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Clinical Trial Results:
Open label, multi-centre, parallel group study to compare the pharmacokinetics (PK), pharmacodynamics (PD) and safety of febuxostat between pediatric patients (>=6<18 years of age) and adults.

Summary
EudraCT number	2016-001445-61
Trial protocol	IT HU ES BG
Global end of trial date	25 Jul 2018

Results information
Results version number	v1(current)
This version publication date	14 Feb 2019
First version publication date	14 Feb 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

FLO-02

ISRCTN number

US NCT number

NCT03605212

WHO universal trial number (UTN)

Sponsor organisation name

Menarini Ricerche S.p.A.

Sponsor organisation address

Via Sette Santi 1, Florence, Italy, 50131

Public contact

Corporate Director of Clinical Sciences, Menarini Ricerche S.p.A., +39 055 56809990, ACapriati@menarini-ricerche.it

Scientific contact

Corporate Director of Clinical Sciences, Menarini Ricerche S.p.A., +39 055 56809990, ACapriati@menarini-ricerche.it

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001417-PIP01-12

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

25 Jul 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Jul 2018

Global end of trial reached?

Yes

Global end of trial date

25 Jul 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

-To assess the pharmacokinetics (PK) of febuxostat in pediatric patients (≥6<18 years of age) and in adults suffering from hematological malignancies at intermediate to high risk of Tumor Lysis Syndrome. -To compare the febuxostat exposure in pediatric patients (≥6<18 years of age) with the one achieved in adults administered with a dose of 120 mg/QD.

Protection of trial subjects

If any event(s) related to the conduct of the study or the development of the IMP affected the safety of the study participants, the Sponsor and the Investigator were to take appropriate urgent safety measures to protect the patients against any immediate hazard. The CAs and IRB/IECs were to be informed forthwith about these new events and the measures taken. For patients participating in the study, Menarini Ricerche S.p.A. had stipulated an insurance policy in accordance with local regulatory requirements.

Background therapy

First cycle of cytotoxic chemotherapy for the treatment of the underlying disease (hematological malignancy) starting 2 days after start of study drug treatment.

Evidence for comparator

Actual start date of recruitment

27 Feb 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Hungary: 8

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

Italy: 11

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The first patient was screened and enrolled on 27 Feb 2017. The last patient completed the study on 16 Jul 2018. The study was conducted at 17 sites in 4 European countries.

Screening details

A total of 31 patients was screened, of whom 30 were enrolled and 28 completed the study regularly. Two enrolled patients were withdrawn from study drug treatment.

Period 1 title

Day 1

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

The study was performed according to an open design; no blinding technique was adopted.

Are arms mutually exclusive

Yes

Cohort 1_Cohort 2_Children

Arm description

Children: DAY 1 before first febuxostat dosing.

Arm type

Cohort 1_Cohort 2_Children

Investigational medicinal product name

not applicable

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Not applicable for baseline period.

Cohort 3_Cohort 4_Adolescents

Arm description

Adolescents: DAY 1 before first febuxostat dosing.

Arm type

Cohort 3_Cohort 4_Adolescents

Investigational medicinal product name

not applicable

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Not applicable for baseline period.

Adults

Arm description

Adults: DAY 1 before first febuxostat dosing.

Arm type

Adults

Investigational medicinal product name

not applicable

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Not applicable for baseline period.

Number of subjects in period 1	Cohort 1_Cohort 2_Children	Cohort 3_Cohort 4_Adolescents	Adults
Started	3	3	24
Completed	3	3	24

Period 2 title

Treatment Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

The study was performed according to an open design; no blinding technique was adopted.

Are arms mutually exclusive

Yes

Cohort 1_Cohort 2_Children

Arm description

Children (aged ≥6 - <12).

Arm type

Experimental

Investigational medicinal product name

Febuxostat 40 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cohort 1: 2x20 mg QD. Minimum treatment duration was for 7 days starting from Visit 1 (Day 1), which should have occurred 2 days prior to the planned start of first chemotherapy cycle. The Investigator was given the possibility to prolong the treatment duration up to 9 days on the basis of the chemotherapy regimen administered to the patient.

Investigational medicinal product name

Febuxostat 60 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cohort 2: 3x20 mg QD. Minimum treatment duration was for 7 days starting from Visit 1 (Day 1), which should have occurred 2 days prior to the planned start of first chemotherapy cycle. The Investigator was given the possibility to prolong the treatment duration up to 9 days on the basis of the chemotherapy regimen administered to the patient.

Cohort 3_Cohort 4_Adolescents

Arm description

Adolescents (aged ≥12 - <18).

Arm type

Experimental

Investigational medicinal product name

Febuxostat 80 mg

Investigational medicinal product code

Other name

ADENURIC® 80 mg

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cohort 3: 1x80 mg QD. Minimum treatment duration was for 7 days starting from Visit 1 (Day 1), which should have occurred 2 days prior to the planned start of first chemotherapy cycle. The Investigator was given the possibility to prolong the treatment duration up to 9 days on the basis of the chemotherapy regimen administered to the patient.

Investigational medicinal product name

Febuxostat 120 mg

Investigational medicinal product code

Other name

ADENURIC® 120 mg

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cohort 4: 1x120mg QD. Minimum treatment duration was for 7 days starting from Visit 1 (Day 1), which should have occurred 2 days prior to the planned start of first chemotherapy cycle. The Investigator was given the possibility to prolong the treatment duration up to 9 days on the basis of the chemotherapy regimen administered to the patient.

Adults

Arm description

Adults

Arm type

Experimental

Investigational medicinal product name

Febuxostat 120 mg

Investigational medicinal product code

Other name

ADENURIC® 120 mg

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1x120 mg QD. Minimum treatment duration was for 7 days starting from Visit 1 (Day 1), which should have occurred 2 days prior to the planned start of first chemotherapy cycle. The Investigator was given the possibility to prolong the treatment duration up to 9 days on the basis of the chemotherapy regimen administered to the patient.

Number of subjects in period 2	Cohort 1_Cohort 2_Children	Cohort 3_Cohort 4_Adolescents	Adults
Started	3	3	24
Completed	2	3	23
Not completed	1	0	1
Physician decision	-	-	1
Adverse event, non-fatal	1	-	-

Baseline characteristics

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Reporting group title

Cohort 1_Cohort 2_Children

Reporting group description

Children: DAY 1 before first febuxostat dosing.

Reporting group title

Cohort 3_Cohort 4_Adolescents

Reporting group description

Adolescents: DAY 1 before first febuxostat dosing.

Reporting group title

Adults

Reporting group description

Adults: DAY 1 before first febuxostat dosing.

Reporting group values	Cohort 1_Cohort 2_Children	Cohort 3_Cohort 4_Adolescents	Adults	Total
Number of subjects	3	3	24	30
Age categorical
Units: Subjects
Children (2-11 years)	3	0	0	3
Adolescents (12-17 years)	0	3	0	3
Adults (18-64 years)	0	0	14	14
From 65-84 years	0	0	10	10
Age continuous
Units: years
arithmetic mean (standard deviation)	7.33 ± 1.528	14.00 ± 1.000	60.21 ± 15.376	-
Gender categorical
Units: Subjects
Female	1	2	11	14
Male	2	1	13	16
Ethnicity
Units: Subjects
Hispanic or Latino	0	1	0	1
Not Hispanic or Latino	3	2	24	29
Race
Units: Subjects
White	3	2	23	28
other	0	1	1	2
Weight
Units: kg
arithmetic mean (standard deviation)	26.13 ± 2.043	60.47 ± 19.747	75.60 ± 15.469	-

End points

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Reporting group title

Cohort 1_Cohort 2_Children

Reporting group description

Children: DAY 1 before first febuxostat dosing.

