WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95...
Transcript of WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95...
MAH:
Active substance /
Product:
Protocol Number EudraCT number
(if applicable)
Trial report
number
PMID / D.O.I.
(if applicable)
Date of trial
report
WM-390 and WM-402
(Integrated Study)
N/A WM-390 and WM-
402
N/A 15-Jun-95
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WM- 375A N/A WM-375A N/A 17-Jul-90
WM- 350 N/A WM-350 N/A 09-Jun-88
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WM-343 N/A WM-343 N/A 08-Sep-88
WM-366 N/A WM-366 N/A 11-Jul-95
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AF-95-05 N/A AF-95-05 N/A 1-Jan-97
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AF-96-01 N/A AF-96-01 N/A 1-Feb-99
WM-376 N/A WM-376 N/A 18-Jul-90
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Is the trial
part of a
Paediatric
Investigati
on Plan?
(Y/N)
Trial design Background for conducting the trial
N This was a single-dose,
double-blind, single-
center, parallel-group,
placebo-controlled
clinical trial.
Ibuprofen has a history of safe and effective use in the United
Kingdom and Europe for the treatment of pain and febrile illness
in children, and has been endorsed by American pediatric
rheumatologists for the symptomatic relief of pain associated
with juvenile rheumatoid arthritis. The model of orthodontic pain
was chosen for these studies because OTC analgesics are widely
used in the treatment of such pain and, unlike oral surgery,
orthodontic treatment involves noninvasive procedures
commonly received by children. This combination of studies
were conducted in order to establish models for the evaluation of
analgesic agents in children.
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N This was a double-blind,
single-dose, parallel,
randomized clinical trial.
A suspension formulation of ibuprofen
(Children's Advil®) has been approved for use in the
management of fever in children 12 months of age or older, and
in the management of juvenile arthritis, rheumatoid arthritis,
osteoarthritis, mild to moderate pain and primary dysmenorrhea.
At the time of this study, the use of Children's Advil® ibuprofen
suspension, however, has not been studied as a treatment for pain
in children.
The measurement and assessment of pain in children is one of
the most difficult challenges in analgesiology. While a number of
approaches have been proposed as measurement instruments of
pain in children, the use of these instruments in children under
double-blind, placebo-controlled conditions to establish the
efficacy of analgesics is rare. Sore throat would appear to be a
painful condition that most, if not all, children would be familiar
with and for which they would be able to evaluate the therapeutic
effect of analgesic agents.
N This was a double-blind,
single-dose, parallel study
Before seeking medical advice, people frequently use mild
analgesic medications to treat soft tissue injuries such as
traumatic ligamentous sprains, muscular strains and contusions.
Despite the frequency of this practice, however, there is no
established methodology for differentiating the analgesic activity
of known analgesic drugs (acetaminophen and ibuprofen) in
patients with acute musculoskeletal pain. The purpose of this
study is to develop a model sensitive for making this comparison.
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N The clinical trial is a
double-blind, placebo
controlled, stratified
parallel study design.
Before seeking medical advice, people frequently use mild
analgesic medications tm treat common soft tissue injuries such a
traumatic ligamentous sprains, muscular strains and contusions.
Despite the frequency of this practice, however, there is no
established methodology for differentiating t he analgesic activity
of a known analgesic drug acetaminophen from that of a
combination analgesic drug (aspirin and caffeine) in patients with
musculoskeletal pain. The purpose of this study was to develop a
model sensitive for making this comparison.
The present study van designed to demonstrate the analgesic
adjuvant effect of caffeine 64 mg in the treatment of pain
associated with acute musculoskeletal injury.
N This study was a
randomized, single dose,
single center, double
blind, paralllel trial.
Children’s Advil Suspension has been approved for use in the
management of fever in children 6 months and older, and in the
management of juvenile arthritis, rheumatoid arthritis,
osteoarthritis, mild to moderate pain in adults, and primary
dysmenorrheal. This single-dose study was designed to evaluate
the safety and analgesic efficacy of liquid formulations of
ibuprofen (10mg/kg) and acetaminophen (15mg/kg) compared to
placebo for the relief of acute sore throat pain in children.
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N Single-center, double-
blind, balanced, parallel
group, randomization
stratified by baseline
temperature.
Since its availability in the late 1950's, acetaminophen has
become the most widely used drug to control fever in children.
This is due in part to the association between the use of aspirin
and Reye syndrome and the danger of overdose. Recently,
however, concerns have arisen concerning the safety of
acetaminophen.
Ibuprofen as a liquid preparation was approved for prescription
use in children with fever and juvenile rheumatoid arthritis in
1989. The antipyretic properties of ibuprofen administered at
5mg/kg or 10mg/kg in children has been well demonstrated in a
number of randomized, blinded trials against acetaminophen. In
fever, the labeled prescription dosing is determined by the child's
level of fever: for fever's of 102.5 °F or less the dose is 5mg/kg;
for fever's over 102.5 °F the dose is 10mg/kg.
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N Double-blind,
randomized, parallel,
stratified by baseline
temperature, 8-hour
follow-up
Since its availability in the late 1950's, acetaminophen has
become the most widely used drug to control fever in children.
This is due in part to the association between the use of aspirin
and Reye syndrome and the danger of overdose. Recently,
however, concerns have arisen concerning the safety of
acetaminophen.
Ibuprofen as a liquid preparation was approved for prescription
use in children with fever and juvenile rheumatoid arthritis in
1989. Ibuprofen as a liquid preparation was approved for
prescription use in children with fever and juvenile rheumatoid
arthritis in 1989. The antipyretic properties of ibuprofen
administered at 5mg/kg or 10mg/kg in children has been well
demonstrated in a number of randomized, blinded trials against
acetaminophen. Children's Advil Suspension has been available
without a prescription since 1996.
N Double-blind, parallel,
single-dose,
randomized controlled
trial
Sore throat pain is one of the most common types of
pain in children, occurring in approximately 30% of
children 6 to 12 years of age with upper respiratory tract
infection. Because of the widespread nature of this
painful condition, and because mothers of children with
sore throats (and pediatricians as well) will treat this
pain with an analgesic, it would be valuable to develop a
model for measuring sore throat pain in children. We
have found sore throat, a common experience for most
people, well suited as a model for the evaluation of mild
systemic analgesics in adults.
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Participants of the trial; Inclusion criteria
• Subject was between 8 and 14 years of age of either gender.
• Subject had the following dental status:
o Class I or II angle malocclusion
o at least 3 mm of crowding of teeth in 1 arch and/or a minimum of 3 mm of
overjet
o undergone orthodontic treatments requiring initial application of high force to
retract teeth (such as vertical or t-loop continuous retraction arch), rotation of
teeth, midline correction, initial placement of banding, archwire or headgear, or
other orthodontic procedure(s) judged by the investigator to result in moderate to
severe pain
• Subject had moderate to severe oral pain following orthodontic treatment,
defined as a score of 100 mm or greater on the 200 mm Orthodontic Visual Analog Pain Scale. • Subject was in generally good health. • Parent or legal guardian was able and willing to complete or supervise the completion of the evaluation scales at home. • Subject was able to understand the scales and willing to participate in the study. • The parent or legal guardian signed an informed consent form; the child also granted permission for the study.
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• Child is 2 to 12 years of age.
• Child has an acute URI accompanied by a sore throat; onset of URI and sore
throat no more than 4 days prior.
• Child indicates at least moderate sore throat pain intensity: score of 10 or more
on the 21-point Sore Throat Pain Thermometer.
• Child has at least moderate sore throat severity judged independently by either
the parent of physician upon simultaneously observing the child swallow saliva.
