Clinical trial NCT02571361: PAracetamol and NSAID in Combination: A Randomised, Blinded, Parallel, 4-group Clinical Trial
Official title: PAracetamol and NSAID in Combination: A Randomised, Blinded, Parallel, 4-group Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pain, Postoperative
Keywords: Acetaminophen
Ibuprofen
Arthroplasty, Replacement, Hip
Lead sponsor: Naestved Hospital
Sponsor class: OTHER
Collaborators: name: Copenhagen Trial Unit, Center for Clinical Intervention Research
First posted: 2015-10-08
Enrollment: 556
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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. :

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

Eligibility criteria: 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.

Primary outcomes:
measure: Morphine consumption the first 24 hours postoperatively
timeFrame: 0-24 hours postoperatively
measure: Serious adverse events
timeFrame: 0-90 days postoperatively
Secondary outcomes:
measure: Pain during movement at 6 hours postoperatively (visual analogue scale)
timeFrame: 6 hours postoperatively
measure: Pain during movement at 24 hours postoperatively (visual analogue scale)
timeFrame: 24 hours postoperatively
measure: Pain at rest at 6 hours postoperatively (visual analogue scale)
timeFrame: 6 hours postoperatively
measure: Pain at rest at 24 hours postoperatively (visual analogue scale)
timeFrame: 24 hours postoperatively
measure: Adverse events
timeFrame: 0-24 hours postoperatively
Other outcomes:
measure: Nausea at 6 hours postoperatively (Verbal rating scale)
timeFrame: 6 hours postoperatively
measure: Nausea at 24 hours postoperatively (Verbal rating scale)
timeFrame: 24 hours postoperatively
measure: Vomiting the first 24 hours postoperatively
timeFrame: 0-24 hours postoperatively
measure: Anti-emetic treatment the first 24 hours postoperatively
timeFrame: 0-24 hours postoperatively
measure: Sedation at 6 hours postoperatively (Verbal rating scale)
timeFrame: 6 hours postoperatively
measure: Sedation at 24 hours postoperatively (Verbal rating scale)
timeFrame: 24 hours postoperatively
measure: Blood loss intraoperatively
timeFrame: intraoperatively
measure: Days alive and outside hospital within 90 days after surgery.
timeFrame: 0-90 days postoperatively
measure: Dizziness at 6 hours postoperatively (Verbal rating scale)
timeFrame: 6 hours postoperatively
measure: Dizziness at 24 hours postoperatively (Verbal rating scale)
timeFrame: 24 hours postoperatively
Locations:
city: København
country: Denmark
facility: Gildhøj Privathospital
state: Brøndby
city: Holbæk
country: Denmark
facility: Holbæk Hospital
city: Køge
country: Denmark
facility: Køge Hospital
city: Nykøbing Falster
country: Denmark
facility: Nykøbing Falster Hospital
city: Næstved
country: Denmark
facility: Næstved Hospital
city: Odense
country: Denmark
facility: Odense University Hospital (OUH)
Study officials:
affiliation: Department of Anaesthesiology, Næstved Hospital
name: Daniel Hägi-Pedersen, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Anaesthesiology, Næstved Hospital
name: Kasper H Thybo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Anaesthesiology, Køge Hospital
name: Ole Mathiesen, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Anaesthesiology, Bispebjerg Hospital
name: Jørgen B Dahl, MD, DMSc
role: STUDY_CHAIR
affiliation: Copenhagen Trial Unit, Center for Clinical Intervention Research
name: Jørn Wetterslev, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Anaesthesiology, Nykøbing Falster Hospital
name: Martin Pohlman, MD
role: STUDY_CHAIR
affiliation: Department of Anaesthesiology, Holbæk Hospital
name: Hans Henrik Bülow, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.