Reporting group title

Cohort 3_Cohort 4_Adolescents

Reporting group description

Adolescents: DAY 1 before first febuxostat dosing.

Reporting group title

Adults

Reporting group description

Adults: DAY 1 before first febuxostat dosing.

Reporting group title

Cohort 1_Cohort 2_Children

Reporting group description

Children (aged ≥6 - <12).

Reporting group title

Cohort 3_Cohort 4_Adolescents

Reporting group description

Adolescents (aged ≥12 - <18).

Reporting group title

Adults

Reporting group description

Adults

Primary: Pharmacokinetic parameter: CL/F

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End point title

Pharmacokinetic parameter: CL/F ^[1]

End point description

End point type

Primary

End point timeframe

At Day 8.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the paucity of data in the minor patient population and in agreement with EMA, there was no statistical analysis. All safety data available were presented until the date of Last Patient Last Visit.

End point values	Cohort 1_Cohort 2_Children	Cohort 3_Cohort 4_Adolescents	Adults
Number of subjects analysed	0 ^[2]	0 ^[3]	0 ^[4]
Units: volume/time
arithmetic mean (standard deviation)	±	±	±

Notes
[2] - This study was prematurely terminated. No statistical analyses have been performed.
[3] - This study was prematurely terminated. No statistical analyses have been performed.
[4] - This study was prematurely terminated. No statistical analyses have been performed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events were collected during Screening, i.e. after ICF signature until DAY 1, Visit 1 before first IMP intake and specifically Treatment Emergent Signs and Symptoms (TESSs) occurring from first IMP intake at Visit 1, DAY 1 until Visit 10, DAY 14.

Adverse event reporting additional description

The safety analysis was run on the safety population (all patients who had received at least one dose of study drug). Safety variables included TESS, namely any reported AE occurred or worsened after first study drug intake or any clinically relevant change in safety laboratory parameters, physical examination, PS, 12-Lead ECG and vital signs.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Cohort 1 (40mg)

Reporting group description

Cohort 1, Children (≥6 - <12) receiving 40 mg febuxostat (2 tablets á 20 mg)

Reporting group title

Cohort 3 (80mg)

Reporting group description

Cohort 3, Adolescents (≥12 - <18) receiving 80 mg febuxostat (1 tablet Adenuric® 80 mg)

Reporting group title

Adults (120mg)

Reporting group description

Adults (≥18) receiving 120 mg febuxostat (1 tablet Adenuric® 120 mg)