• Child has severe tonsillo-pharyngitis: a score of 4 or more on the 12-point
Tonsillo-Pharyngitis Scale.
• Child is otherwise in generally good health.
• Child and parent are willing to conduct the trial under the required condition for the evaluations. • The child is willing to take “nothing by mouth” except treatment during the 2-hour “in-office” phase of the study (the child will be allowed a drink of water at the end of the “in-office” phase); not to take any candy, lozenges, chewing gum, ice cream of caffeine-containing substance (e.g. chocolate, cola, tea) during the full 6 hours of the study; and to snack and have a drink only during the first 15 minutes following the 3, 4, or 5-hour post-treatment evaluations. • Informed consent is granted by parent or guardian (and by child if older than 7 years of age).
Adults with acute (within the past 72 hours) pain due to muscular strain and/or
contusion of the leg, thigh, arm, or neck, or ligamentous sprain of the shoulder,
ankle, toe, or finger were eligible for inclusion in the study. Subjects were
additionally required to have severe pain, defined as a score of 67 mm or greater
on the Pain on Movement Scale, at baseline.
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• History and physical findings consistent with:
o Muscular strain and/or contusion of the leg, thigh, arm, or neck; or,
o Ligamentous sprains of the shoulder, ankle, toe, or finger.
• Onset of the acute, painful condition within the 72 hours preceding enrollment.
• Severe pain at Baseline, defined as a score of 67mm or greater, on the Rain on
Movement Scale. (This criterion was lowered to 50mm or greater after the study
started to increase the rate of enrollment. After 11 patients were enrolled, the
original requirement of 67, or greater at baseline wee restored.)
• Otherwise in general good health. • Agreement by the patient's informed consent to participate in the clinical trial according to the study conditions.
• Subject was between 2 and 12 years of age of either gender
• Subject had been diagnosed as having an acute upper respiratory infection
(URI) accompanied by a complaint of sore throat. This URI and sore throat must
have had an onset of no more than 4 days prior to study participation.
• Subject indicated at least moderate sore throat pain evidence by a score greater
than 10 (100mm) on the 21-point (200 mm) Children’s Sore Throat Pain
Thermometer.
• Subject’s sore throat severity was rated to be at least moderate by either the
parent or the physician upon observing the child swallow saliva.
• Subject had a diagnosis of sever tonsillo-pharyngitis, as documented by a score
of 4 or more on the 12 point Tonsillo-Pharyngitis Scale completed during the physical examination. • Subject was otherwise in generally good health. • Subject was willing to take “nothing by mouth” except treatment during the 2-hour “in-office” phase of the study (a drink of water was allowed at 2 hours); not too take any candy, lozenges, chewing gum, ice cream, o r caffeine-containing substances during the full 6 hours of the study; to have a snack and rink only during the first 15 minutes following the 3, 4, or 5-hour post-treatment evaluations. • Subject was able to understand the scales and willing to participate in the study under the study conditions. •
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Subjects were eligible for inclusion in the study provided they met all of the
following inclusion criteria:
a. Male or female children between the ages of 6 months through 11 years and
within a weight range of 13 to 95 lbs.
b. As determined by the parent/guardian, an initial onset of fever at least 2 hours
prior to entering the study
c. Children with a rectal or oral temperature at baseline established by the
average of two consecutive temperature readings taken within a 15 minute period:
- 101.5 °F to 104.9 °F rectally in children 6 months through 3 years old
- 101 °F to 103.9 °F orally in children 4 through 11 years old
e. able to take medicine by mouth;
f. The parent or guardian provided written informed consent
as well as the child if 7 years of age or older.
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Subjects were eligible for inclusion in the study provided they met all of the
following inclusion criteria:
a. Male or female children between the ages of 6 months through 11 years and
within a weight range of 13 to 95 lbs.
b. As determined by the parent/guardian, an initial onset of fever at least 2 hours
prior to entering the study
c. Children with a rectal or oral temperature at baseline established by the
average of two consecutive temperature readings taken within a 15 minute period:
- 101.5 °F to 104.9 °F rectally in children 6 months through 3 years old
- 101 °F to 103.9 °F orally in children 4 through 11 years old
e. able to take medicine by mouth;
f. The parent or guardian provided written informed consent
as well as the child if 7 years of age or older.
a. Children 2-12 years old with onset of URI in past 72 hours.
b. Child's indication of at least moderate sore throat pain intensity, as
indicated by a score greater than 10 on the 21-point Sore Throat Pain
Thermometer.
c. Sore throat severity judged to be at least moderate by either the
parent or physician upon observing the child swallow saliva.
d. Objective findings which confirm the diagnosis of severe tonsillo-
pharyngitis (i.e., a minimum of 4 points on the -12-point Tonsillo-
Pharyngitis Scale 5 of the physical examination).
e. Child is otherwise in generally good health.
f. The child is willing to take "nothing by mouth" except treatment
during the 2-hour "in-office" phase of the study (the child will be
allowed a drink of water at the end, of the "in-office"
phase), not to take any candy, lozenges, chewing gum., ice cream, or
caffeine-containing substance
(e.g. chocolate, cola, tea) during the full 6 hours of the study; and to
snack and have a drink only during the first 15 minutes following the 3,
4, or iz,-ho-ur post-treatment evaluations.
g. Willingness to conduct the trial under the required conditions for the evaluation.
h. Informed consent granted by parent or guardian (and by child if 7 years of age or older).
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Participants of the trial; Exclusion criteria
• Subject had restorative dental care within 1 week of the
orthodontic procedure.
• Subject had dental extraction within 7 days before the
orthodontic procedure.
• Subject was known to be hypersensitive to nonsteroidal
anti-inflammatory drugs (e.g., aspirin or ibuprofen) or
acetamninophen. •
Subject had any condition that required the chronic use of
aspirin or non-steroidal anti-inflammatory drugs.
• Subject had a history of chronic asthma, urticaria, or
serious allergy.
• Subject had used any type of analgesic, sedative, or
psychotropic agent within 6 hours before taking the study
medication.
• Subject had ingested any caffeinated beverage or food within 6 hours before taking the study medication or during the 4-hour treatment period.
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• Child has a known hypersensitivity to ibuprofen, aspirin,
or acetaminophen. • Child has any evidence of
mouth-breathing due to nasal congestion.
• Child has severe coughing. •
Child has any systemic or other disease that might
compromise respiratory function. • Child
has used any “cold medication” (i.e. decongestant,
antihistamine, expectorant, antitussive, analgesic,
antipyretic, throat lozenge), candy, chewing gum, ice cream
or caffeine-containing substance (e.g. chocolate, cola, tea,
coffee) within 4 hours of the study or any time during the 6
hours post-treatment. • Child or parent is unwilling
to cooperate or fulfill the conditions of the protocol.
No subjects were admitted to the study if they had a history
of a chronic musculoskeletal disorder, intervertebral disc
degeneration, peripheral nerve involvement, fracture or
dislocation, acute or chronic arthritis, or hypersensitivity to
ibuprofen or acetaminophen.
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• Any history or evidence of chronic musculoskeletal
disorder.
• Any evidence of intervertebral disc degeneration or
peripheral nerve involvement associated with the present
condition. •
Any evidence of dislocation or fracture associated with this
injury.
• Any evidence of acute or chronic arthritis.
• The use of any drugs (including mood-altering agents)
during the four-hour period preceding the start of the
evaluation (exception: birth control Pills or medication
being taken for existing conditions that would not interfere
with study medication) •
Inability to comprehend and satisfactorily use the
measurement instruments as determined by the investigator
upon screening or upon review of the case records.
