Brief Summary

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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"

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.

• Study Type: Interventional
• Study Design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
• Study Primary Completion Date: June 2014

Interventions Used in this Clinical Trial

• Drug: IV Acetaminophen
  • 7.5 mg/kg IV over 15 minutes, given q6h X 4 doses for 24 hours; 10 mg/kg IV over 15 minutes, given q6h X 4 doses for 24 hours; 12.5 mg/kg IV over 15 minutes, given q6h X 4 doses for 24 hours; 15 mg/kg IV over 15 minutes, given q6h X 4 doses for 24 hours
• Other: Normal Saline as Placebo

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: IV Acetaminophen
• Placebo Comparator: Normal Saline

Outcome Measures for this Clinical Trial

Primary Measures

• 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.
    Safety Issue?: No

Secondary Measures

• 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
    Safety Issue?: No
• 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.
    Safety Issue?: Yes

Criteria for Participation in this Clinical Trial

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 a bodyweight as follows:
• For premature neonates, at least 1 kg
• For full-term neonates, at least 2 kg
• For infants, ≥ 5th percentile for age according to national statistics
• Subject has reliable vascular access for administration of study medication and PK sampling
• 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 (for example, neurologic diseases such as hemiplegia, demyelinating disorders, or neuromuscular paralysis, or requirement for prolonged mechanical ventilation making it impossible to assess pain scales using the LNPS or the FLACC)
• 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 8 hours of T0
• IV corticosteroid within 12 hours of T0
• or received a regional or neuraxial (caudal, epidural or spinal) anesthetic with local anesthetics within 8 hours of T0
• Subject does not have abnormal LFTs from a sample obtained post-operatively/post-trauma and prior to randomization above the following limits:
• TBL > 2 times upper limit of normal range for age (2 X ULN) OR
• ALT (SGPT) > 2.5 X ULN, OR
• In the absence of intentional anticoagulation, INR > 1.5 X ULN or PT > 1.5 X ULN
• Subject does not have significantly impaired renal function or known significant renal disease, as evidenced by an estimated glomerular filtration rate (using the Schwartz formula or other applicable formula) calculated to be less than 1/3 of normal for the applicable age group
• Subject had a nursing assessment documenting moderate to severe pain (pain intensity score of at least 4 on the LNPS or FLACC) within 8 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 8-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 acetamionphen containing product in the previous 8 hours to T0 and througout the treament period

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 2 Years

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

• Lead Sponsor
  • Cadence Pharmaceuticals
• Collaborator
  • Pharsight
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Malcolm C Lloyd-Smith, M.Sc, Study Director, Cadence Pharmaceuticals
• Overall Contact(s)
  • Brian Kenney, BS, 858-436-1400, bkenney@cadencepharm.com