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

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.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative
• Intervention / Treatment: Drug: Paracetamol (1g x 4); Drug: Ibuprofen (400 mg x 4); Drug: Placebo (x4); Drug: Paracetamol (0,5 g x 4); Drug: Ibuprofen (200 mg x 4)

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

• Study Type: Interventional
• Enrollment (Actual): 556
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Holbæk, Denmark, 4300
    • Holbæk Hospital
  • Køge, Denmark, 4600
    • Køge Hospital
  • Nykøbing Falster, Denmark, 4800
    • Nykøbing Falster Hospital
  • Næstved, Denmark, 4700
    • Næstved Hospital
  • Odense, Denmark, 5000
    • Odense University Hospital (OUH)
  • Brøndby
    • København, Brøndby, Denmark, 2605
      • Gildhøj Privathospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Paracetamol (1g x 4); Dose of 1 g given in 6 hour intervals the first 24 hours postoperatively; Other Names: Acetaminophen; Drug: Ibuprofen (400 mg x 4); Dose of 400 mg given in 6 hour intervals the first 24 hours postoperatively
Active Comparator: 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.	Drug: Paracetamol (1g x 4); Dose of 1 g given in 6 hour intervals the first 24 hours postoperatively; Other Names: Acetaminophen; Drug: Placebo (x4); Given in 6 hour intervals the first 24 hours postoperatively
Active Comparator: 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.	Drug: Ibuprofen (400 mg x 4); Dose of 400 mg given in 6 hour intervals the first 24 hours postoperatively; Drug: Placebo (x4); Given in 6 hour intervals the first 24 hours postoperatively
Active Comparator: 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.	Drug: Paracetamol (0,5 g x 4); Dose of 0,5 g given in 6 hour intervals the first 24 hours postoperatively; Other Names: Acetaminophen; Drug: Ibuprofen (200 mg x 4); Dose of 200 mg given in 6 hour intervals the first 24 hours postoperatively

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nausea at 6 hours postoperatively (Verbal rating scale)	Level of nausea at 6 hours postoperatively. Verbal rating scale: none, mild, moderate or severe	6 hours postoperatively
Nausea at 24 hours postoperatively (Verbal rating scale)	Level of nausea at 24 hours postoperatively. Verbal rating scale: none, mild, moderate or severe	24 hours postoperatively
Vomiting the first 24 hours postoperatively	Number of vomiting episodes (0-24 hours) measured in the periods 0-6 and 6-24 hours postoperatively	0-24 hours postoperatively
Anti-emetic treatment the first 24 hours postoperatively	Consumption of ondansetron in the period 0-24 hours postoperatively	0-24 hours postoperatively
Sedation at 6 hours postoperatively (Verbal rating scale)	Level of sedation at 6 hours postoperatively. Verbal rating scale: none, mild, moderate or severe	6 hours postoperatively
Sedation at 24 hours postoperatively (Verbal rating scale)	Level of sedation at 24 hours postoperatively. Verbal rating scale: none, mild, moderate or severe	24 hours postoperatively
Blood loss intraoperatively	Blood loss during the surgical procedure (intraoperatively)	intraoperatively
Days alive and outside hospital within 90 days after surgery.	Days alive and outside hospital within 90 days after surgery.	0-90 days postoperatively
Dizziness at 6 hours postoperatively (Verbal rating scale)	Level of dizziness at 6 hours postoperatively. Verbal rating scale: none, mild, moderate or severe	6 hours postoperatively
Dizziness at 24 hours postoperatively (Verbal rating scale)	Level of dizziness at 24 hours postoperatively. Verbal rating scale: none, mild, moderate or severe	24 hours postoperatively

Collaborators and Investigators

• Sponsor: Daniel Hägi-Pedersen
• Collaborators: Copenhagen Trial Unit, Center for Clinical Intervention Research
• Investigators: Study Chair: Daniel Hägi-Pedersen, MD, PhD, Department of Anaesthesiology, Næstved Hospital; Principal Investigator: Kasper H Thybo, MD, Department of Anaesthesiology, Næstved Hospital; Study Chair: Ole Mathiesen, MD, PhD, Department of Anaesthesiology, Køge Hospital; Study Chair: Jørgen B Dahl, MD, DMSc, Department of Anaesthesiology, Bispebjerg Hospital; Study Chair: Jørn Wetterslev, MD, PhD, Copenhagen Trial Unit, Center for Clinical Intervention Research; Study Chair: Martin Pohlman, MD, Department of Anaesthesiology, Nykøbing Falster Hospital; Study Chair: Hans Henrik Bülow, MD, Department of Anaesthesiology, Holbæk Hospital

Publications and helpful links

General Publications

• 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.

Helpful Links

• Trial Website

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: October 7, 2015
• First Submitted That Met QC Criteria: October 7, 2015
• First Posted (Estimate): October 8, 2015

Study Record Updates

• Last Update Posted (Actual): February 12, 2018
• Last Update Submitted That Met QC Criteria: February 9, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Ibuprofen; Acetaminophen; Arthroplasty, Replacement, Hip
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Acetaminophen; Ibuprofen
• Other Study ID Numbers: SM2-KHT-2015 - v2; 2015-002239-16 (EudraCT Number)