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

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ClinicalTrials.gov Identifier: NCT04123873
Recruitment Status : Recruiting
First Posted : October 11, 2019
Last Update Posted : June 9, 2020
Sponsor:
Information provided by (Responsible Party):
Naestved Hospital

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 (400 mg x 4) Drug: Dexamethasone Drug: Placebo oral tablet (x 4) Drug: Placebo IV (x 1) Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : March 5, 2020
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine


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.

Drug: Ibuprofen (400 mg x 4)
400mg x 4 p.o.

Drug: Placebo IV (x 1)
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.

Drug: Dexamethasone
24mg IV x 1 after induction om anaesthesia

Drug: Placebo oral tablet (x 4)
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 (400 mg x 4)
400mg x 4 p.o.

Drug: Dexamethasone
24mg IV x 1 after induction om anaesthesia

Drug: Placebo oral tablet (x 4)
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.

Drug: Ibuprofen (400 mg x 4)
400mg x 4 p.o.

Drug: Dexamethasone
24mg IV x 1 after induction om anaesthesia




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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


Other Outcome Measures:
  1. 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'

  2. 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

  3. 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

  4. Incidence of nausea [ Time Frame: 6 and 24 hours after end of surgery ]
  5. 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

  6. Consumption of ondansetron and DHBP [ Time Frame: 0-24 hours after end of surgery ]
    Consumption fon ondansetron and DHBP in mg

  7. Incidence of dizziness during mobilization [ Time Frame: 24 hours after end of surgery ]
  8. Blood loss [ Time Frame: Intraoperatively ]
    Blood loss during the surgical procedure in ml

  9. Quality of sleep (VAS) [ Time Frame: 24 hours after end of surgery ]
    Quality of sleep (VAS) Worst possible sleep = 0; best possible sleep = 100

  10. Days alive and outside hospital within 90 days after surgery [ Time Frame: Within 90 days after surgery ]
  11. 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)

  12. Quality of life [ Time Frame: At 90 days after surgery ]
    EuroQol five dimensions 5 point Lipert scale (EQ-5D-5L)

  13. Opioid use [ Time Frame: At 90 days after surgery ]
    Patient consumption of opioids within 90 days after surgery



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04123873


Contacts
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Contact: Daniel Hägi-Pedersen, MD, PhD 0045 21517167 dhag@regionsjaelland.dk
Contact: Joakim Steiness, MD joast@regionsjaelland.dk

Locations
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Denmark
Gildhøj Privathospital Not yet recruiting
København, Brøndby, Denmark, 2605
Contact: Niels Anker Pedersen, MD       nap@gildhoj.dk   
Principal Investigator: Niels Anker Pedersen, MD         
Næstved-Slagelse-Ringsted Hospitals Recruiting
Næstved, Danmark, Denmark, 4700
Contact: Daniel Hägi-Pedersen, Ph.D.    +45 56514792    dhag@regionsjaelland.dk   
Principal Investigator: Joakim Steiness         
Aarhus University Hospital Not yet recruiting
Aarhus, Denmark, 8200
Contact: Kjeld Søballe       kjeld@soballe.com   
Bispebjerg Hospital Recruiting
Copenhagen, Denmark, 2400
Contact: Troels H Lunn, DMSc         
Gentofte Hospital Recruiting
Hellerup, Denmark, 2900
Contact: Ulrik Grevstad, MD, PhD       ulrik.grevstad@hotmail.com   
Køge Hospital Not yet recruiting
Køge, Denmark, 4600
Contact: Ole Matiesen, MD, PhD       omat@regionsjaelland.dk   
Principal Investigator: Ole Matiesen, MD, PhD         
Odense University Hospital (OUH) Not yet recruiting
Odense, Denmark, 5000
Contact: Søren Overgaard, MD, DMsc    +45 59484105    soeren.overgaard@rsyd.dk   
Sponsors and Collaborators
Naestved Hospital
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Responsible Party: Naestved Hospital
ClinicalTrials.gov Identifier: NCT04123873    
Other Study ID Numbers: SM1-JOAST-2019
First Posted: October 11, 2019    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Naestved Hospital:
RECIPE
Hip arthroplasty
Postoperative pain
Analgesia
Multimodal analgesia
Non-opioid analgesia
Acute pain
Additional relevant MeSH terms:
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Joint Diseases
Pain, Postoperative
Acute Pain
Postoperative Complications
Pathologic Processes
Pain
Neurologic Manifestations
Signs and Symptoms
Musculoskeletal Diseases
Acetaminophen
Dexamethasone
Ibuprofen
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors