WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95...

80
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 090177e182b31c62\0.1\Draft\Versioned On:16-Dec-2011 10:27

Transcript of WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95...

Page 1: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 2: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

WM- 375A N/A WM-375A N/A 17-Jul-90

WM- 350 N/A WM-350 N/A 09-Jun-88

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 3: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

WM-343 N/A WM-343 N/A 08-Sep-88

WM-366 N/A WM-366 N/A 11-Jul-95

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 4: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

AF-95-05 N/A AF-95-05 N/A 1-Jan-97

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 5: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

AF-96-01 N/A AF-96-01 N/A 1-Feb-99

WM-376 N/A WM-376 N/A 18-Jul-90

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 6: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 7: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 8: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 9: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 10: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 11: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 12: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 13: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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. •

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 14: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 15: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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).

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 16: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 17: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 18: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 19: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 20: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 21: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 22: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 23: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 24: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 25: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 26: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 27: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 28: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 29: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 30: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 31: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 32: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 33: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 34: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 35: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 36: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 37: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 38: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 39: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 40: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 41: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 42: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 43: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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**

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 44: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 45: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 46: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

Recruitment

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 47: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N/A

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 48: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N/A

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 49: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 50: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N/A

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 51: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 52: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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)

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 53: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 54: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 55: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 56: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

Trial

interruption

(Y/N)

Reasons for trial interruption

N N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 57: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N N/A

N N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 58: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N N/A

N N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 59: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 60: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N N/A

N N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 61: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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).

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 62: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 63: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

• 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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 64: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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."

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 65: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 66: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 67: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 68: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 69: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 70: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 71: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 72: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 73: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 74: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 75: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

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.

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 76: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

Discussion and interpretation of study results- by

competent authority (if available)

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 77: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N/A

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 78: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N/A

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 79: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7

Page 80: WM-390 and WM-402 N/A WM-390 and WM- N/A 15-Jun-95 402art45-paediatric-studies-docs.ema.europa.eu/GROUP P/Paracetamol... · • Child has severe tonsillo-pharyngitis: a score of 4

N/A

N/A

0901

77e1

82b3

1c62

\0.1

\Dra

ft\V

ersi

oned

On:

16-D

ec-2

011

10:2

7