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

Sponsor

Naestved Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04123873

Collaborator

(none)

1,060

Enrollment

Locations

Arms

36.9

Anticipated Duration (Months)

151.4

Patients Per Site

4.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pain, Acute Hip Arthropathy Analgesia Postoperative Pain	Drug: Paracetamol Drug: Ibuprofen Drug: Dexamethasone Drug: Placebo oral capsules Drug: Placebo IV	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1060 participants

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

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

Actual Study Start Date :

Mar 5, 2020

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
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	Drug: Paracetamol 1g x 4 p.o. Other Names: Acetaminophen Drug: Ibuprofen 400mg x 4 p.o. Drug: Placebo IV IV x 1
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	Drug: Paracetamol 1g x 4 p.o. Other Names: Acetaminophen Drug: Dexamethasone 24mg IV x 1 after induction om anaesthesia Drug: Placebo oral capsules p.o. x 4
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	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
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	Drug: Paracetamol 1g x 4 p.o. Other Names: Acetaminophen Drug: Ibuprofen 400mg x 4 p.o. Drug: Dexamethasone 24mg IV x 1 after induction om anaesthesia

Outcome Measures

Primary Outcome Measures

Cumulative opioid consumption in the first 24 hours after surgery [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

Secondary Outcome Measures

Pain scores during mobilisation 24h [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 [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 [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 [From end of surgery + 24 hours]
Proportion of patients with one or more AEs in the intervention period

Other Outcome Measures

Serious adverse events within one year [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 [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 [6 hours after end of surgery]
Pain scores at rest (VAS 0-100 mm; no pain = 0; worst imaginable pain = 100)
Prevalence of nausea [6 and 24 hours after end of surgery]
Prevalence of nausea, 6 and 24 hours after end of surgery
Number of vomiting episodes [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 [0-24 hours after end of surgery]
Consumption of ondansetron and dehydrobenzperidole in mg
Incidence of dizziness during 5 meter walk [24 hours after end of surgery]
Incidence of dizziness during 5 meter walk 24 hours after surgery
Blood loss [Intraoperatively]
Blood loss in ml during the surgical procedure
Quality of sleep [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 [Within 90 days after surgery]
Days alive and outside hospital within 90 days after surgery
Oxford Hip Score at 90 days [At 90 days after surgery]
5-point Lipert-scale (no, mild, moderate, severe and extreme)
Quality of life (EQ-5D-5L) at 90 days [At 90 days after surgery]
EuroQol five-dimensions 5 point Lipert scale (EQ-5D-5L)
Opioid use at 90 days [Within 90 days after surgery]
Consumption of opioids within 90 days after surgery
Serious adverse events within 1 year [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 [One year after surgery]
5-point Lipert-scale (no, mild, moderate, severe and extreme)
Quality of life (EQ-5D-5L) at one year [One year after surgery]
EuroQol five-dimensions 5 point Lipert scale (EQ-5D-5L)
Opioid use at one year [Within one year after surgery]
Consumption of opioids within one year after surgery

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Næstved-Slagelse-Ringsted Hospitals	Næstved	Danmark	Denmark	4700
2	Bispebjerg Hospital	Copenhagen		Denmark	2400
3	Gentofte Hospital	Hellerup		Denmark	2900
4	Hillerød Hospital	Hillerød		Denmark	3400
5	Køge Hospital	Køge		Denmark	4600
6	Odense University Hospital (OUH)	Odense		Denmark	5000
7	Svendborg Hospital	Svendborg		Denmark	5700