A Multi-Center Study of the Efficacy, Pharmacokinetics (PK) and Pharmacodynamics (PD) of IV Acetaminophen for the Treatment of Acute Pain in Pediatric Patients

• ClinicalTrials.gov Identifier: NCT01635101
• Recruitment Status: Completed
• First Posted: July 6, 2012
• Results First Posted: January 21, 2020
• Last Update Posted: January 21, 2020
• Sponsor: Mallinckrodt
• Information provided by (Responsible Party): Mallinckrodt

Tracking Information

• First Submitted Date: June 29, 2012
• First Posted Date: July 6, 2012
• Results First Submitted Date: September 10, 2019
• Results First Posted Date: January 21, 2020
• Last Update Posted Date: January 21, 2020
• Study Start Date: June 2012
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 10, 2020)

Total Rescue Opioid Consumption [ Time Frame: in 24 hours ]

Total micrograms per kilogram (µg/kg) of rescue opioid used during the same 24 hours the subject is on study medication

Original Primary Outcome Measures (submitted: July 5, 2012)

Total Rescue Opioid Consumption [ Time Frame: T0-T24; A total opiod consumption will be obtained from T0-T24. Total rescue opioid consumption will be collected during the 24 hours while the subject is on study medication. ]

Total rescue opioid consumption from T0 to T24 (total milligrams (mg) per kilogram (kg) IV morphine equivalent), comparing each IV Acetaminophen Group to the combined Control Groups

• Change History: Complete list of historical versions of study NCT01635101 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: January 10, 2020)

• Time to First Rescue Medication [ Time Frame: within 24 hours ]
• Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates [ Time Frame: within 24 Hours ]
  The LNPS is used for assessing pain intensity in neonates. Scores on the scale run from 0-14. Higher scores mean worse pain.
• Summary of Pain Intensity Using the LNPS in Younger Infants [ Time Frame: within 24 hours ]
  The LNPS is used for assessing pain intensity in younger infants. Scores on the scale run from 0-14. Higher scores mean worse pain.
• Pain Intensity Using the FLACC Score in Intermediate Aged Infants [ Time Frame: within 24 hours ]
  The Face, Leg, Activity, Cry, and Consolability (FLACC) scale is used to assess pain intensity in intermediate aged infants. The scale is scored in a range of 0-10 with 0 representing no pain. A higher score means more pain.
• Pain Intensity Using the FLACC Score in Older Infants [ Time Frame: within 24 hours ]
  The FLACC scale is used to assess pain intensity in older infants. The scale is scored in a range of 0-10 with 0 representing no pain. A higher score means more pain.

Original Secondary Outcome Measures (submitted: July 5, 2012)

• Correlation between efficacy concentration and rescue medication consumption. [ Time Frame: T0 to T12 FLAAC or LNPS will be assessed at T0, T0.05, T1, T2, T3, T4, T6, T12, T18, T24 and prior to each dose of rescue medication ]
  Correlation between efficacy concentration Ceff and total opioid rescue medication consumption (in IV morphine equianalgesic dose equivalents) from T0 to T12 comparing each IV Acetaminophen Group to the combined Control Groups. The correlation will be measured by the mean slope of the linear regression comparing acetaminophen exposure area under the curve (AUC) in the effect compartment and total milligrams (mg)/kilogram (kg) IV morphine equivalent doses from T0 to T12.
• Subjects with clinically meaningful changes in laboratory parameters [ Time Frame: T0-T24 Baseline labs as compared to End of Study Labs. Subject will be followed for an average of 24 hours while hospitalized. ]
  The percentage of subjects with clinically meaningful changes in laboratory parameters will be summarized by treatment group