• History of hypersensitivity to aspirin, acetaminophen, or caffeine. (NOTE: gastrointestinal intolerance such as 'upset stomach' did not constitute a reason for exclusion.) • Currently pregnant or lactating. • History of peptic ulcer or bleeding disorders.
• Subject had a history of hypersensitivity to ibuprofen,
aspirin, or acetaminophen.
• Subject had any evidence of mouth-breathing, severe
coughing or any other conditions that might compromise
respiratory function. •
Subject had used any cold medication or analgesic, candy,
chewing gum, ice cream or caffeine-containing substance
within 4 hours of entering the study or at any time during the
6 hour study. •
Subject could not cooperate, comprehend, and/or use the
rating scales.
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Subjects were not eligible for inclusion in the study if any of
the following were noted:
a. The child was dehydrated (>10%), malnourished, or
severely debilitated in any way
b. The child was below the 5 thpercentile or above the 95th
percentile of their appropriate weight for age
c. The child had received an antipyretic medication within 8
hours prior to enrollment in the study
d. The child had a history of febrile seizures
e. The child had a known hypersensitivity to acetaminophen,
aspirin, ibuprofen, or any other nonsteroidal
antiinflammatory drug
f. The child had a diagnosis of any chronic renal disorder,
blood coagulation defect, metabolic disease, hepatic disease,
or anemia secondary to blood loss
g. The child had a diagnosis of asthma or any other broncho
spastic condition, or a history of recurrent hives or urticaria
h. The child had received systemic antibiotics or steroids
within 72 hours prior to entering the study
i. The child was related to a member of the study site staff
directly involved with the study or the Sponsor;
j. The child had received any investigational drug within the past 30 days.
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Subjects were not eligible for inclusion in the study if any of
the following were noted:
a. The child was dehydrated (>10%), malnourished, or
severely debilitated in any way
b. The child was below the 5th percentile or above the 95th
percentile of their appropriate weight for age
c. The child had received an antipyretic medication within 8
hours prior to enrollment in the study
d. The child had a history of febrile seizures
e. The child had a known hypersensitivity to acetaminophen,
aspirin, ibuprofen, or any other nonsteroidal
antiinflammatory drug
f. The child had a diagnosis of any chronic renal disorder,
blood coagulation defect, metabolic disease, hepatic disease,
or anemia secondary to blood loss
g. The child had a diagnosis of asthma or any other
bronchospastic condition, or a history of recurrent hives or
urticaria
h. The child had received systemic antibiotics or steroids
within 72 hours prior to entering the study
i. The child was related to a member of the study site staff
directly involved with the study or the Sponsor;
j. The child had received any investigational drug within the past 30 days.
a. Child has a known hypersensitivity to ibuprofen,
aspirin or acetaminophen.
b. Child has any evidence of mouth-breathing due to
nasal congestion or severe coughing, untreated
conditions which could worsen sore throat pain.
c. Child has any systemic or other disease that
might compromise respiratory function.
d. Child has used any "cold medication" (i.e.,
decongestant, antihistamine, expectorant,
antitussive, analgesic, antipyretic, throat
lozenge) or any candy, chewing gum, ice cream, or
cola, tea) within 4 hours of participating in the study
or at any time during the 6-hour study.
e. Child or parent is unwilling to cooperate or
fulfill the conditions of the protocol.
f. Inability to cooperate, comprehend ana/or use the
rating scales as determined by the investigator at
screening or upon review of case report forms.
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Interventions Objective(s) of the trial
Subjects were numbered sequentially as they entered the study. The numbers
that subjects received were matched to the number on the bottle of study
medication that would be dispensed to them. The assignment of the subject
number, therefore, determined whether the subject received ibuprofen,
acetaminophen, or placebo.
Treatment
Ibuprofen 10 mg/kg
Acetaminophen 15 mg/kg
Placebo
Pain intensity was rated by the child on a 200-mm visual analog scale at
baseline and at 0.5, 1, 2, 3, and 4 hours after dosing.
These studies were designed to
evaluate the analgesic efficacy and
safety of liquid formulations of
ibuprofen (10 mg/kg),
acetaminophen (15 mg/kg), and
placebo (vehicle control) for the
relief of pain after orthodontic
treatment of children.
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Single dose of ibuprofen 10 mg/kg (n=3g), acetaminophen 15 mg/kg (n=38),
or placebo (n=39). Child received single dose of double-blind study
medication and efficacy assessments made at 30 minutes, I and 2 hours in the
pediatrician's office and at 3, 4.5, and 6 hours at home. Oral temperature
recorded if >99F at baseline. Dosing
was determined by weight based standards.
The objective of this trial was to
determine the safety and efficacy of
liquid ibuprofen 10 mg/kg and
acetaminophen 15 mg/kg.
A single dose of ibuprofen 400 mg, acetaminophen 1000 mg, or placebo. All
capsules were identical in appearance.
Following treatment, subjects evaluated efficacy at 0.5, 1, 2, 3, and 4 hours.
Side effects were reported throughout the 4-hour treatment period.
The objective of this study was to
compare safety and efficacy in
patients with acute musculoskeletal
pain over a 4 hour period.
Weight (kg/lb) Dose (mL/tsp)
11.3 - < 15.4/ 25- < 34 6.25/ 1.25
15.4 - < 19.2 / 34- <42 8.75/ 1.75
19.2 - < 26.6/ 42- <59 11.25/ 2.25
26.6 - < 34.2 / 59 - < 75 15.00/ 3.00
34.2 – 46.8/ 75 – 103 20.00/ 4.00
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Aspirin 800mg and caffeine 64 mg (ASA/CAF)
Acetaminophen 1000mg (APAP)
Placebo (PLC)
The patients swallowed two capsules of the assigned medication with
approximately 4 ounces of water.
The duration of the study was 4 hours.
The objective of the trial was to
compare the safety and efficacy of
aspirin 800 mg and caffeine 64mg
(ASA/CAF) with acetaminophen
(APAP) 1000mg in patients with
acute musculoskeletal pain over a 4-
hour period.
Treatment: Ibuprofen
10mg/kg
Acetaminophen 15 mg/kg
Placebo
Time-observation points:
Baseline, 0.5, 1, 2, 3, 4, 5, and 6 hours after dosing
This report presents the results of a
double blind, placebo controlled,
parallel, randomized clinical trial to
evaluate the analgesic efficacy of
Children’s Advil (ibuprofen)
Suspension (10mg/kg) in children 2
to 12 years of age with acute sore
throat pain. As recommended by the
FDA, acetaminophen 15 mg/kg was
selected as a positive control, and a
control vehicle as the negative
control.
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Ibuprofen pediatric suspension 100mg/5mL (Children's Advil® Suspension)
given at 7.5mg/kg.
Acetaminophen suspension 160mg/5mL (Children's Tylenol® Suspension)
given at 10 to 15mg/kg.
Both medications were administered according to age following the labeled
dosing schedule.
To compare the antipyretic efficacy
and safety of a single dose of
ibuprofen pediatric suspension
(100mg/5ml) administered at
7.5mg/kg to the labeled dose of
acetaminophen suspension
(l60mg/5ml) administered at 10 - 15
mg/kg in children with fever
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Ibuprofen pediatric suspension 100mg/5mL (Children's Advil® Suspension)
given at 7.5mg/kg.
Acetaminophen suspension 160mg/5mL (Children's Tylenol® Suspension)
given at 10 to 15mg/kg.
Both medications were administered according to age following the labeled
dosing schedule.
