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Clinical Trial Results:
A multicentre, randomised, double-blind, parallel group study on the therapeutic efficacy and safety of Febuxostat (taken once daily) and the therapeutic efficacy and safety of Allopurinol on serum urate concentration in subjects suffering from hyperuricemia and gout.

Summary
EudraCT number	2012-001858-25
Trial protocol	GR IT ES BG
Global end of trial date	02 Jul 2015

Results information
Results version number	v1(current)
This version publication date	21 Mar 2018
First version publication date	21 Mar 2018
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

MEIN/11/FEB-GOU/001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Menarini International Operations Luxemburg S.A.

Sponsor organisation address

1, Avenue de la Gare, Luxembourg, Luxembourg, L-1611

Public contact

Medical Scientific Management, Menarini International Operations Luxemburg S.A., 00352 264976,

Scientific contact

Menarini Corporate Medical Department, A. Menarini Industrie Farmaceutiche Riunite S.A., 0039 05556801,

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

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?

Analysis stage

Final

Date of interim/final analysis

20 Dec 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

02 Jul 2015

Global end of trial reached?

Yes

Global end of trial date

02 Jul 2015

Was the trial ended prematurely?

Main objective of the trial

The primary study objective is to determine whether Febuxostat 80 mg, given once a day, is better than Allopurinol 300 mg/die considering the proportion of subjects, at visit 1 (week 4), whose serum urate concentrations will be below 6 mg/dL (357 µmol/L).

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinky, Good Clinical Practice (GCP) guidelines and local law requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Apr 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 37

Country: Number of subjects enrolled

Spain: 44

Country: Number of subjects enrolled

Bulgaria: 115

Country: Number of subjects enrolled

Greece: 2

Country: Number of subjects enrolled

Romania: 62

Country: Number of subjects enrolled

Italy: 70

Worldwide total number of subjects

330

EEA total number of subjects

330

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)

249

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 59 investigational study sites in 6 European countries (16 in Italy, 13 in Bulgaria, 13 in Romania, 9 in Poland, 7 in Spain and 1 in Greece). FPI: 04 June 2013 - LPO: 02 July 2015 Phase IV Treatment duration 24 weeks

Screening details

Eligible subjects underwent a 14-day run-in/wash-out period with placebo to evaluate subjects compliance. Subjects with placebo compliance below 60% were not to be randomised. Qualified subjects were randomised to Febuxostat 80 mg or Allopurinol 300 mg.

Period 1 title

Period 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

The blinding procedure is performed by the over encapsulation technique, that will guarantee the maintenance of blind conditions. The tablets of the study drug or the comparator will be placed in hard gelatine capsules in order to obtain that the three pharmaceutical dosage forms will have the same appearance.

Are arms mutually exclusive

Yes

Febuxostat 80 mg

Arm description

Febuxostat 80 mg given once a day. Dosage form is Oral capsules as result of the over encapsulation of the 80 mg oral tablets. Treatment period of 4 weeks +/- 4 days.

Arm type

Experimental

Investigational medicinal product name

Febuxostat 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 80 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Allopurinol 300 mg

Arm description

Allopurinol 300 mg given once a day. Dosage form is Oral capsules as result of the over encapsulation of three 100 mg oral tablets. Treatment period of 4 weeks +/- 4 days.

Arm type

Active comparator

Investigational medicinal product name

Allopurinol 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 300 mg once a day. Three oral tablets of 100 mg administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Number of subjects in period 1	Febuxostat 80 mg	Allopurinol 300 mg
Started	167	163
Completed	143	140
Not completed	24	23
non compliance treatment	1	1
Adverse event, serious fatal	1	2
Consent withdrawn by subject	2	2
death	1	-
Protocol deviation	16	16
not specified	3	2

Period 2 title

Period 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Febuxostat 80 mg/Febuxostat 80 mg

Arm description

Patients coming from Period 1 (4 weeks of Febuxostat 80 mg) and with serum urate < di 6 mg/dl, continue same treatment for further 4 weeks +/- 4 days. Febuxostat 80 mg given once a day. Dosage form is Oral capsules as result of the over encapsulation of the 80 mg oral tablets.

