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

Summary

This is a prospective, multicenter, double-blind, placebo-controlled study of pediatric subjects
less than age 2 years with acute pain requiring multiple doses of analgesics where there is a
medically reasonable need for IV medication due to a surgical procedure or underlying medical
condition. Eligible subjects will be enrolled and randomized to receive either IV acetaminophen
plus standard of care on demand rescue opioids [SOC] (IV Acetaminophen Groups) or saline
placebo plus SOC (Control Groups).
Total opioid consumption over an 8-hour pre-randomization qualification period will be used to
characterize a subject[Right Quote]s consumption as either [Double Quote]lower[Double Quote] or [Double Quote]higher[Double Quote] based upon a threshold
average of 30 ug/kg/h IV morphine equivalent (a total of 240 ug/kg over the 8 hour period).
Approximately 200 subjects will be enrolled and randomized into the study in order to obtain a
total of 192 treated and [Double Quote]efficacy[Double Quote] evaluable subjects (128 IV acetaminophen Group A and B and
64 Control Group C and D). Efficacy evaluable subjects include all randomized subjects who
received at least one completed dose of study medication and had at least one pain assessment
after T0.
Eligible patients will be stratified according to 4 dose regimen age categories (extreme preterm
neonates, preterm neonates, full-term neonates and all infants) and 2 opioid consumption
categories (lower and higher), and randomized to either the IV Acetaminophen or Control
Groups. Eligible subjects will be randomly assigned to one of two IV Acetaminophen Groups
(A [target n = 64] or B [target n = 64]) or two matched Control Groups (C [target n = 32] or
D [target n = 32]) who will receive a normal saline placebo in the same volume as the
IV Acetaminophen Group. The treatment groups will be assigned in a
2:2:1:1 ratio: Acetaminophen Group A; Acetaminophen Group B; Control Group C; Control
Group D; respectively.

Participant Eligibility

Screening Inclusion Criteria:

1. Subject is ≥ 28 weeks gestational age and < 2 years old at study enrollment

2. 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

3. 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

4. Subject has a bodyweight as follows:
a. For premature neonates, at least 1 kg
b. For full-term neonates, at least 2 kg
c. For infants, ≥ 5th percentile for age according to national statistics

5. Subject has reliable vascular access for administration of study medication and PK
sampling

6. 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

7. Subject’s parent or guardian must provide written informed consent prior to participation
in the study

8. 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

Pre-randomization inclusion criteria:

1. Subject has not been administered the following:
a. any acetaminophen-containing product directly or from breast feeding,
nonsteroidal anti-inflammatory agent or central alpha-adrenergic agents (e.g.,
clonidine, dexmedetomidine or ketamine) within 8 hours of T0
b. IV corticosteroid within 12 hours of T0
c. or received a regional or neuraxial (caudal, epidural or spinal) anesthetic with
local anesthetics within 8 hours of T0

2. Subject does not have abnormal LFTs from a sample obtained post-operatively/posttrauma
and prior to randomization above the following limits:
a. TBL > 2 times upper limit of normal range for age (2 X ULN) OR
b. ALT (SGPT) > 2.5 X ULN, OR
c. In the absence of intentional anticoagulation, INR > 1.5 X ULN or PT > 1.5 X
ULN

3. 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

4. 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

5. 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

6. If subject is breast feeding, mother has not been administered any acetaminophencontaining
product in the previous 8 hours prior to T0 and throughout the treatment
period.