PAracetamol and NSAID in Combination: A Randomised, Blinded, Parallel, 4-group Clinical Trial
NCT ID: NCT02571361
Last Updated: 2018-02-12
Study Results
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Basic Information
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COMPLETED
PHASE4
556 participants
INTERVENTIONAL
2015-11-30
2018-01-31
Brief Summary
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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.
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Detailed Description
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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. :
1. 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
2. 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
3. Longer follow-up than the specified 90 days (1 year)
4. An analysis of the association between VAS-scores and opioid consumption
5. Time-to-event analyses regarding use of PCA-morphine
6. An analysis of the association between preoperative analgesic use and pain/morphine consumption
7. 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
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Treatment A:
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.
Paracetamol (1g x 4)
Dose of 1 g given in 6 hour intervals the first 24 hours postoperatively
Ibuprofen (400 mg x 4)
Dose of 400 mg given in 6 hour intervals the first 24 hours postoperatively
Treatment B:
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.
Paracetamol (1g x 4)
Dose of 1 g given in 6 hour intervals the first 24 hours postoperatively
Placebo (x4)
Given in 6 hour intervals the first 24 hours postoperatively
Treatment C:
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.
Ibuprofen (400 mg x 4)
Dose of 400 mg given in 6 hour intervals the first 24 hours postoperatively
Placebo (x4)
Given in 6 hour intervals the first 24 hours postoperatively
Treatment D:
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.
Paracetamol (0,5 g x 4)
Dose of 0,5 g given in 6 hour intervals the first 24 hours postoperatively
Ibuprofen (200 mg x 4)
Dose of 200 mg given in 6 hour intervals the first 24 hours postoperatively
Interventions
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Paracetamol (1g x 4)
Dose of 1 g given in 6 hour intervals the first 24 hours postoperatively
Ibuprofen (400 mg x 4)
Dose of 400 mg given in 6 hour intervals the first 24 hours postoperatively
Paracetamol (0,5 g x 4)
Dose of 0,5 g given in 6 hour intervals the first 24 hours postoperatively
Ibuprofen (200 mg x 4)
Dose of 200 mg given in 6 hour intervals the first 24 hours postoperatively
Placebo (x4)
Given in 6 hour intervals the first 24 hours postoperatively
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
18 Years
ALL
No
Sponsors
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Copenhagen Trial Unit, Center for Clinical Intervention Research
OTHER
Daniel Hägi-Pedersen
OTHER
Responsible Party
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Daniel Hägi-Pedersen
Consultant
Principal Investigators
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Daniel Hägi-Pedersen, MD, PhD
Role: STUDY_CHAIR
Department of Anaesthesiology, Næstved Hospital
Kasper H Thybo, MD
Role: PRINCIPAL_INVESTIGATOR
Department of Anaesthesiology, Næstved Hospital
Ole Mathiesen, MD, PhD
Role: STUDY_CHAIR
Department of Anaesthesiology, Køge Hospital
Jørgen B Dahl, MD, DMSc
Role: STUDY_CHAIR
Department of Anaesthesiology, Bispebjerg Hospital
Jørn Wetterslev, MD, PhD
Role: STUDY_CHAIR
Copenhagen Trial Unit, Center for Clinical Intervention Research
Martin Pohlman, MD
Role: STUDY_CHAIR
Department of Anaesthesiology, Nykøbing Falster Hospital
Hans Henrik Bülow, MD
Role: STUDY_CHAIR
Department of Anaesthesiology, Holbæk Hospital
Locations
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Gildhøj Privathospital
Copenhagen, Brøndby, Denmark
Holbæk Hospital
Holbæk, , Denmark
Køge Hospital
Køge, , Denmark
Nykøbing Falster Hospital
Nykøbing Falster, , Denmark
Næstved Hospital
Næstved, , Denmark
Odense University Hospital (OUH)
Odense, , Denmark
Countries
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References
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Thybo KH, Hagi-Pedersen D, Wetterslev J, Dahl JB, Schroder HM, Bulow HH, Bjorck JG, Mathiesen O. PANSAID - PAracetamol and NSAID in combination: study protocol for a randomised trial. Trials. 2017 Jan 10;18(1):11. doi: 10.1186/s13063-016-1749-7.
Thybo KH, Hagi-Pedersen D, Dahl JB, Wetterslev J, Nersesjan M, Jakobsen JC, Pedersen NA, Overgaard S, Schroder HM, Schmidt H, Bjorck JG, Skovmand K, Frederiksen R, Buus-Nielsen M, Sorensen CV, Kruuse LS, Lindholm P, Mathiesen O. Effect of Combination of Paracetamol (Acetaminophen) and Ibuprofen vs Either Alone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty: The PANSAID Randomized Clinical Trial. JAMA. 2019 Feb 12;321(6):562-571. doi: 10.1001/jama.2018.22039.
Thybo KH, Jakobsen JC, Hagi-Pedersen D, Pedersen NA, Dahl JB, Schroder HM, Bulow HH, Bjorck JG, Overgaard S, Mathiesen O, Wetterslev J. PANSAID-PAracetamol and NSAID in combination: detailed statistical analysis plan for a randomised, blinded, parallel, four-group multicentre clinical trial. Trials. 2017 Oct 10;18(1):465. doi: 10.1186/s13063-017-2203-1.
Related Links
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Trial Website
Other Identifiers
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2015-002239-16
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
SM2-KHT-2015 - v2
Identifier Type: -
Identifier Source: org_study_id
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