The objective of this study was to
compare the antipyretic efficacy and
safety of a single dose of Children's
Advil Suspension (l00mg/5mL)
administered at 7.5mg/kg to the
labeled dose of Children's Tylenol
Suspension (l60mg/5mL), 10-
15mg/kg, in children with fever.
Ibuprofen 20 mg/ml (10mg/kg)
Acetaminophen 32 mg/ml (15 mg/kg)
This double-blind, parallel,
single-dose randomized
controlled trial is designed to
evaluate the safety and efficacy
of liquid formulations of
ibuprofen (approx. 10 mg/kg),
acetaminophen (approx. 15
mg/kg), and a vehicle control
administered orally in an out-
patient population of children
suffering from acute sore throat
pain.
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Outcome measures_1
(Primary endpoint)
Outcome measures_2
(secondary endpoints)
Pain relief efficacy was the outcome used to assess the
comparative safety and efficacy in ibuprofen and
acetaminophen (pain intensity and pain relief scales).
Pain relief was also assessed at the same post-dosing time
points using a 5-point categorical relief rating scale. At
the conclusion of the 4-hour evaluation period, or at the
time rescue medication was taken, an overall (global)
evaluation of the study medication was provided by the
subject, using a numerical scale of 0-10.
N/A
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• Completed by child - pain thermometer, sad-happy face
relief scale;
• Completed by parent – categorical sore throat pain
intensity scale, change-in-pain scale, overall evaluation;
• Completed by pediatrician - categorical sore throat pain
intensity scale, change-in-pain scale.
N/A
Relief of pain was used as an outcome measure. N/A
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At 1/2, 1, 2, 3, and 4 hours after treatment, measurements
were obtained in the following order: • Pain on
Movement •
Pain Relief
• Sensory Pain Qualities
At the conclusion of the 4-hour study period, the patient
provided him/her Global Assessment. The Global
Assessment included patients answering the question
“how would you rate this medication as a pain reliever?”
with the possible choices of excellent, very good, good,
fair, or poor. This
Global Assessment was used to determine the outcome of
the efficacy of pain relief between aspirin/caffeine
combination, acetaminophen and placebo.
N/A
The primary outcome for this trial was pain relief efficacy
of Children's Advil. This was measured using the
collapsing children's 200 mm pain intensity scale and the
combined pain relief and pain intensity differences.
N/A
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The primary efficacy variable was the time-weighted sum
of the temperature differences from baseline over 8 hours
Additional parameters: the time weighted sum
of the temperature differences from baseline
over 2, 4, and 6 hours, the maximum
temperature difference from baseline over 8
hours; temperature difference from baseline at
each post-dosing timepoint, the proportion of
subjects who were treatment failures, the time
to treatment failure, time to onset and duration
of temperature control
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The primary efficacy variable was the time-weighted sum
of the temperature differences from baseline over 8 hours
Additional parameters: the timeweighted
sum of the temperature differences from
baseline over 2, 4, and 6 hours, the maximum
temperature difference from baseline over 8
hours; temperature difference from baseline at
each post-dosing timepoint, the proportion of
subjects who were treatment failures, the time
to treatment failure, time to onset and duration
of temperature control, proportion of subjects
who achieved temperature control
Pain relief based on assessment by patients,
parents and physician
None
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Randomisation
implementation
Blinding
Each bottle of study medication was
numbered sequentially, and these
numbers were randomly assigned to 1
of the 3 treatments. The randomization
schedules provided by Whitehall
Laboratories, New York, NY.
Both the subject and the investigator were blinded
with respect to the treatment assignment during
the study. All study medications, active and
placebo, were identical in appearance. Dosing
instructions were identical on all bottles.
Each bottle label had 2 panels, 1 permanently
attached to the bottle, the second removable.
When a bottle was given to the subject's parent or
guardian, the second panel was torn off and
attached to the CRE. This panel contained the
same information as that on the bottle, and, in
addition, had a sealed sleeve, the inside of which
contained information regarding the actual
contents of the bottle. The sleeve could be opened
in the case of an emergency to determine what
medication the subject was taking. This allowed a
subject to be treated properly in an emergency
without breaking the blind for the entire trial.
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The patients in this study were
randomized through the use of a
compute generated random co
This clinical trial was a double blinded study.
Patients were allocated by a computer-
generated randomization code.
Two stratifications were established
depending on the type of soft tissue
injury (either ligamentous sprain or
muscular strain and/or contusion).
Within each stratum, each patient was
randomly assigned to one of the three
treatment groups to assure equal
distribution of treatments with respect
to the type of injury.
This clinical trial was a double blinded study.
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Subjects satisfying the entry
requirements for the study were
allocated by a computer-generated
randomization code to receive a single
dose of aspirin 800 mg with caffeine
64 mg, acetaminophen 1000 mg. or
identical placebo. Following
treatment, subjects evaluated efficacy
at 0.5, 1, 2, 3, and 4 hours.
This clinical trial was a double blinded study.
• Each bottle of study medication was
numbered sequentially and these
numbers were randomly assigned to 1
of 3 treatments. Treatment
assignments were determined by
computer-generated randomization
schedule maintained by Biostatistics
Department of Whitehall
Laboratories. •
Following the baseline screening
period, subjects were numbered
sequentially as they entered the study.
The number that a subject received
was matched to the number on the
bottle of study medication that was
dispensed to them. The assignment of
the subject number, therefore,
determined whether the subject
received ibuprofen, acetaminophen or
placebo.
Both the subject and the investigator were blinded
with respect to the treatment assignment during
the study. All study medications active and
placebo were identical in appearance. Dosing
instructions were identical on all bottles.
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Subjects eligible to participate in the
study were randomly assigned to one
of two treatment groups in a 1:1 ratio.
The treatment assignment was
determined by a randomization
schedule generated by the Biostatistics
Department of Whitehall- Robins
Healthcare.
A member of the Investigator's staff not associated
with this study administered the appropriate dose
of study medication at time 0 keeping the
Investigator, study nurse, subject, and his/her
parent/guardian blinded as to the identity of the
treatment.
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Approximately 160 children
(depending upon subject availability)
will complete the study. In order to
accomplish this goal up to 200
subjects may be enrolled. Children
will be randomized in a 1:1 ratio (i.e.,
100 randomized children per
treatment group). The treatment
assignment will be determined by a
randomization schedule generated by
the Biostatistics Department of
Whitehall-Robins Healthcare.
Investigator under blinded conditions for each of
the two treatment groups. The appropriate dose of
the correct randomly assigned study medication
was then administered by a study nurse. To
maintain the blindness of the study, the study
nurse administering the study medication did so
out of sight from the Investigator and
parent/guardian. This study nurse was not directly
involved with the study.
Treatment assignment was
determined by a computer-
generated randomization
schedule maintained by the
Biostatistics Department of
Whitehall Laboratories. Patients
were randomly allocated to
receive either ibuprofen,
acetaminophen or a vehicle
control.
Double-blinded
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Statistical methods
Neither investigator from each of the two studies was able to enroll 150 qualified subjects. Per protocol,
data from the two studies were combined for all analyses. Analyses were also performed within each
study. All analyses were
performed using SAS Version 6. Statistical results were declared significant if the probability of
obtaining the result by chance was 0.05 or less.
In order to provide the full clinical picture, all differences (p < 0.05) in pairwise comparisons are
presented. When the ANOVA p-value is > 0.05, it is presented parenthetically to indicate that the
pairwise p-values are technically ineligible for significance.
