Art45-paediatric-studies-docs.ema.europa.eu

Clinical Study ReportIbuprofen Suspension 100mg per 5mLMcNeil Consumer Healthcare 1. SYNOPSIS
Name of Sponsor/Company
Individual Study Table
Referring to Part of the
Name of Finished Product:
Children’s Motrin® 100 mg/5 ml
suspensionChildren’s Tylenol® 160 mg/5 ml Name of Active Ingredient:
Ibuprofen
Acetaminophen
Title of Study: A Single-Dose, Randomized, Double-Blind Trial to Compare the Efficacy and Safety of
Ibuprofen Suspension 7.5 mg/kg with Acetaminophen Suspension 12.5 mg/kg for the Treatment of Febrile
Children
Investigators: Multiple, see Section 4, Investigators and Study Administrative Structure.
Study Centers: Multiple, see Section 4, Investigators and Study Administrative Structure.
Publication (reference): none
Study Period:
Phase of development: IV
(date of first enrollment) September 25, 1996(date of last completed) May 21, 1997 Objectives: The objectives of the study were to evaluate and compare the antipyretic efficacy of a single
dose of ibuprofen suspension (Children’s Motrin®) (100 mg/5 ml) at a dose of 7.5 mg/kg with the efficacy of a
single dose of acetaminophen suspension (Children’s Tylenol®) (160 mg/5 ml) at a dose of 12.5 mg/kg (10-15
mg/kg) in the treatment of febrile children, to evaluate and compare the rate of temperature reduction of these
products, and to evaluate and compare the safety profiles of these products.
Methodology: The study was a randomized, parallel, single-dose, double-blind, multicenter study of
ibuprofen suspension at a dose of 7.5 mg/kg and acetaminophen suspension at a dose of 12.5 mg/kg given to
110 subjects. Subjects with oral temperatures between 101.0°F to 104.5°F or rectal temperatures between
102.0°F to 105.5°F were enrolled. Qualified subjects were stratified into two groups: High Fever (>102.5°F) or
Low Fever (≤102.5°F). Following the recording of baseline temperature and the administration of study
medication, temperature readings were taken relative to baseline at 15, 30, 45 and 60 minutes (at the
investigator’s office), and 2, 3, 4, 5, 6, 7 and 8 hours (at the subject’s home).
Number of Subjects (Planned and Analyzed): Study design assumed a minimum of 100 subjects.
The study enrolled 110 subjects. All subjects were eligible for the intent-to treat analysis. Ninety subjects were
eligible for the per-protocol analysis.
Diagnosis and Main Criteria for Inclusion: Subjects were of either sex, between two to eleven
years of age, and within the fifth to the ninety-fifth percentiles for weight and height (based on sex and age).
Subjects must have presented with an oral baseline temperature ranging from 101.0°F to 104.5°F or a rectal
baseline temperature ranging from 102.0°F to 105.5°F. Initial onset of fever was at least four hours but not
Clinical Study ReportIbuprofen Suspension 100mg per 5mLMcNeil Consumer Healthcare Name of Sponsor/Company
Individual Study Table
Referring to Part of the
Name of Finished Product:
Children’s Motrin® 100 mg/5 ml
suspensionChildren’s Tylenol® 160 mg/5 ml Name of Active Ingredient:
Ibuprofen
Acetaminophen
more than forty-eight hours prior to study entry.
Test Product, Dose and Mode of Administration, Batch Number:
Children’s Motrin® 100 mg/5 ml suspension, 7.5 mg/kg dose, Z-4233
Duration of Treatment: Subjects received a single dose of study medication. Subjects remained at the
site and were monitored for one hour following study medication administration. Parents/guardians monitored
the subjects at home for the remaining seven hours (totaling 8 hours from drug administration).
Reference Therapy, Dose and Mode of Administration, Batch Number:
Children’s Tylenol® 160 mg/5 ml suspension, 12.5 mg/kg dose, Z-4234
Criteria for Evaluation:
Efficacy:
The following outcome measures were considered in this study:
(1) temperature differences from baseline at 15 minutes, 30 minutes, 45 minutes, and hours one to eight,
(2) weighted sum of temperature differences from baseline over four-hour, six-hour, and eight-hour intervals,
(3) percent temperature reduction at 15 minutes, 30 minutes, 45 minutes, and hours one to eight,
(4) weighted sum of percent temperature reduction over four-hour, six-hour, and eight-hour intervals,
(5) rate of temperature reduction from 15 minutes to one hour, and
(6) time until rescue.
Safety: Safety assessments consisted of monitoring adverse events throughout the course of the study.
Statistical Methods: The analysis of baseline-adjusted temperature difference and percent temperature
reduction at each of the measurement intervals proceeded as follows. “Between subject” effects were
assessed by analyzing weighted sums of temperature differences from baseline over eight hours and weighted
sums of percent temperature reductions over eight hours. Assessments of “within subject effects” over time
were based on the results of two-way (treatment, baseline fever group) repeated measures ANOVA of the
temperature differences from baseline and the percent temperature reductions. For these analyses, baseline
fever group was treated as a blocking factor. Treatments were compared at each measurement interval.
