Acute Pain
Conditions
Keywords
Moderate to severe acute pain following surgery or trauma
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.
Interventions
DRUGIV Acetaminophen
IV Acetaminophen given every 6 hours (q6h); 4 doses, in 24 hours
DRUGIV Control
IV Control q6h; 4 doses, in 24 hours
Sponsors
Mallinckrodt
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Days to 2 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Rescue Opioid Consumption | in 24 hours | Total micrograms per kilogram (µg/kg) of rescue opioid used during the same 24 hours the subject is on study medication |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Rescue Medication | within 24 hours | — |
| Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | 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 | 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 | 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 | 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. |
Countries
United States
Participant flow
Pre-assignment details
Of 215 participants screened, 197 were actually enrolled and received study drug
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Acetaminophen Participants received a low dose of acetaminophen for 24 hours | 61 |
| High Dose Acetaminophen Participants receive a high dose of acetaminophen for 24 hours | 67 |
| Placebo Participants receive matching placebo for 24 hours | 69 |
| Total | 197 |
Baseline characteristics
| Characteristic | Total | Placebo | High Dose Acetaminophen | Low Dose Acetaminophen |
|---|---|---|---|---|
| Age, Customized All Participants Intermediate aged infants (≥ 6 mos to <12 mos) | 55 Participants | 20 Participants | 17 Participants | 18 Participants |
| Age, Customized All Participants Neonates (birth to ≤ 28 days) | 38 Participants | 13 Participants | 12 Participants | 13 Participants |
| Age, Customized All Participants Older infants (≥12 mos to <24 mos) | 50 Participants | 18 Participants | 18 Participants | 14 Participants |
| Age, Customized All Participants Younger infants (≥ 29 days to < 6 mos) | 54 Participants | 18 Participants | 20 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 6 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 30 Participants | 9 Participants | 9 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 8 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) White | 135 Participants | 46 Participants | 49 Participants | 40 Participants |
| Region of Enrollment United States | 197 participants | 69 participants | 67 participants | 61 participants |
| Sex: Female, Male Female | 70 Participants | 26 Participants | 27 Participants | 17 Participants |
| Sex: Female, Male Male | 127 Participants | 43 Participants | 40 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 67 | 0 / 69 |
| other Total, other adverse events | 21 / 61 | 8 / 67 | 24 / 69 |
| serious Total, serious adverse events | 0 / 61 | 1 / 67 | 2 / 69 |
Outcome results
Primary
Total Rescue Opioid Consumption
Total micrograms per kilogram (µg/kg) of rescue opioid used during the same 24 hours the subject is on study medication
Time frame: in 24 hours
Population: mITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Acetaminophen | Total Rescue Opioid Consumption | 166.9 µg/kg | Standard Deviation 225.06 |
| High Dose Acetaminophen | Total Rescue Opioid Consumption | 179.9 µg/kg | Standard Deviation 193.47 |
| Placebo | Total Rescue Opioid Consumption | 180.2 µg/kg | Standard Deviation 184.7 |
Comparison: Difference in Least Squares (LS) Meansp-value: 0.73697.5% CI: [-91, 67.3]ANOVA
Comparison: LS Mean Differencep-value: 0.96797.5% CI: [-75.9, 78.7]ANOVA
Secondary
Pain Intensity Using the FLACC Score in Intermediate Aged Infants
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.
Time frame: within 24 hours
Population: Intermediate aged infants in the mITT population with a score at each data collection time
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 24 hours | 1.4 score on a scale | Standard Deviation 2.29 |
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 18 hours | 1.4 score on a scale | Standard Deviation 2.01 |
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 6 hours | 0.7 score on a scale | Standard Deviation 0.83 |
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 12 hours | 1.2 score on a scale | Standard Deviation 1.41 |
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 0 hours | 0.6 score on a scale | Standard Deviation 1.3 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 18 hours | 0.9 score on a scale | Standard Deviation 1.19 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 6 hours | 2.1 score on a scale | Standard Deviation 2.71 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 12 hours | 0.08 score on a scale | Standard Deviation 1.39 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 24 hours | 0.9 score on a scale | Standard Deviation 1.56 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 0 hours | 1.6 score on a scale | Standard Deviation 2.27 |
| Placebo | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 0 hours | 1.2 score on a scale | Standard Deviation 2.05 |
| Placebo | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 24 hours | 0.3 score on a scale | Standard Deviation 0.65 |
| Placebo | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 6 hours | 1.4 score on a scale | Standard Deviation 2.59 |
| Placebo | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 18 hours | 0.5 score on a scale | Standard Deviation 0.97 |
| Placebo | Pain Intensity Using the FLACC Score in Intermediate Aged Infants | at 12 hours | 1.8 score on a scale | Standard Deviation 2.49 |
Secondary
Pain Intensity Using the FLACC Score in Older Infants
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.