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After enrollment patients' demographic data (including age, weight, height, sex and race), physical
examination results, current sore throat condition (temperature, number of days with sore throat, and
symptoms) as well as inclusion/exclusion criteria were recorded. In order to determine the severity of the
child's pain and the efficacy of the medication's pain relief an upper respiratory infection questionnaire,
tonsillo-pharyngitis assessment at baseline, evaluation of sore throat pain by physician, parent and child
at baseline were recorded. Specific efficacy assessments included a pain thermometer and a sad-happy
face relief scale completed by the patient; a sore throat pain intensity scale, change-in-pain scale, and an
overall evaluation completed by the parent; and a categorical intensity scale and change-in-pain scale
completed by the pediatrician. Post treatment the parent was asked "considering the effect the medicine
had on your child's sore throat over the past 6 hours, how would you rate it as a pain medication?". This
question helped to further determine the final efficacy of the medication.
Demographic, historical, and baseline clinical characteristics were compared using analysis of variance
and chi-square. Observed differences among the three treatment groups were tested for statistical
significance (P <0.55) with the two-tailed, two-sample b-test. Pain intensity was analyzed at individual
time points as the absolute difference and percent difference from baseline (PID, %PID) on the Pain on
Movement Scale, and as the sum of pain intensity differences (SPID, %SPID) weighted by time over 4
hours. Data from the relief scale were analyzed at individual time points and cumulatively (TOTPAR).
The qualities of pain scales were analyzed for all words whose scores were greater than 66 mm at
baseline as Lbs sum quality of pain (calculated as for SPID); as the number of words chosen with
intensities greater than 66 mm; and as the quality of pain word selected by the subject that best described
pain at baseline.
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• The comparability of the three treatment groups at baseline for demographic and clinical characteristics
was determined by analysis of variance for variables with continuous distribution (e.g., age, weight,
baseline pain intensity) and by chi-square for categorical variables (e.g.. sex). Differences were declared
statistically significant if the tests indicated that the probability of obtaining the result by random
occurrence was 0.05 or less. Pain intensity was analyzed at individual time points as the absolute
difference from baseline (PID) on the Pain on Movement Scale, and as the arm of pain intensity
differences (IPID) weighted by time over 4 hours as an indicator of overall (area-under-the-curve)
efficacy. Data from the relief scale were analyzed at individual time points and cumulatively (TOTPAR).
The qualities of pain scales were analyzed for all words whose scores were greater than 66 mm at
baseline as the sum quality of pain (calculated as for SPID); as the number of words chosen at baseline
greater than 66 mm; and as the quality of pain word selected by the subject that best described pain at
baseline. Scores on the Global Evaluation were assigned as 0 = poor to 5 = excellent. • Treatment failures (i.e.,-patients reporting no relief for the first 2 or more hours and taking a "rescue' analgesic) were assigned as their subsequent scores their baseline or last score, whichever was worse, on the Pain on Movement and Quality of Pain Scales, and their last score on the relief scale. • Summary efficacy parameters were compared using two-ay analysis of variance with treatment and type of injury as the dependent variables. Analysis of variance was used to compare between-treatment mean differences for each efficacy measure. Duncan's Multiple Range Test was used to make pairwise comparisons between treatments when significant differences were found.
All analyses were performed using SAS Version 6. Statistical results were declared significant if the
probability of obtaining the result by chance was 0.05 or less.
Onset of pain relief was defined as the time to reach a mean PRID score of 1 (derived from the inverse
of the mean PRID score at 30 minutes post-dose multiplied by 30). Since no subject took rescue
medication, the duration of pain relief (estimated by the median time to remedication) was not
calculated). In order to provide the full clinical picture, all differences (p< 0.05) in pairwise comparisons
are presented. When the ANOVA p-value is >0.05, it is presented parenthetically to indicate that the
pairwise p-values are ineligible for significance. Protection for
Multiple Comparisons: The protocol indicated that Dunnett’s test would be employed (using placebo as
the common control group). Instead, Fisher’s protected least significant difference test was used by
which pairwise comparisons (two-tailed) would be eligible for being declared significant only if the corresponding among-treatments test was significant.
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Analysis was done using two-way ANOVA with effects for treatment and baseline temperature stratum.
Kaplan-Meier estimates were utilized to estimate rates of the treatment groups for time to treatment
failure and time to onset and duration of temperature control; the Cox proportional hazards model was
used to test for treatment differences. The proportions of subjects who were treatment failures were
compared using the Cochran-Mantel- Haenszel test. Pulse and respiration rate were analyzed as the
change from baseline using two-way ANOVA with effects for treatment, baseline temperature stratum,
and their interaction. Fisher's Exact test compared the incidence of adverse effects between treatments.
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Analysis was done using two-way analysis of variance (ANOVA) with effects for treatment and baseline
temperature stratum. Kaplan-Meier estimates were utilized to estimate rates of the treatment groups for
time to treatment failure and time to onset and duration of temperature control; the Cox proportional
hazards model was used to test for treatment differences. The proportions of subjects who were
treatment failures were compared using the Cochran-Mantel-Haenszel test. Pulse and respiration rate
were analyzed as the change from baseline using two-way ANOVA with effects for treatment and
baseline temperature stratum. For ANOVA and the Cox proportional hazards model, the interaction of
treatment and baseline temperature strata was initially assesed by adding the interaction effect to the
model. If the interaction effect was generally not significant (i.e., p>0.15), then it was not retained in the
final model. Fisher's Exact test compared the incidence of adverse effects between treatments.
No statistics were done because study was terminiated prematurely. The intended
statistical approach was as follows:
Demographic data will be tabulated and descriptive statistics will be provided.
The Sore Throat Pain Thermometer will be analyzed at individual time points (PID, %PID)
and as the sum of the scores weighted by time interval and as the sum of the percent of
baseline weighted by time interval (SPID and %SPID). The Sore Throat Relief Scale will be
analyzed at individual time points and as the sum of scores weighted by time interval
(TOTPAR). The Investigator's and Parent's Evaluation of Sore Throat Pain Scale data will be
analyzed at individual time points and as a cumulative score weighted by time. The
Investigator's and Parent's Change in Sore Throat Pain Scale data will be arranged to obtain
scores at individual time points and a cumulative score relative to the baseline Sore Throat
Pain Thermometer score weighted by time interval. Dunnett's Test will be used to compare
the active treatments to the vehicle control. Other approaches such as stratified
subanalyses based on cogent clinical features and stratification by age may be used if appropriate. Statistical significance will be declared when analyses yield p-values less than or equal to 0.05. Depending on patient availability and power calculations, data from this study may be pooled with that from a different investigative site(s) following the same protocol.
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Participant flow
Flow of participants through each stage (diagram, if appropriate). For each group the numbers of
participants randomly assigned, receiving intended
treatment, completing the study protocol, and analyzed for the primary outcome should be stated. This
should include the number of participants in each group included in each analysis and whether the
analysis was by "intention-to-treat" or “per protocol”. Protocol deviations from the study as planned,
together with reasons should be stated.
• A total of 264 subjects were randomized to treatment in the 2 studies: 89 were assigned to the ibuprofen group, 86 were
assigned to the acetaminophen group, and 89 were assigned to the placebo group.
• Among the subjects who were randomized, 159 actually took the study medication: 53 subjects from the ibuprofen
group, 49 subjects from the acetaminophen group, and 57 subjects from the placebo group. One hundred and five
subjects who were randomized (40%) did not experience sufficient baseline pain to meet the study entry criteria and
never took study medication.
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• 120 children entered; primary efficacy analysis on 116 children 3.8-12.5 years of age (8.7+±2.3 yrs); 57 male (49%)
and 59 females (51%) with acute upper respiratory infection, sore throat pain, and objective evidence of tonsillo-
pharyngits.
• Single dose of ibuprofen 10 mg/kg (n=39), acetaminophen 15 mg/kg (n=38), or placebo (n=39).