Two-way (treatment, baseline fever group) ANOVA was used to analyze the weighted sums of temperaturedifferences from baseline and the weighted sums of percent temperature reductions. For these analyses,baseline fever group was treated as a blocking factor. Treatments were compared over four, six, and eighthour intervals. Two-way (treatment, baseline fever group) ANOVA was used to analyze the regression slopesderived from baseline-adjusted temperatures at 15, 30, 45, and 60 minutes. For this analysis, baseline fevergroup was treated as a blocking factor.
The number of subjects rescuing during each one hour interval and the cumulative number of subjects rescuingby the end of each one hour interval were tabulated. The chi square test was used to compare treatments with Clinical Study ReportIbuprofen Suspension 100mg per 5mLMcNeil Consumer Healthcare Name of Sponsor/Company
Individual Study Table
Referring to Part of the
Name of Finished Product:
Children’s Motrin® 100 mg/5 ml
suspensionChildren’s Tylenol® 160 mg/5 ml Name of Active Ingredient:
Ibuprofen
Acetaminophen
respect to the number of subjects who rescued, and the log-rank test was used to compare Kaplan-Meierproduct limit estimates of the survival distributions. The frequency of adverse events was compared withFisher’s exact test.
Efficacy Results:
For the primary endpoint of temperature differences from baseline at each measurement interval, the response
profiles for ibuprofen and acetaminophen were similar. Subjects treated with ibuprofen exhibited significantly
greater temperature reduction at hours four and five (Table 1-1). Similar results were observed for both the
intent-to-treat and the per-protocol analysis.
Table 1-1. TEMPDIFF Least Squares Means (LSM) and Pairwise Comparison p-values (Intent-to-Treat)
Ibuprofen (7.5 mg/kg)
Acetaminophen (12.5 mg/kg)
Time (Hrs)
LSM (SEM)
LSM (SEM)
For the secondary endpoint of weighted sum of temperature differences from baseline, subjects treated withibuprofen exhibited greater temperature reduction than acetaminophen over the four, six and eight hourintervals for both the intent-to-treat and per-protocol analysis. All levels were statistically significant (p≤0.0486)except the eight hour interval in the intent-to-treat analysis. The response profiles for both ibuprofen andacetaminophen were similar for percent temperature reduction at each measurement interval and no significantdifferences were observed between the two treatments. However, in the per-protocol analysis, borderlinesignificant differences in percent temperature reduction from baseline were observed at hours four (p=0.0753)and five (p=0.0679); the differences favored ibuprofen. The analysis of weighted sums of percent temperaturereduction revealed no statistically significant differences between treatments. However, subjects on ibuprofenexhibited greater percent temperature reduction over each of the intervals considered and the pairwisecomparison p-values were of borderline significance (p≤0.0707) for the four-hour and six-hour intervals. Nosignificant differences were observed between treatments for the rate of temperature reduction from 15 min toone hour, the time to rescue, or the number of subjects that rescued.
Clinical Study ReportIbuprofen Suspension 100mg per 5mLMcNeil Consumer Healthcare Name of Sponsor/Company
Individual Study Table
Referring to Part of the
Name of Finished Product:
Children’s Motrin® 100 mg/5 ml
suspensionChildren’s Tylenol® 160 mg/5 ml Name of Active Ingredient:
Ibuprofen
Acetaminophen
Safety Results: All study medications were well tolerated and no safety issues were identified. Four
subjects (7.3%) assigned to ibuprofen 7.5 mg/kg and one subject (1.8%) assigned to acetaminophen 12.5
mg/kg reported adverse events; the difference between treatment groups was not statistically significant. Drug-
related adverse events were reported by 1.8% of subjects; there was no significant difference between the
treatment groups. No serious adverse events or deaths were reported. No subjects discontinued due to an
adverse event.
Conclusion:
For the primary endpoint of temperature differences from baseline at each measurement interval, theresponse profiles for ibuprofen 7.5 mg/kg and acetaminophen 12.5 mg/kg were similar.
For the secondary endpoint of weighted sum of temperature differences from baseline, subjectstreated with ibuprofen 7.5 mg/kg exhibited greater temperature reduction than acetaminophen 12.5mg/kg over the four-, six- and eight-hour intervals. All differences were statistically significant exceptat the eight-hour interval in the intent-to-treat analysis, which was of borderline statistical significance.
No statistically significant differences between ibuprofen 7.5 mg/kg and acetaminophen 12.5 mg/kgwere observed for the rate of temperature reduction from 15 min to one hour, time to rescue, or rescuerates.
All study medications were well tolerated and no safety issues were identified. There was nosignificant difference between treatments in the incidence of adverse events. No serious adverseevents or deaths were reported. No subjects discontinued due to an adverse event.
Date of the report: December 14, 2000

Source: http://art45-paediatric-studies-docs.ema.europa.eu/GROUP%20I/ibuprofen-paracetamol/ibuprofen_paracetamol%2096-608.pdf