Time frame: within 24 hours
Population: Older infants in the mITT population with a score at each data collection time
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 18 hours | 1.3 score on a scale | Standard Deviation 1.95 |
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 6 hours | 0.5 score on a scale | Standard Deviation 0.9 |
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 12 hours | 0.8 score on a scale | Standard Deviation 1.27 |
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 24 hours | 2.0 score on a scale | Standard Deviation 2.59 |
| Low Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 0 hours | 2.2 score on a scale | Standard Deviation 2.64 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 24 hours | 0.8 score on a scale | Standard Deviation 1.12 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 0 hours | 1.8 score on a scale | Standard Deviation 2.65 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 6 hours | 1.2 score on a scale | Standard Deviation 2.07 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 18 hours | 0.1 score on a scale | Standard Deviation 0.36 |
| High Dose Acetaminophen | Pain Intensity Using the FLACC Score in Older Infants | at 12 hours | 1.7 score on a scale | Standard Deviation 2.76 |
| Placebo | Pain Intensity Using the FLACC Score in Older Infants | at 6 hours | 1.5 score on a scale | Standard Deviation 2.42 |
| Placebo | Pain Intensity Using the FLACC Score in Older Infants | at 12 hours | 2.4 score on a scale | Standard Deviation 1.78 |
| Placebo | Pain Intensity Using the FLACC Score in Older Infants | at 18 hours | 1.3 score on a scale | Standard Deviation 2.67 |
| Placebo | Pain Intensity Using the FLACC Score in Older Infants | at 24 hours | 0.1 score on a scale | Standard Deviation 0.29 |
| Placebo | Pain Intensity Using the FLACC Score in Older Infants | at 0 hours | 1.8 score on a scale | Standard Deviation 2.37 |
Secondary
Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates
The LNPS is used for assessing pain intensity in neonates. Scores on the scale run from 0-14. Higher scores mean worse pain.
Time frame: within 24 Hours
Population: Neonates in the mITT population with scores at each data collection time
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 0 hours | 0.8 score on a scale | Standard Deviation 1.09 |
| Low Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 24 hours | 0.8 score on a scale | Standard Deviation 1.4 |
| Low Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 6 hours | 1.1 score on a scale | Standard Deviation 1.04 |
| Low Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 18 hours | 1.0 score on a scale | Standard Deviation 1.53 |
| Low Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 12 hours | 2.2 score on a scale | Standard Deviation 1.92 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 18 hours | 1.8 score on a scale | Standard Deviation 1.99 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 24 hours | 1.3 score on a scale | Standard Deviation 1.42 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 0 hours | 0.8 score on a scale | Standard Deviation 1.27 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 6 hours | 1.0 score on a scale | Standard Deviation 1.41 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 12 hours | 1.8 score on a scale | Standard Deviation 1.76 |
| Placebo | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 6 hours | 1.2 score on a scale | Standard Deviation 1.82 |
| Placebo | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 24 hours | 0.9 score on a scale | Standard Deviation 1.4 |
| Placebo | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 18 hours | 0.8 score on a scale | Standard Deviation 0.99 |
| Placebo | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 0 hours | 1.1 score on a scale | Standard Deviation 1.26 |
| Placebo | Summary of Pain Intensity Using the Leuven Neonatal Pain Scale (LNPS) in Neonates | at 12 hours | 2.0 score on a scale | Standard Deviation 1.83 |
Secondary
Summary of Pain Intensity Using the LNPS in Younger Infants
The LNPS is used for assessing pain intensity in younger infants. Scores on the scale run from 0-14. Higher scores mean worse pain.
Time frame: within 24 hours
Population: Younger Infants in the mITT population with scores at each data collection time
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 18 hours | 1.6 score on a scale | Standard Deviation 2.25 |
| Low Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 12 hours | 2.2 score on a scale | Standard Deviation 2.4 |
| Low Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 0 hours | 2.1 score on a scale | Standard Deviation 2.85 |
| Low Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 6 hours | 2.1 score on a scale | Standard Deviation 2.36 |
| Low Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 24 hours | 2.3 score on a scale | Standard Deviation 1.59 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 12 hours | 1.8 score on a scale | Standard Deviation 1.58 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 0 hours | 1.5 score on a scale | Standard Deviation 1.85 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 6 hours | 1.3 score on a scale | Standard Deviation 1.33 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 18 hours | 1.7 score on a scale | Standard Deviation 2.06 |
| High Dose Acetaminophen | Summary of Pain Intensity Using the LNPS in Younger Infants | at 24 hours | 1.3 score on a scale | Standard Deviation 1.63 |
| Placebo | Summary of Pain Intensity Using the LNPS in Younger Infants | at 24 hours | 2.9 score on a scale | Standard Deviation 2.51 |
| Placebo | Summary of Pain Intensity Using the LNPS in Younger Infants | at 18 hours | 2.1 score on a scale | Standard Deviation 1.44 |
| Placebo | Summary of Pain Intensity Using the LNPS in Younger Infants | at 0 hours | 2.2 score on a scale | Standard Deviation 2.05 |
| Placebo | Summary of Pain Intensity Using the LNPS in Younger Infants | at 12 hours | 1.9 score on a scale | Standard Deviation 1.24 |
| Placebo | Summary of Pain Intensity Using the LNPS in Younger Infants | at 6 hours | 2.4 score on a scale | Standard Deviation 3.1 |
Secondary
Time to First Rescue Medication
Time frame: within 24 hours
Population: mITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose Acetaminophen | Time to First Rescue Medication | 4.78 hours |
| High Dose Acetaminophen | Time to First Rescue Medication | 4.76 hours |
| Placebo | Time to First Rescue Medication | 3.81 hours |