Oral vs IV Acetaminophen for Long-bone Fracture in Children

Oral Versus Intravenous Acetaminophen for the Treatment of Pain Secondary to Long Bone Fracture Requiring Surgery in Children

Intravenous (IV) acetaminophen entered the Canadian market recently and children with acute pain following a trauma are ideal candidates for the IV formulation as it may improve analgesia and consequently decrease the amount of opioids needed to achieve pain control. Due to the limited data on bioavailability, adverse effect profile and efficacy of IV versus oral acetaminophen, it is of paramount importance to generate evidence-based data to guide clinicians with a rational choice of route of administration of acetaminophen.

Therefore, we propose a pilot study to inform a future large randomized controlled trial (RCT) to compare pharmacokinetics, feasibility, preliminary effects and side effects profile of oral versus IV acetaminophen in children admitted for surgical fixation of a long-bone fracture.

Study Overview

• Status: Recruiting
• Conditions: Pain
• Intervention / Treatment: Drug: Acetaminophen; Drug: Acetaminophen IV

Detailed Description

Patients admitted for a long-bone fracture needing surgical fixation are generally initially treated with intranasal and/or IV opioids in association to oral acetaminophen and ibuprofen. Following surgery they are treated with a combination of morphine and acetaminophen. To address the issue of opioid epidemics, the Pediatric Orthopaedic Society of North America recommends reduction of their prescription as much as possible by promoting, among others, use of multimodal analgesia after surgery. The current proposal aims to improve post-operative pain control in children following a surgical fixation of a long-bone fracture and decrease the use of opioids through better co-analgesia. As such, this study aims to assess the pharmacokinetics (PK) and the efficacy of oral versus IV formulations of acetaminophen after surgery for long bone fractures in children.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Niina Kleiber, MD; Phone Number: (514) 3454931; Email: niina.kleiber.med@ssss.gouv.qc.ca
• Study Contact Backup: Name: Evelyne Trottier; Phone Number: (514) 3454931; Email: evelyne.doyon-trottier.med@ssss.gouv.qc.ca

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada
      • Recruiting
      • CHU Sainte-Justine
      • Contact: Niina kleiber, MD; Phone Number: 514 3454931; Email: niina.kleiber.med@ssss.gouv.qc.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Likely to undergo surgery for a long-bone fracture
• Aged between 2-18 years (IV acetaminophen is approved for children ≥2 years)
• IV line per standard of care

Exclusion Criteria:

• Contraindication to oral drug administration
• Patients unable to take oral solution
• Known hypersensitivity or allergy to acetaminophen or any of the excipients in the IV or oral formulation
• Use of any medication known to interact with acetaminophen including, but not restricted to phenytoin and carbamazepine (1)
• Pregnancy
• Known Hepatic insufficiency or hepatic disease
• Known or diagnosed severe renal failure
• Multiple trauma (more than two long bone fractures)
• Hemodynamic or respiratory compromise
• Altered level of consciousness (Glasgow coma scale <15)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Oral acetaminophen arm; they will receive oral acetaminophen, placebo (saline) IV	Drug: Acetaminophen; A liquid oral acetaminophen suspension will be administered regularly every 6h at a dose of 15mg/kg (maximum single dose: 1g). An IV infusion of NaCl 0.9% corresponding to the volume of IV acetaminophen will be administered as a 15-minute intravenous infusion at the same time as the oral dose. PrACETAMINOPHEN INJECTION ® is a clear and colorless liquid undistinguishable from NaCl 0.9%.
ACTIVE_COMPARATOR: IV acetaminophen arm; they will receive IV acetaminophen, placebo oral	Drug: Acetaminophen IV; An IV infusion of 15mg/kg of acetaminophen (PrACETAMINOPHEN INJECTION, AVIR Pharma Inc.) (maximum single dose:1g) will be administered regularly every 6h as a 15-minute intravenous infusion. At the same time, an oral placebo with similar appearance as the corresponding acetaminophen oral solution will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain scores	Pain scores within the first 24 hours following initiation of study drug, using the scales Face, Legs, Activity, Cry, Consolability (FLACC, 0-2 per item for a total of 10, 10 being the worst pain) and verbal numerical rating (VNR, 0-10, 10 being the worst pain).	During 24h (starting with the first dose of study drug)
Difference in quantity of rescue opioids	Quantity of rescue opioids (morphine equivalent in mg/kg) within the first 24 hours following initiation of study drug	During 24h (starting with the first dose of study drug)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Any other adverse effect whether or not attributed to the study drug will be carefully recorded. Opioid-related adverse effects will be recorded (pruritus, time to first bowel movement, nausea (self-reported), vomiting, days of bladder catheterization, oxygen supplementation, episodes of respiratory depression (< 10/min in children older than 5 years), use of diphenhydramine, naloxone, antiemetics, laxatives).	During 24h (starting with the first dose of study drug)
Determination of oral bioavailability	Blood level of acetaminophen will be determined	During 24 hours after the first dose of study drug

Collaborators and Investigators

• Sponsor: Dr. Niina Kleiber
• Investigators: Principal Investigator: Niina Kleiber, MD PhD, St. Justine's Hospital

Publications and helpful links

General Publications

• Ulrich M, Chamberland M, Bertoldi C, Garcia-Bournissen F, Kleiber N. Newly approved IV acetaminophen in Canada: Switching from oral to IV acetaminophen. Is IV worth the price difference? A systematic review. Paediatr Child Health. 2021 Mar 13;26(6):337-343. doi: 10.1093/pch/pxaa137. eCollection 2021 Oct.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 21, 2021
• Primary Completion (ANTICIPATED): September 1, 2023
• Study Completion (ANTICIPATED): March 1, 2024

Study Registration Dates

• First Submitted: August 24, 2022
• First Submitted That Met QC Criteria: September 23, 2022
• First Posted (ACTUAL): September 28, 2022

Study Record Updates

• Last Update Posted (ACTUAL): September 28, 2022
• Last Update Submitted That Met QC Criteria: September 23, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: pediatrics; pain; pharmacokinetics; acetaminophen; analgesics; orthopedics
• Additional Relevant MeSH Terms: Wounds and Injuries; Fractures, Bone; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: Acetaminophen IV vs PO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No