Effect of Combinations of Paracetamol, Ibuprofen, and Dexamethasone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty (RECIPE)

• ClinicalTrials.gov Identifier: NCT04123873
• Recruitment Status: Recruiting
• First Posted: October 11, 2019
• Last Update Posted: March 4, 2022
• Sponsor: Naestved Hospital
• Information provided by (Responsible Party): Naestved Hospital

Tracking Information

• First Submitted Date: September 27, 2019
• First Posted Date: October 11, 2019
• Last Update Posted Date: March 4, 2022
• Actual Study Start Date: March 5, 2020
• Estimated Primary Completion Date: January 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 17, 2022)

Cumulative opioid consumption in the first 24 hours after surgery [ Time Frame: 0-24 hours after end of surgery ]

Cumulative opioid consumption in units of intravenous morphine equivalents in the first 24 postoperative hours. This includes opioids administered as (a) patient-controlled analgesia (PCA); (b) supplemental opioid administered at the post-anaesthesia care unit the first hour after end of surgery (general anaesthesia) or the first hour after ceasing of spinal anaesthesia; and (c) any supplemental opioid given at the ward

Original Primary Outcome Measures (submitted: October 9, 2019)

Cumulative morphine-consumption during the first 24 hours after end of surgery [ Time Frame: 0-24 hours after end of surgery ]

Total need for IV-morphine mg (eqv) for the first 24 hours postoperatively, administered as patient-controlled analgesia (PCA)-morphine (0-24 hours), and supplemental opioid administered at the post-anaesthesia care unit the first hour postoperatively after end of surgery (general anaesthesia) or end of spinal anaesthesia, or any supplemental opioid given at the ward

Current Secondary Outcome Measures (submitted: February 17, 2022)

• Pain scores during mobilisation 24h [ Time Frame: 24 hours after end of surgery ]
  Pain scores (visual analogue scale (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)) with active 30 degrees flexion of the hip
• Pain scores at rest 24h [ Time Frame: 24 hours after end of surgery ]
  Pain scores at rest (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)
• Maximum level of pain [ Time Frame: 24 hours after end of surgery ]
  Maximum level of pain (VAS 0-100 mm No pain = 0; worst imaginable pain = 100) during walk of 5 meters
• Adverse events in the intervention period [ Time Frame: From end of surgery + 24 hours ]
  Proportion of patients with one or more AEs in the intervention period

Original Secondary Outcome Measures (submitted: October 9, 2019)

• Pain scores during mobilisation 24h [ Time Frame: 24 hours after end of surgery ]
  Pain scores (visual analogue scale (VAS)) with active 30 degrees flexion of the hip No pain = 0; worst imaginable pain = 100
• Pain scores at rest 24h [ Time Frame: 24 hours after end of surgery ]
  Pain scores at rest (VAS) No pain = 0; worst imaginable pain = 100
• Maximum level of pain [ Time Frame: 24 hours after end of surgery ]
  Maximum level of pain (VAS) during walk of 5 meters No pain = 0; worst imaginable pain = 100
• Number of patients with adverse events [ Time Frame: 24 hours after end of surgery ]
  Number of patients with one or more AEs in the intervention period

Current Other Pre-specified Outcome Measures (submitted: February 17, 2022)

• Serious adverse events within one year [ Time Frame: Within 90 days ]
  SAEs, including death, within 90 days after surgery defined as SAE (according to ICH-GCP-guidelines) except 'prolongation of hospitalisation' that has been modified to 'prolongation of hospitalization with ≥4 days'
• Pain scores during mobilisation 6h [ Time Frame: 6 hours after end of surgery ]
  Pain scores (visual analogue scale (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)) with active 30 degrees flexion of the hip
• Pain scores at rest 6h [ Time Frame: 6 hours after end of surgery ]
  Pain scores at rest (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)
• Prevalence of nausea [ Time Frame: 6 and 24 hours after end of surgery ]
  Prevalence of nausea, 6 and 24 hours after end of surgery
• Number of vomiting episodes [ Time Frame: 0-24 after end of surgery. Reported by interview 24 hours after end of surgery ]
  The number of productive vomiting events (volume estimated over 10 ml) is recorded corresponding to the period 0-24 hours
• Consumption of ondansetron and dehydrobenzperidole [ Time Frame: 0-24 hours after end of surgery ]
  Consumption of ondansetron and dehydrobenzperidole in mg
• Incidence of dizziness during 5 meter walk [ Time Frame: 24 hours after end of surgery ]
  Incidence of dizziness during 5 meter walk 24 hours after surgery
• Blood loss [ Time Frame: Intraoperatively ]
  Blood loss in ml during the surgical procedure
• Quality of sleep [ Time Frame: 24 hours after end of surgery ]
  Quality of sleep (VAS 0-100 mm; worst possible sleep = 0; best possible sleep = 100) Worst possible sleep = 0; best possible sleep = 100
• Days alive and outside hospital within 90 days after surgery [ Time Frame: Within 90 days after surgery ]
  Days alive and outside hospital within 90 days after surgery
• Oxford Hip Score at 90 days [ Time Frame: At 90 days after surgery ]
  5-point Lipert-scale (no, mild, moderate, severe and extreme)
• Quality of life (EQ-5D-5L) at 90 days [ Time Frame: At 90 days after surgery ]
  EuroQol five-dimensions 5 point Lipert scale (EQ-5D-5L)
• Opioid use at 90 days [ Time Frame: Within 90 days after surgery ]
  Consumption of opioids within 90 days after surgery
• Serious adverse events within 1 year [ Time Frame: Within one year after surgery ]
  Proportion of participants with one or more serious adverse events, including death, within one year after surgery, according to ICH-GCP guidelines[24] (except for 'prolongation of hospitalization' that has been modified to 'prolongation of hospitalization with ≥4 days')
• Oxford Hip Score at one year [ Time Frame: One year after surgery ]
  5-point Lipert-scale (no, mild, moderate, severe and extreme)
• Quality of life (EQ-5D-5L) at one year [ Time Frame: One year after surgery ]
  EuroQol five-dimensions 5 point Lipert scale (EQ-5D-5L)
• Opioid use at one year [ Time Frame: Within one year after surgery ]
  Consumption of opioids within one year after surgery