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Multi-Center Study of the Efficacy, Pharmacokinetics (PK) and Pharmacodynamics (PD) of IV Acetaminophen for the Treatment of Acute Pain in Pediatric Patients
• Official Title: A Randomized, Placebo Controlled, Multi-Center Study of the Efficacy, Pharmacokinetics (PK) and Pharmacodynamics (PD) of IV Acetaminophen for the Treatment of Acute Pain in Pediatric Patients
• Brief Summary: The purpose of this study is to demonstrate the efficacy and safety of Intravenous (IV) acetaminophen plus rescue opioids for the relief of moderate to severe acute pain in neonates and infants (age < 2 years) compared to placebo plus standard of care rescue opioids as well as characterize the concentration-effect relationship (PK/PD) of the intravenous acetaminophen as compared to the control group.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Acute Pain

Intervention

• Drug: IV Acetaminophen
  IV Acetaminophen given every 6 hours (q6h); 4 doses, in 24 hours
  Other Name: OFIRMEV
• Drug: IV Control
  IV Control q6h; 4 doses, in 24 hours
  Other Names:

  • Saline
  • Placebo

Study Arms

• Experimental: Low Dose Acetaminophen
  Participants receive a low dose of acetaminophen intravenously (IV) for 24 hours
  Intervention: Drug: IV Acetaminophen
• Experimental: High Dose Acetaminophen
  Participants receive a low dose of acetaminophen (IV) for 24 hours
  Intervention: Drug: IV Acetaminophen
• Placebo Comparator: Placebo
  Participants receive matching placebo (IV) for 24 hours
  Intervention: Drug: IV Control

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 10, 2020): 197
• Original Estimated Enrollment (submitted: July 5, 2012): 200
• Actual Study Completion Date: November 2015
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subject is ≥ 28 weeks gestational age and < 2 years old at study enrollment
• Subject will undergo surgery or had a traumatic injury expected to produce moderate to severe pain and patient is expected to require analgesic treatment for acute pain for 24 hours
• Subject has a medically reasonable need for IV treatment due to their underlying procedure(s) or medical condition(s) for the duration of the study
• Subject has reliable vascular access for administration of study medication and PK sampling
• Subject has a bodyweight which, in the opinion of the Investigator does not preclude participation in the study.
• Subject is free of other physical, mental, or medical conditions which, in the opinion of the Investigator, make study participation inadvisable or make it impossible to accurately assess efficacy or safety endpoints
• Subject's parent or guardian must provide written informed consent prior to participation in the study
• Subject's parent or guardian must have the ability to read and understand the study procedures and have the ability to communicate meaningfully with the study investigator and staff

Exclusion Criteria:

• Subject is not able to comply with the sampling requirements of the study
• Subject has known or suspected hypersensitivity to acetaminophen or the excipients of IV acetaminophen
• Subject has any significant medical condition that in the opinion of the Investigator contraindicates participation in the study or impairs the assessment of efficacy or safety
• Subject has participated in another interventional clinical study within 30 days of the planned study randomization date

Pre-Randomization (Qualification) Inclusion Criteria

Subject has not been administered any of the following:

• any acetaminophen-containing product, nonsteroidal anti-inflammatory agent, central alpha-adrenergic agents (e.g., clonidine, dexmedetomidine) or ketamine within 6 hours of baseline (T0)
• received a regional or neuraxial (caudal, epidural or spinal) anesthetic with local anesthetics within 6 hours of T0
• Subject does not have abnormal liver function tests from a sample obtained post-operatively/post-trauma and prior to randomization above protocol-specified limits
• Subject does not have significantly impaired renal function or known significant renal disease which in the opinion of the Investigator would contraindicate study participation.
• Subject had a nursing assessment documenting moderate to severe pain within 6 hours prior to randomization
• Subject required at least one dose of parenteral opioid medication for pain management (i.e., not pre-emptive therapy) during the 6-hour pre-randomization period, and is anticipated to require at least one dose of parenteral opioid medication during the 24 hour treatment period
• If subject is breast feeding, mother has not been administered any acetaminophen containing product in the previous 6 hours to T0 and throughout the treatment period

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 2 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01635101
• Other Study ID Numbers: CPI-APA-353
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Mallinckrodt
• Study Sponsor: Mallinckrodt
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Team Leader; Mallinckrodt

• PRS Account: Mallinckrodt
• Verification Date: May 2017