary: dyspepsia, diarrhoea.
Time frame: Postoperative day 0 to 8.
A composite outcome of opioid related adverse events based on an eight-day postoperative diary: nausea, vomiting, constipation, dizziness, confusion, sedation, headache.
Time frame: Postoperative day 0 to 8.
Health related quality of life questionnaire (EQ-5D-5L) after 90 days
Time frame: Postoperative day 90.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2025.
- Individual participant dataSharing planned: Yes. Data will be published anonymised according to ICMJEs (International Committee of Medical Journal Editors) guidelines
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ole Mathiesen, Professor study chair
Zealand University Hospital
11 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ibuprofen in people with Pain, Acute and Hip Arthropathy, run by Naestved Hospital at 11 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: Postoperative day 0 to 90.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2025; AzTrials last refreshed its copy on 8 Nov 2026.