Arm type

Experimental

Investigational medicinal product name

Febuxostat 80mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 80 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Febuxostat 80 mg/Febuxostat 120 mg

Arm description

Patients coming from Period 1 (4 weeks of Febuxostat 80 mg) and with serum urate >= di 6 mg/dl, shift treatment to Febuxostat 120mg for further 4 weeks +/- 4 days. Febuxostat 120 mg is given once a day. Dosage form is oral capsules as result of the over encapsulation of the 120 mg oral tablets.

Arm type

not a pure line

Investigational medicinal product name

Febuxostat 120 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 120 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Investigational medicinal product name

Febuxostat 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet, Capsule, hard

Routes of administration

Buccal use

Dosage and administration details

Dosage 80 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Allopurinol 300 mg/Allopurinol 300 mg

Arm description

Patients coming from Period 1 (4 weeks of Allopurinol 300 mg) and with serum urate < di 6 mg/dl, continue treatment with Allopurinol 300 mg for further 4 weeks +/- 4 days.Allopurinol 300 mg is given once a day. Dosage form is oral capsules as result of the over encapsulation of three 100 mg oral tablets. Treatment period of 4 weeks +/- 4 days.

Arm type

Active comparator

Investigational medicinal product name

Allopurinol 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 300 mg once a day. Three oral tablets of 100 mg administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Allopurinol 300 mg/Febuxostat 80 mg

Arm description

Patients coming from Period 1 (4 weeks of Allopurinol 300 mg) and with serum urate >= di 6 mg/dl, shift treatment to Febuxostat 80 mg for further 4 weeks +/- 4 days. Febuxosta 80 mg given once a day. Dosage form is oral capsules as result of the over encapsulation of 80 mg oral tablets.

Arm type

not a pure line

Investigational medicinal product name

Febuxostat 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 80 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Investigational medicinal product name

Allopurinol 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 300 mg once a day. Three oral tablets of 100 mg administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Number of subjects in period 2	Febuxostat 80 mg/Febuxostat 80 mg	Febuxostat 80 mg/Febuxostat 120 mg	Allopurinol 300 mg/Allopurinol 300 mg	Allopurinol 300 mg/Febuxostat 80 mg
Started	97	46	90	50
Completed	94	43	87	49
Not completed	3	3	3	1
non compliance treatment	1	-	-	-
Adverse event, serious fatal	-	1	1	1
Consent withdrawn by subject	-	1	-	-
Lost to follow-up	1	-	1	-
Protocol deviation	1	-	1	-
not specified	-	1	-	-

Period 3 title

Period 3

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Febuxostat 80 mg pure line

Arm description

Patients in this arm have always taken Febuxostat 80 mg during the previous 8 weeks of treatment and are randomized to take the same treatment in the next 16 weeks till the end of the study. Febuxostat 80 mg given once a day. Dosage form are oral capsules as results of the over encapsulation of the 80 mg oral tablets.

Arm type

Experimental

Investigational medicinal product name

Febuxostat 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 80 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Febuxostat 80 mg/Febuxostat 120 mg

Arm description

Patients have previously taken during the study Febuxostat 80 mg (4 weeks) and Febuxostat 120 mg (4 weeks). They are now randomized to continue Febuxostat 120 mg treatment for 16 weeks, till the end of the study. Febuxostat 120 mg is given once a day. Dosage form is oral capsules as result of the over encapsulation of the 120 mg oral tablets.

Arm type

not a pure line

Investigational medicinal product name

Febuxostat 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 80 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Investigational medicinal product name

Febuxostat 120 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 120 mg once a day. Coated tablets administered over encapsulated by hard gelatin capsule as result of the blinding treatment

Allopurinol 300 pure line

Arm description

Patients in this arm have always taken Allopurinol 300 mg during the previous 8 weeks of treatment and are randomized to take the same treatment in the next 16 weeks till the end of the study. Allopurinol 300 mg given once a day. Dosage form are oral capsules as results of the over encapsulation of three 100 mg oral tablets.