Reporting group title

Overall

Reporting group description

Overall

Serious adverse events	Cohort 1 (40mg)	Cohort 3 (80mg)	Adults (120mg)	Overall
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 24 (20.83%)	6 / 30 (20.00%)
number of deaths (all causes)	1	0	0	1
number of deaths resulting from adverse events	0	0	0	0
Investigations
Enterobacter test positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Proctitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Septic shock
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 24 (4.17%)	2 / 30 (6.67%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Staphylococcal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort 1 (40mg)	Cohort 3 (80mg)	Adults (120mg)	Overall
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	20 / 24 (83.33%)	26 / 30 (86.67%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	1
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Thrombophlebitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 24 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	1	0	2
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Facial pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Inflammation
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 24 (8.33%)	2 / 30 (6.67%)
occurrences all number	0	0	2	2
Oedema peripheral
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 24 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	1	0	2
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 24 (12.50%)	4 / 30 (13.33%)
occurrences all number	1	0	3	4
Respiratory, thoracic and mediastinal disorders
Bronchospasm
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	1
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Epistaxis
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 24 (4.17%)	3 / 30 (10.00%)
occurrences all number	3	0	1	4
Hiccups
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Psychiatric disorders
Depression
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	1
Hallucination
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Investigations
ALT increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
AST increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
BP increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Blood triglycerides increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Hemoglobin decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	2	0	0	2
Neutrophil count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Platelet count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	2	0	0	2
White blood cell (WBC) count decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 24 (8.33%)	4 / 30 (13.33%)
occurrences all number	1	1	2	4
Cardiac disorders
Arrhythmia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Extrasystoles
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	1
Headache
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 24 (16.67%)	6 / 30 (20.00%)
occurrences all number	1	2	4	7
Language disorder
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	4 / 24 (16.67%)	6 / 30 (20.00%)
occurrences all number	2	0	4	6
Lymphopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 24 (12.50%)	3 / 30 (10.00%)
occurrences all number	0	0	3	3
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 24 (8.33%)	2 / 30 (6.67%)
occurrences all number	0	0	2	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	4 / 24 (16.67%)	6 / 30 (20.00%)
occurrences all number	2	0	4	6
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	2	0	0	2
Abdominal rigidity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Anorectal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Aphthous ulcer
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Constipation
subjects affected / exposed	1 / 3 (33.33%)	3 / 3 (100.00%)	4 / 24 (16.67%)	8 / 30 (26.67%)
occurrences all number	1	3	5	9
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 24 (16.67%)	4 / 30 (13.33%)
occurrences all number	0	0	5	5
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Faeces soft
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Gingival swelling
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Hematemesis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Hematochezia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Lip pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Nausea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 24 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	1	0	2
Vomiting
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 24 (8.33%)	4 / 30 (13.33%)
occurrences all number	4	0	2	6
Skin and subcutaneous tissue disorders
Cold sweat
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Erythema
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Rash
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	1
Skin discolouration
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 24 (8.33%)	3 / 30 (10.00%)
occurrences all number	0	1	2	3
Limb discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	1
Pain in extremity
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Temporomandibular joint syndrome
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 24 (0.00%)	2 / 30 (6.67%)
occurrences all number	1	1	0	2
Infections and infestations
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1
Fluid retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 24 (8.33%)	2 / 30 (6.67%)
occurrences all number	0	0	2	2
Hyperglycaemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 24 (4.17%)	4 / 30 (13.33%)
occurrences all number	1	2	1	4
Hyperkalaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Hyperphosphataemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	0	1	0	1
Hypo HDL cholesterolaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 24 (0.00%)	1 / 30 (3.33%)
occurrences all number	1	0	0	1
Hypocalcaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 24 (4.17%)	2 / 30 (6.67%)
occurrences all number	1	0	1	2
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 24 (4.17%)	1 / 30 (3.33%)
occurrences all number	0	0	1	1

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Were there any global substantial amendments to the protocol? Yes

02 Feb 2017

Besides others, clarification that UA analyses in blood sample safety tests could be done in both specimen, serum or plasma, with the same normal reference ranges.

03 Feb 2017

Country specific Protocol Amendment for Hungary clarifying that the exclusion or withdrawal of adult and pediatric patients with severe renal dysfunction will be based on the cut off of the CLcr < 30 mL/min and < 60 mL/min/1.73 m2, respectively.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Per EMA waiver, the Sponsor early stopped the study on 25July2018 because febuxostat was of no benefit in TLS prevention in minors over existing treatments. Adverse Events are reported, primary endpoint data are not reported due to paucity of data.

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Clinical trials

Clinical Trial Results:
Open label, multi-centre, parallel group study to compare the pharmacokinetics (PK), pharmacodynamics (PD) and safety of febuxostat between pediatric patients (>=6<18 years of age) and adults.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

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End points

Primary: Pharmacokinetic parameter: CL/F

Primary: Pharmacokinetic parameter: CL/F

Adverse events

Adverse events

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: Open label, multi-centre, parallel group study to compare the pharmacokinetics (PK), pharmacodynamics (PD) and safety of febuxostat between pediatric patients (>=6<18 years of age) and adults.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Pharmacokinetic parameter: CL/F

Primary: Pharmacokinetic parameter: CL/F

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Open label, multi-centre, parallel group study to compare the pharmacokinetics (PK), pharmacodynamics (PD) and safety of febuxostat between pediatric patients (>=6<18 years of age) and adults.