PAracetamol and NSAID in Combination: A Randomised, Blinded, Parallel, 4-group Clinical Trial

Study Overview
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Brief Summary
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Trial name: PAracetamol and NSAID in combination: A randomised, blinded, parallel, 4-group clinical trial Trial acronym: PANSAID Background: Effective postoperative pain management is essential for the well-being and rehabilitation of the surgical patient. No gold standard exists after total hip arthroplasty (THA) and combinations of different non-opioid medications are used with virtually no evidence for additional analgesic efficacy compared to monotherapy. Objectives: The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen and their combination in different dosages after THA. Intervention: Patients are randomised to 4 groups: A) paracetamol 1 g x 4 and ibuprofen 400 mg x 4; B) paracetamol 1 g x 4 and placebo (ibuprofen); C) placebo (paracetamol) and ibuprofen 400 mg x 4; and D) paracetamol 0,5 g x 4 and ibuprofen 200 mg. Design: Placebo controlled, parallel 4-group, multicentre trial with adequate centralised computer-generated allocation sequence and allocation concealment with varying block size and stratification by site. Blinding of assessor, investigator, caregivers, patients, and statisticians. Sample size: 556 eligible patients are needed to detect a difference of 10 mg morphine the first postoperative day with a standard deviation of 20 mg and a type 1 error rate of 0,004 (two-sided) and a type 2 error rate of 0,10.

Detailed Description
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Trial name: PAracetamol and NSAID in combination: A randomised, blinded, parallel, 4-group clinical trial Trial acronym: PANSAID Background: Effective postoperative pain management is essential for the well-being and rehabilitation of the surgical patient. No gold standard exists after total hip arthroplasty (THA) and combinations of different non-opioid medications are used with virtually no evidence for additional analgesic efficacy compared to monotherapy. Objectives: The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen and their combination in different dosages after THA. Intervention: Patients are randomised to 4 groups: A) paracetamol 1 g x 4 and ibuprofen 400 mg x 4; B) paracetamol 1 g x 4 and placebo (ibuprofen); C) placebo (paracetamol) and ibuprofen 400 mg x 4; and D) paracetamol 0,5 g x 4 and ibuprofen 200 mg. Design: Placebo controlled, parallel 4-group, multicentre trial with adequate centralised computer-generated allocation sequence and allocation concealment with varying block size and stratification by site. Blinding of assessor, investigator, caregivers, patients, and statisticians. Sample size: 556 eligible patients are needed to detect a difference of 10 mg morphine the first postoperative day with a standard deviation of 20 mg and a type 1 error rate of 0,004 (two-sided) and a type 2 error rate of 0,10. Sub-studies: We preplan the following sub-studies. : A subgroup analysis of benefit outcomes (pain and opioid consumption) with respect to the following sub-groups: sex, age (below vs above 65 years old), ASA-score (I+II vs III), Use of analgesic medication before surgery (none vs any) and anaesthetic technique (general anaesthesia vs. spinal anaesthesia). Please find a detailed protocol at www.pansaid.dk A subgroup analysis of harm (serious adverse events and adverse events) with respect to the following groups sex, age (below vs above 65 years old), use of NSAIDs before surgery, and ASA-score (I+II vs III). Please find a detailed protocol at www.pansaid.dk Longer follow-up than the specified 90 days (1 year) An analysis of the association between VAS-scores and opioid consumption Time-to-event analyses regarding use of PCA-morphine An analysis of the association between preoperative analgesic use and pain/morphine consumption An analysis of the individual patients: how many will achieve no worse than mild pain (NRS<3). Please find a detailed protocol at www.pansaid.dk More sub-studies may be performed post-hoc and they will be clearly identified as such. Oversight of amendments and approvals Protocol version 2: Approved 12 August 2015: First approved version of the trial protocol Protocol version 3: Approved 21 January 2016: Clarification of what happens in case of an SAE and definition of major protocol violations Protocol version 4: Approved 15 June 2016: Clarification of the primary outcome, clarification that steroids are not permitted in the intervention period, and addition of an exploratory outcome (dizziness) Protocol version 5: Approved 21 December 2016: Clarification of the exclusion criteria of contraindication to paracetamol and addition of stub-studies

Official Title
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PAracetamol and NSAID in Combination: A Randomised, Blinded, Parallel, 4-group Clinical Trial

Conditions
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Pain, Postoperative