Original Other Pre-specified Outcome Measures (submitted: October 9, 2019)

• Serious adverse events (SAEs) [ Time Frame: Within 90 days ]
  SAEs, including death, within 90 days after surgery defined as SAE (according to ICH-GCP-guidelines) except 'prolongation of hospitalisation'
• Pain scores during mobilisation 6h [ Time Frame: 6 hours after end of surgery ]
  Pain scores (VAS) with active 30 degrees flexion of the hip No pain = 0; worst imaginable pain = 100
• Pain scores at rest 6h [ Time Frame: 6 hours after end of surgery ]
  Pain scores (VAS) at rest No pain = 0; worst imaginable pain = 100
• Incidence of nausea [ Time Frame: 6 and 24 hours after end of surgery ]
• Number of vomiting episodes [ Time Frame: 0-24 after end of surgery. Reported by interview 24 hours after end of surgery ]
  The number of productive vomiting events (volume estimated over 10 ml) is recorded corresponding to the period 0-24 hours
• Consumption of ondansetron and DHBP [ Time Frame: 0-24 hours after end of surgery ]
  Consumption fon ondansetron and DHBP in mg
• Incidence of dizziness during mobilization [ Time Frame: 24 hours after end of surgery ]
• Blood loss [ Time Frame: Intraoperatively ]
  Blood loss during the surgical procedure in ml
• Quality of sleep (VAS) [ Time Frame: 24 hours after end of surgery ]
  Quality of sleep (VAS) Worst possible sleep = 0; best possible sleep = 100
• Days alive and outside hospital within 90 days after surgery [ Time Frame: Within 90 days after surgery ]
• Hip disability and Osteoarthritis Outcome Score [ Time Frame: At 90 days after surgery ]
  5 point Lipert-scale 0 to 4 (no, mild, moderate, severe and extreme)
• Quality of life [ Time Frame: At 90 days after surgery ]
  EuroQol five dimensions 5 point Lipert scale (EQ-5D-5L)
• Opioid use [ Time Frame: At 90 days after surgery ]
  Patient consumption of opioids within 90 days after surgery

Descriptive Information

• Brief Title: Effect of Combinations of Paracetamol, Ibuprofen, and Dexamethasone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty
• Official Title: Effect of Combinations of Paracetamol, Ibuprofen, and Dexamethasone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty. The RECIPE Randomized Clinical Trial

Brief Summary

Multimodal pain management is essential for recovery after surgery, aiming to target different pain mechanisms to minimize opioid usage and opioid-related adverse effects. Evidence for benefits and harms of various non-opioid analgesic combinations is, however, nearly non-existing, and large-scale trials are urgently needed.

Recently, the investigators have demonstrated that combining paracetamol and ibuprofen is superior to each single drug when assessing pain after hip replacement. Further improvement is needed, investigating additional non-opioid analgesics to this combination. Glucocorticoids have anti-emetic and analgesic properties, but evidence for analgesic efficacy in combination with paracetamol and ibuprofen is lacking.

The RECIPE trial is an investigator-initiated randomized, placebo-controlled, parallel, 4-group, blinded multicentre trial with 90-day follow-up investigating benefits and harms of different combinations of paracetamol, ibuprofen, and dexamethasone for patients undergoing total hip arthroplasty.

The primary outcome is total use of IV morphine 0-24 hours postoperatively. Secondary outcomes are pain (upon mobilisation, at rest, and during 5 m walk), and adverse events. Exploratory outcomes include quality of sleep, opioid-related adverse effects, serious adverse events (< 90 days), and patient reported disability score and quality of life (at 90 days).

Based on sample-size calculations, 1060 patients are needed to detect a minimal clinically important difference in 24-hour morphine consumption of 8 mg, using a familywise type 1 error rate of 0.05 and a type 2 error rate of 0.2. The primary analyses will be based on the intention to treat population. More than six Danish university- and regional hospitals will participate in the trial.

With this trial the investigators expect to lay the foundation for the best postoperative multimodal analgesic regimen for both total hip arthroplasty and possibly other surgeries, thereby facilitating recovery for millions of future surgical patients worldwide.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

The study medication will be masked by the pharmacy. The experimental medicine will be packed and labelled by Skanderborg Pharmacy in accordance with the Good Manufacturing Practice regulations. The sponsor has a set of sealed, opaque envelopes with the participants' allocation, and these will only be revealed for the investigators when the data has been analysed and abstracts and conclusions covering the different possibilities for interpreting the trial results, have been agreed upon by the steering committee

Primary Purpose: Treatment

Condition

• Pain, Acute
• Hip Arthropathy
• Analgesia
• Postoperative Pain

Intervention

• Drug: Paracetamol
  1g x 4 p.o.
  Other Name: Acetaminophen
• Drug: Ibuprofen
  400mg x 4 p.o.
• Drug: Dexamethasone
  24mg IV x 1 after induction om anaesthesia
• Drug: Placebo oral capsules
  p.o. x 4
• Drug: Placebo IV
  IV x 1

Study Arms

• Experimental: Group A

  Paracetamol 1000 mg + Ibuprofen 400 mg administered orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day.

  Plus placebo (matching DXM) IV administered after induction of anaesthesia

  Interventions:

  • Drug: Paracetamol
  • Drug: Ibuprofen
  • Drug: Placebo IV
• Experimental: Group B

  Paracetamol 1000 mg and placebo (matching ibuprofen) orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day.

  Plus DXM 24 mg IV after induction of anaesthesia

  Interventions:

  • Drug: Paracetamol
  • Drug: Dexamethasone
  • Drug: Placebo oral capsules
• Experimental: Group C

  Placebo (matching paracetamol) + ibuprofen 400 mg orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day.

  Plus DXM 24 mg IV after induction of anaesthesia

  Interventions:

  • Drug: Ibuprofen
  • Drug: Dexamethasone
  • Drug: Placebo oral capsules
• Experimental: Group D

  Paracetamol 1000 mg + ibuprofen 400 mg orally 1 hour before surgery and given with 6-hour intervals to a total of 4 times the first postoperative day.

  Plus DXM 24 mg IV after induction of anaesthesia

  Interventions:

  • Drug: Paracetamol
  • Drug: Ibuprofen
  • Drug: Dexamethasone

• Publications *: Steiness J, Hagi-Pedersen D, Lunn TH, Lindberg-Larsen M, Graungaard BK, Lundstrom LH, Lindholm P, Brorson S, Bieder MJ, Beck T, Skettrup M, von Cappeln AG, Thybo KH, Gasbjerg KS, Overgaard S, Jakobsen JC, Mathiesen O. Paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty: protocol for the randomised, placebo-controlled, parallel 4-group, blinded, multicentre RECIPE trial. BMJ Open. 2022 Sep 1;12(9):e058965. doi: 10.1136/bmjopen-2021-058965.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 9, 2019): 1060
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 2023
• Estimated Primary Completion Date: January 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Scheduled for elective, unilateral, primary THA
• Age ≥ 18
• ASA 1-3
• BMI > 18 and < 40
• Negative urine HCG pregnancy test and use of anti-conception for women in the fertile age
• Give written informed consent to participate 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 involving medication
• Patients who cannot understand or speak Danish
• Patients with allergy to medication used in the trial
• Patients with daily use of high dose opioid (> oral morphine 30 mg/day or oxycodone 30 mg/day or tramadol 150 mg/day) or any use of other opioids including methadone and transdermal opioids.
• Patients with daily use of systemic glucocorticoids (within 3 months before the trial)
• Contraindications against ibuprofen or paracetamol, for example previous ulcer, known heart failure, known liver failure, or known renal failure (eGRF < 60 ml/kg/1,73m2), known thrombocytopenia (< 100 x 109/l); or against treatment with glucocorticoids
• Dysregulated diabetes (investigator's judgement)
• Patients suffering from alcohol and/or drug abuse - based on the investigator's judgement

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Daniel Hägi-Pedersen, MD, PhD; 0045 21517167; dhag@regionsjaelland.dk

Contact: Joakim Steiness, MD; joast@regionsjaelland.dk

• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT04123873
• Other Study ID Numbers: SM1-JOAST-2019
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Naestved Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Naestved Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Naestved Hospital
• Verification Date: February 2022