Though 127 patients were enrolled in the study, 10 were excluded and therefore analysis of efficacy was carried out on
117 subjects and data on all 127 patients were included in an "intent to treat" analysis in the evaluation of safety. 41
subjects were randomly allocated to the ibuprofen treatment group, 37 to acetaminophen, and 39 to placebo. The
different scales for measuring acute treatment response and the objective measurements of the pre-treatment state
include: the pain on movement scale (identifying one activity which is difficult to perform), pain relief rating (circling a
word to describe pain relief), and sensory qualities of musculo-skeletal pain (before and after treatment patients rate the
severity of 12 words that desribe musculoskeletal pain). Also, clinical assessments of tenderness and limitation of motion
were also completed.
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• Number: 150 (50 per treatment groups).
• Age: 18 years of age and older.
• A total of 166 subjects were enrolled in the study. Of these, 11 were excluded from the analysis of efficacy due to
rescindment of a protocol amendment.
• Thus, analyses of efficacy were carried out on 149 subjects; data on 165 patients (pt. no. 147 excluded done to missing
data) were used for an "Intent to treat" analysis and in the evaluation of safety.
• Included in the analysis of efficacy were 50 subjects randomly allocated to aspirin with caffeine treatment group, 49 to acetaminophen, and 50 to placebo. The three treatment groups were similar in terms of demographics, historical data, clinical features, and baseline efficacy variables.
* Evaluable subjects
** Evaluable subjects with baseline scores of 100-150mm on 200 mm visual analog scale (ie 1 or 2 on the collapsed
scale) Subject Description:
• A total of 177 children were documented as having been screened for possibly study entry.
• 71 of those 177 were not entered in the study.
• Among the 106 subjects who were enrolled in the study: 35 were randomized to receive ibuprofen 10 mg/kg, 36 were
randomized to receive acetaminophen 15 mg/kg, and 35 were randomized to receive placebo. • 105 of the 106 were included in the safety analysis. No data was available for subject 108 (ibuprofen) since the case report form for this subject was inadvertently lost. • Of the 105 subjects included in the safety analysis, 5 (5%) subjects discontinued the study; 2 of the 36 (6%) subjects from the acetaminophen group, and 3 of the 35 (9%) subjects from the placebo group. No subject who received ibuprofen discontinued the study. The reasons for discontinuation were protocol violation, adverse event, inability to use rating scales, and other.
Ibuprofen 10mg/kg Acetaminophen 15 mg/kg Placebo
34 subjects *20 subjects **
30 subjects*22 subjects **
29 subjects *20 subjects**
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Subject Disposition. A total of 164 subjects entered the study; all were administered study medication: 81 subjects were
randomized to receive ibuprofen and 83 to receive acetaminophen. Of these 164 subjects, 162 completed the study of
whom 160 were evaluable for the primary efficacy analysis (78 in the ibuprofen group and 82 in the acetamninophen
group). Two subjects were classified as discontinued, both in the acetaminophen treatment group: one subject was less
than 6 months of age and was classified as discontinued (the subject entered the study in violation of the protocol's
minimum age requirement) after completing the 8-hour study and one subject vomited immediately after dosing and was
withdrawn from the study.
Four subjects, three randomized to ibuprofen suspension and one randomized to acetaminophen suspension, were not
included in the primary efficacy analysis. In the ibuprofen treatment group, one exceeded the protocol's upper weight
limit by 25 lbs, one participated in a vaccine trial within 30 days prior to joining this study, and one received the wrong
dose of study medication (1 tsp instead of 3/4 tsp). In the acetaminophen treatment group, one subject vomited immediately after dosing.
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Subject Disposition: One hundred sixty-nine subjects were randomized into the study; all 169 subjects took study
medication and are included in the analysis of safety: 92 received ibuprofen suspension and 77 received acetaminophen
suspension. Ten subjects were classified as discontinued (seven on ibuprofen and three on acetaminophen) and were
excluded from the primary efficacy analysis: five (two on ibuprofen and three on acetaminophen) vomited within 1 hour
after dosing; two (both on ibuprofen) received antibiotic within 2 hours after dosing; three (all on ibuprofen) received the
wrong dose of medication. Thus, the primary efficacy analysis was conducted on 159 subjects, 85 in the ibuprofen
treatment group and 74 in the acetaminophen treatment group. The intent-to-treat analysis was carried out on 168
subjects (one subject on acetaminophen vomited within 1 hour after dosing and had no post-dosing efficacy
assessments).
Demographics: There were 71 (45%) males and 87 (55%) females. The majority of subjects were Caucasian (96%). The
average age was 4.7 yrs. (range: 0.5 to 11.8 yrs.); the average weight was 40.2 lbs. (range: 16.0 to 92.0 lbs.); the average height was 41.3 ins. (range: 26.0 to 59.0 ins.). The two treatment groups were comparable with respect to all demographic variables.
Twenty-two children were entered in this trial which was discontinued due to poor patient enrollment.
Seven children received ibuprofen 10 mg/kg, 7 received acetaminophen 15 mg/kg, and 8 received
placebo. No analysis was done.
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Recruitment
N/A
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N/A
N/A
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N/A
N/A
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N/A
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N/A
N/A
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Baseline data
The comparability of the three treatment groups for demographic, dental background, and baseline pain characteristics
were determined. Categorical measurements were analyzed via the Cochran-Mantel-Haenszel (CMII) test, adjusting for
study. Ordered variables were analyzed by two-way analysis of variance with effects for treatment, study and treatment-
by-study interaction.
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A physical examination was conducted, including tonsillo-pharyngitis assessment and child, parent and pediatrician
ratings of sore throat pain.
The muscular-skeletal examination (including the Clinical Assessments of Tenderness and Limitation of Motion on the
predominant injury for evaluation in this study) will be performed on all patients by one examiner. The Muscular-
Skeletal Pain Questionnaire along with Pain on Movement Scale and Sensory Quality of Pain Scales were administered
by the same interviewer in order to identify qualifying candidates.
Demographic and clinical features at baseline
Age 7.9 + 3.1 yrs
Sex 12 M, 8 F
Height 128.5 + 18.6 cm (50.6 + 7.3 in)
Weight 30.4 + 12.9 kog (67.1 + 28 lbs)
Race 20 Caucasian
Tonsil-Pharyngitis Score 5.4 + 1.3
Pain Intensity (child) 12.2 + 4.7 cm
Parents’ Categorical Rating 2.3 + 0.7
Physicians’ Categorical Rating 2.4 + 0.5
Dose 11.6 + 2.6 mg/kg (336 + 109 mg)
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The musculoskeletal examination (Including the Clinical Assessments of Tenderness and L imitation of motion of the
predominant injury for evaluation in this study) was performed on all patients by one examiner. The Musculoskeletal
Pain Questionnaire along with Pain on Movement Scale and Sensory Quality of Pain scales were administered by the
same interviewer in order to identify qualifying candidates.
• The mean age of the children enrolled was 8.0 + 2.5 years with a range of 3.0 to 12.9 years. The mean age of the
children in each treatment group were comparable.
• There were 49 males(47%) and 55 females (52%) with a similar distribution of males and females among the three
treatment groups.
• The three treatment groups were evenly distributed for the other demographic variables, except for race, where a
significantly higher proportion (8%) of subjects who received acetaminophen were classified as either “other” or
“missing” compared to those who received ibuprofen or placebo (0%).