Intervention / Treatment
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* Drug: Paracetamol (1g x 4)
* Drug: Ibuprofen (400 mg x 4)
* Drug: Paracetamol (0,5 g x 4)
* Drug: Ibuprofen (200 mg x 4)
* Drug: Placebo (x4)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled for unilateral, primary Total Hip Arthroplasty (THA) Age > 18 ASA 1-3. BMI > 18 and < 40 Women in the fertile age must have negative urine HCG pregnancy test Patients who gave their written informed consent to participating in the trial after having fully understood the contents of the protocol and restrictions. Exclusion Criteria: Patients who cannot cooperate with the trial. Concomitant participation in another trial Patients who cannot understand or speak Danish. Daily use of strong opioids (tramadol and codein are accepted) Patients with allergy to the medicines used in the trial. Contraindications against NSAID, for example previous ulcer, heart failure, liver failure, or renal failure (eGRF < 60 ml/kg/1,73m2), known thrombocytopenia (<100 mia/L) Patients suffering from alcohol and/or drug abuse - based on the investigator's judgement.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment A:<br>Paracetamol 1g + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative. | Drug: Paracetamol (1g x 4)<br>* Dose of 1 g given in 6 hour intervals the first 24 hours postoperatively<br>* Other names: Acetaminophen;Drug: Ibuprofen (400 mg x 4)<br>* Dose of 400 mg given in 6 hour intervals the first 24 hours postoperatively<br>|
| Active Comparator: Treatment B:<br>Paracetamol 1g + placebo orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative. | Drug: Paracetamol (1g x 4)<br>* Dose of 1 g given in 6 hour intervals the first 24 hours postoperatively<br>* Other names: Acetaminophen;Drug: Placebo (x4)<br>* Given in 6 hour intervals the first 24 hours postoperatively<br>|
| Active Comparator: Treatment C:<br>Placebo + ibuprofen 400 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative. | Drug: Ibuprofen (400 mg x 4)<br>* Dose of 400 mg given in 6 hour intervals the first 24 hours postoperatively<br>Drug: Placebo (x4)<br>* Given in 6 hour intervals the first 24 hours postoperatively<br>|
| Active Comparator: Treatment D:<br>Paracetamol 0,5 g + ibuprofen 200 mg orally starting 1 hour before surgery and given with 6-hour intervals (+/- 1 hour) i.e. a total of 4 times the first 24 hours postoperative. | Drug: Paracetamol (0,5 g x 4)<br>* Dose of 0,5 g given in 6 hour intervals the first 24 hours postoperatively<br>* Other names: Acetaminophen;Drug: Ibuprofen (200 mg x 4)<br>* Dose of 200 mg given in 6 hour intervals the first 24 hours postoperatively<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morphine consumption the first 24 hours postoperatively | Total need for morphine administered as BOTH patient controlled analgesia (PCA) for the first 24 hours postoperatively AND supplemental morphine administered at the post-anaesthesia unit the first hour postoperatively. Bolus 2.0 mg; lockout: 10 min | 0-24 hours postoperatively | 
| Serious adverse events | Serious adverse events, including death, within 90 days after surgery defined as SAE (according to ICH-GCP-guidelines) except prolongation of hospitalisation | 0-90 days postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain during movement at 6 hours postoperatively (visual analogue scale) | Pain scores (visual analogue scale (VAS)) with active 30 degrees flexion of the hip at 6 hours postoperatively. No pain = 0; worst imaginable pain = 100 | 6 hours postoperatively | 
| Pain during movement at 24 hours postoperatively (visual analogue scale) | Pain scores (visual analogue scale (VAS)) with active 30 degrees flexion of the hip at 24 hours postoperatively. No pain = 0; worst imaginable pain = 100 | 24 hours postoperatively | 
| Pain at rest at 6 hours postoperatively (visual analogue scale) | Pain scores (visual analogue scale (VAS)) at rest at 6 hours postoperatively. No pain = 0; worst imaginable pain = 100 | 6 hours postoperatively | 
| Pain at rest at 24 hours postoperatively (visual analogue scale) | Pain scores (visual analogue scale (VAS)) at rest at 24 hours postoperatively. No pain = 0; worst imaginable pain = 100 | 24 hours postoperatively | 
| Adverse events | Number of patients with one or more adverse events in the intervention period (0-24 hours) | 0-24 hours postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acetaminophen, Ibuprofen, Arthroplasty, Replacement, Hip