• Subjects who were included in the primary efficacy analyses were evenly distributed demographically, except for age; subjects who received acetaminophen were significantly older (9.0 years) compared to the ibuprofen (7.5 years) and placebo (7.6 years) groups. • All children included in the primary efficacy analyses reported a sore throat. The other most common symptoms reported were headache (54%), stuffy nose (44%), feverish (43%) and stomach ache (40%). These symptoms were indicative of an upper respiratory infection with tonsillo-pharyngitis, which was confirmed by an objective tonsillo-pharyngitis assessment and physical examination.
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Oral or rectal temperature was recorded twice within a 15-minute interval at time 0. The average of the two temperature
readings was recorded as the baseline temperature for determination of subject eligibility and randomization sequence.
The mean baseline temperature was 102.4 °F for both
groups.
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The mean baseline temperatures for the two treatment groups were comparable (102.4 °F and 102.5 °F for ibuprofen and
acetaminophen, respectively). Eighty-seven subjects (45 and 42 in the ibuprofen and acetaminophen group, respectively)
were classified into the low baseline temperature stratum (102.5 °F); 72 subjects (40 and 32 in the ibuprofen and
acetaminophen group,
respectively) were classified into the high baseline temperature stratum (>102.5 °F).
N/A
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Trial
interruption
(Y/N)
Reasons for trial interruption
N N/A
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N N/A
N N/A
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N N/A
N N/A
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N N/A
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N N/A
N N/A
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Outcomes and estimation
• Among the 159 subjects, 125 (79%) were included in the primary efficacy analyses: 46 of 53 (87%) subjects from the
ibuprofen group, 35 of 49 (71%) subjects from the acetaminophen group, and 44 of 57 (77%) subjects from the placebo
group. • The 159 subjects who took study medication were included in
all safety analyses. Of these, 152 subjects provided an assessment of baseline pain and were included in an intent-to-treat
analysis of efficacy data. • Among the 159 subjects who took study medication, 46
(29%) subjects discontinued the study: 13 of 53 (25%) subjects from the ibuprofen group, 15 of 49 (3 1%) subjects from
the acetaminophen group, and 18 of 57 (32%) subjects from the placebo group. The reasons for discontinuation (across
treatment groups) were protocol violation (19 subjects), other (15 subjects), failure to complete forms (7 subjects) and
inability to use rating scales (5 subjects).
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Children's assessments: Ibuprofen and acetaminophen statistically significantly (P <0.05) superior to placebo at most
post treatment time points and for SPID and TOTPAR calculated at 2, 4, and 6 hours.
Parent's assessments: Ibuprofen and acetaminophen numerically greater than placebo at all time points and overall at 2,
4, and 6 hours on change-in-an and categorical sore throat pain scale; statistically significant differences (P <0.05) for
both actives over placebo at 4 and 6 hours and the change-in-pain scale and at several post-treatment time points on both
scales. Ibuprofen statistically significantly (P < 0.05) greater than placebo and acetaminophen numerically greater than
placebo on the overall evaluation.
Pediatrician’s assessments: ibuprofen and acetaminophen statistically (P < 0.05) superior to placebo overall at 2 hours and at several time points on the change-in-pain and categorical sore throat pain scales.
A total of 127 subjects were enrolled in the study, of these, 10 were excluded from the analyses of efficacy due to
significant protocol violations. Thus, analyses of efficacy were carried out on 117 subjects; data on all 127 patients was
used for an 'intent to treat' analysis and in the evaluation of safety. Included in the analysis of efficacy were 41 subjects
randomly allocated to the ibuprofen treatment group, 37 to acetaminophen, and 39 to placebo. The three treatment
groups were similar in terms of demographics, historical data and pertinent clinical features. For the sums of the efficacy
variables, ibuprofen
400 mg was significantly (P £ 0.03) different from placebo for SPID and %SPID, acetaminophen 1000 mg was
significantly (P= 0.04) different from placebo for %SPID and TOTPAR, no significant differences were found between
the two active treatments. At individual time points, few significant differences were found between the two active
treatments and placebo and no differences between the two active treatments. Similar results were found in the "intent to
treat' analysis of 127 patients . No patients remedicated with a rescue analgesic during the study.
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• The summary efficacy variables (SPID, TOTPAR, Sum Quality of Pain. GLOBAL, and Sum Selected Word) were
analyzed using treatment and type of injury as dependent variables. A significant difference among treatments was found
for TOTPAR (P = 0.04), and pairwise comparisons demonstrated aspirin 800 mg with caffeine 64 mg to be significantly
different from placebo (P < 0.01); acetaminophen 1000 mg was not different from placebo and there was no significant
difference between the two active medications. A significant difference among injury type (sprain, contusion, strain) was
found for Sum Selected Word (P = 0.05), and pairwise comparisons showed a significant difference (P < 0.05) between
contusion (117.17; n-19) and strain (73.00, n=71); sprain (90.64; n=14) was not different from contusion and strain.
There was no significant interaction between treatment and injury type (P = 0.84). For the individual post-treatment
evaluations , no significant differences were found between active treatments and placebo, but the numerical ranking
consistently favored aspirin 800 mg + caffeine 64 mg > acetaminophen 1000 mg and placebo on pain intensity, pain relief, qualities of pain, number of words chosen, and selected pain word. At most time points, acetaminophen 1000 mg was favored over placebo. As 'intent-to-treat" analysis (not presented in this report) of 56 patients receiving aspirin 800 mg with caffeine 64 mg, 55 receiving acetaminophen 1000 mg, and 54 receiving placebo confirmed the above results.
Ibuprofen was numerically superior to placebo for all summed efficacy measures over 0-2, 0-4, and 0-6 hours, as well
as for Peak Relief and Peak PID scores during those time intervals. Over the first 2 hours of the study, acetaminophen
was significantly superior to placebo for summed efficacy measures derived from pain intensity difference scores (SPID)
and for pain relief combined with pain intensity difference scores (SPRID overall p>0.05), as well as for Peak PID
(overall p>0.05), and numerically superior to placebo for summed pain relief scores (TOTPAR) and Peak Relief.
Acetaminophen was numerically superior to placebo for all summer efficacy scores over 0-4 and 0-6 hours, as well as for
Peak Relief over 0-4 hours and Peak PID over 0-4 and 0-6 hours. Acetaminophen was numerically superior to, but now
statistically different from ibuprofen for all summed efficacy scores over 0-2 hours, as well as for Peak Relief and Peak
PID scores. Ibuprofen was numerically superior to acetaminophen for all summed efficacy scored over 0-4 and 0-6
hours, as well as for Peak Relief during those time periods.
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In this single dose pediatric study in children with fever, ibuprofen suspension (Children's Advil Suspension® 100
mg/5mL) administered at 7.5mg/kg was clearly shown to be a superior antipyretic agent compared to acetaminophen
suspension administered at 10-15mg/kg (Children's Tylenol Suspension® 160mg/5mL). This was clinically demonstrated
by a faster onset of temperature control, a greater degree of temperature reduction, and a longer duration of effect. There
was no evidence that factors other than differences in effects of the two drugs contributed to the observed difference in
antipyresis. The results of this trial support previously reported trials in children that showed ibuprofen 10 mg/kg
producing greater antipyresis than 10-15mg/kg acetaminophen. The superior antipyretic efficacy of ibuprofen suspension
7.5mg/kg over acetaminophen suspension 10-15mg/kg was maintained when several subanalyses addressing potential
confounding variables were performed: ibuprofen was superior to acetaminophen in children <4 years of age; ibuprofen
was superior to acetaminophen in children with baseline temperature >102.5 The mean baseline temperature was 102.4 °F for both groups. Ibuprofen was superior to acetaminophen in the subpopulations; of children with a medical diagnosis of otitis media, upper respiratory infection, or " other."
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In this single dose study in children with fever, ibuprofen suspension (Children's Advil Suspension, 100mg/5mL)
administered at 7.5mg/kg provided a greater antipyretic effect compared to acetaminophen suspension (Children's
Tylenol Suspension l60mg/5mL). This was demonstrated clinically by a significantly faster onset of temperature control,
numerically greater reductions in temperature at each post-dosing timepoint for the full 8-hour duration of the study,
numerically greater sums of the temperature reduction from baseline over 2, 4, 6, and 8 hours, and a lower rate of
therapeutic failure. These results, when viewed with respect to a previous implementation of this study design as well as
previously reported trials in children using ibuprofen suspension 7.5mg/kg, establish the superior antipyretic efficacy of
Children's Advil Suspension administered at 7.5mg/kg compared to Children's Tylenol Suspension administered at 10-
15mg/kg.
N/A
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Ancillary analysis Adverse events Trial
termination
N/A Of the 159 subjects who took study medication in
these two studies, four subjects reported a total of
5 adverse experiences (AEs). One subject who
received ibuprofen experienced a mild headache
and mild nausea; one subject who received
acetaminophen experienced a moderate headache;
and two subjects who received placebo
experienced mild nausea. No subject was
withdrawn from either study due to an AE.
N
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N/A One patient (on the ibuprofen treatment group)
had a single episode of vomiting upon swallowing
the medication and was withdrawn from the stud
(considered unrelated to study drug and attributed
by the investigator to a gag reflex).
N
N/A One patient experienced a side effect (moderate
drowsiness while receiving ibuprofen, which was
probably related to study medication).
N
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N/A Four patients experienced adverse events in this
study (heartburn, nausea, shakiness, light
headedness) , all rated as "possible related": three
receiving APAP and one three receiving
ASA/CAF. All adverse reactions resolved,
without treatment.
N
N/A Adverse effects were recorded for four children;
one subject who received ibuprofen, 2 who
received acetaminophen and one who received
placebo. One of the patients who experienced
the adverse reaction to acetaminophen vomited
immediately after taking the dose. The other
patient that experienced an adverse reaction to
acetaminophen had a mild nosebleed. The
ibuprofen adverse event was an episode of
vomiting. Lastly, the child who experienced the
adverse reaction to placebo fainted.
N
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N/A Three ibuprofen-treated subjects and three
acetamninophen treated
subjects had adverse experiences. Vomiting
occurred in two ibuprofen-treated subjects and
three acetam inophen-treated subjects. One
ibuprofen-treated subject had a rash. All of the
AEs were rated mild in severity. There were no
significant differences between the treatment
groups.
N
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N/A Adverse experiences were seen in 10 (11%)
subjects receiving ibuprofen and nine (11%)
subjects receiving acetaminophen. Vomiting
occurred in six (6.5%) subjects receiving
ibuprofen and seven (9.1%) subjects receiving
acetaminophen. There were no significant
differences between the two treatment groups.
Five subjects were discontinued from the study
due to adverse experiences (all vomiting): two
receiving ibuprofen and three receiving
acetamninophen.
N
N/A No adverse effects were reported. Y
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Reason for trial termination Discussion and interpretation of study results- by
sponsor (if available)
N/A In these studies, children who took ibuprofen reported greater pain
relief and required less rescue medication than children who took
either acetaminophen or placebo. Only a few, mild adverse events
were reported, and the incidence of adverse events among children
who took ibuprofen was equal to that for children who took
acetaminophen. The incidence for both active treatments (2%) was
half of that for placebo (4%). The
results of this study demonstrate that liquid ibuprofen 10mg/kg is
effective for the relief of orthodontic pain and is superior in
efficacy to acetaminophen 15mg/mL.
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N/A The results of this double-bind, single-dose study show Children's
Advil* ibuprofen suspension 10 mg/kg to be a safe and effective
analgesic/antipyretic agent compared to placebo and that ibuprofen
10 mg/kg is at least as effective and as safe as acetaminophen
15mg/kg.
N/A There were no differences discernable between the active agents
using this model at this site, When used concurrently at another
investigative site, this musculoskeletal pain model failed to detect
any significant differences between the same two active treatments
(ibuprofen 400 mg and acetaminophen 1000 mg) and placebo. A
lack of differentiation between active medication and placebo in a
musculoskeletal pain model has also been reported for
indomethacin by van Marion, Hustisson et al., and Fitch and Gray.
In this instance, a musculoskeletal pain model differentiated
between the effects of over-the-counter analgesics and placebo but
requires refinement in order to distinguish between the two active
agents.
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N/A • The musculoskeletal pain model used at this investigative site
detected a significant difference in total pain relief between aspirin
800 mg with caffeine 64 mg and placebo, indicating the
combination analgesic to be affective in relieving that pain
associated with acute musculoskeletal injury. Although no
statistically significant differences were detected between
acetaminophen and placebo or between acetaminophen and aspirin
with caffeine, numerical trends consistently favored aspirin with
caffeine over acetaminophen and placebo. An increase in sample
size to approximately 70 patients per treatment group would
probably have been sufficient to differentiate the three treatment
groups. The difficulty in using musculoskeletal pain as a pain
model is evidenced by reports in the literature failing to distinguish
between active medication and placebo.
• We conclude that aspirin 800 mg with caffeine 64 mg is an
effective analgesic for the treatment of pain associated with
musculoskeletal injury, and, because a 20% lesser dose of aspirin in combination with caffeine provided pain relief comparable to acetaminophen, caffeine 64 mg is an analgesic adjuvant.
N/A This study demonstrates that single doses of ibuprofen (10mg/kg)
and acetaminophen (15 mg/kg) are safe and effective analgesics
for the relief of sore throat pain in children up to 12 years of age.
Further, ibuprofen 10 mg/kg was shown to be at least as effective
and as safe as acetaminophen 15 mg/kg.
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N/A When administered in accordance with labeling instructions,
ibuprofen pediatric suspension 7.5mg/kg (Children's Advil
Suspension 100mg/15mL) is superior to acetaminophen suspension
10-15mg/kg (Children's Tylenol Suspension 160mg/5mL) in
treating fever in children. Ibuprofen pediatric suspension provides
a significantly greater reduction in temperature than
acetaminophen suspension. Additionally, temperature control is
achieved in a significantly shorter period of time and lasts for a
significantly longer period of time with ibuprofen. Both treatments
are well-tolerated.
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N/A When administered in accordance with labeled OTC instructions,
ibuprofen pediatric suspension 7.5mg/kg (Children's Advil
Suspension 100mg/5mL)
provided a significantly faster onset of temperature control than
acetaminophen suspension at 10-15 mg.kg (Children's Tylenol
Suspension 160mg/5mL) in children with fever. Ibuprofen
pediatric suspension provided a greater overall reduction in
temperature and temperature control was achieved in a
significantly shorter period of time and lasted for a numerically
longer period of time than with acetaminophen suspension. Both
treatments were well-tolerated.
The study was discontinued on June 12,
1990 due to poor patient enrollment. over
a period exceeding 2 years, only 22
patients were enrolled in the study; the
enrollment rate was less than one patient
per month, on average. The first patient
entered the study on February 7, 1988
and the last patient entered the study on
March 1, 1990.
Twenty-two children were entered in this trial which
was discontinued due to poor patient enrollment. Seven
children received ibuprofen 10 mg/kg, 7 received
acetaminophen 15 mg/kg, and 8 received placebo.
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Discussion and interpretation of study results- by
competent authority (if available)
N/A
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N/A
N/A
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N/A
N/A
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N/A
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N/A
N/A
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