Arm type

Active comparator

Investigational medicinal product name

Allopurinol 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 300 mg once a day. Three oral tablets of 100 mg administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Allopurinol 300 mg/Febuxostat 80 mg

Arm description

Patients have previously taken during the study Allopurinol 300 mg (4 weeks) and Febuxostat 80 mg (4 weeks). If their serum urate is < 6 mg/dl, they are now randomized to continue Febuxostat 80 mg treatment for 16 weeks, till the end of the study. Febuxostat 80 mg is given once a day. Dosage form is oral capsules as result of the over encapsulation of the 80 mg oral tablets.

Arm type

not a pure line

Investigational medicinal product name

Febuxostat 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet, Capsule, hard

Routes of administration

Buccal use

Dosage and administration details

Dosage 80 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Investigational medicinal product name

Allopurinol 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 300 mg once a day. Three oral tablets of 100 mg administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Allopurinol 300 mg/Febuxostat 80 mg/Febuxostat 120

Arm description

Patients have previously taken during the study Allopurinol 300 mg (4 weeks) and Febuxostat 80 mg (4 weeks). If their serum urate is >= 6 mg/dl, they shift treatment to Febuxostat 120 mg for 16 weeks, till the end of the study. Febuxostat 120 mg is given once a day. Dosage form is oral capsules as result of the over encapsulation of the 120 mg oral tablets.

Arm type

not a pure line

Investigational medicinal product name

Allopurinol 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 300 mg once a day. Three oral tablets of 100 mg administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Investigational medicinal product name

Febuxostat 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 80 mg once a day. Coated tablets administered over encapsulated by a hard gelatin capsule as result of the blinding treatment.

Investigational medicinal product name

Febuxostat 120 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Coated tablet

Routes of administration

Buccal use

Dosage and administration details

Dosage 120 mg once a day. Coated tablets administered over encapsulated by hard gelatin capsule as result of the blinding treatment

Number of subjects in period 3	Febuxostat 80 mg pure line	Febuxostat 80 mg/Febuxostat 120 mg	Allopurinol 300 pure line	Allopurinol 300 mg/Febuxostat 80 mg	Allopurinol 300 mg/Febuxostat 80 mg/Febuxostat 120
Started	94	43	87	27	22
Completed	94	43	87	27	22

Baseline characteristics

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Reporting group title

Febuxostat 80 mg

Reporting group description

Febuxostat 80 mg given once a day. Dosage form is Oral capsules as result of the over encapsulation of the 80 mg oral tablets. Treatment period of 4 weeks +/- 4 days.

Reporting group title

Allopurinol 300 mg

Reporting group description

Allopurinol 300 mg given once a day. Dosage form is Oral capsules as result of the over encapsulation of three 100 mg oral tablets. Treatment period of 4 weeks +/- 4 days.

Reporting group values	Febuxostat 80 mg	Allopurinol 300 mg	Total
Number of subjects	167	163	330
Age categorical
Units: Subjects
Adults (18-64 years)	128	121	249
From 65-84 years	38	39	77
85 years and over	1	3	4
Age continuous
Units: years
arithmetic mean (standard deviation)	56.17 ± 11.49	57.42 ± 12.29	-
Gender categorical
Units: Subjects
Female	151	145	296
Male	16	18	34

Subject analysis set title

Modified Safety/Febuxostat 80 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Modified Safety population includes all enrolled subjects who received at least one dose of placebo treatment during the run in/wash out period and took at least a dose of double-blind, randomized treatment.

Subject analysis set title

Modified Safety/Allopurinol 300 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Full Analysis Set/Febuxostat 80 mg

Subject analysis set type

Full analysis

Subject analysis set description

The FAS population includes all randomized subjects, who received at least one dose of study medication (including placebo) and with at least one assessment after visit 0 (Day 0) of serum urate.

Subject analysis set title

Full Analysis Set/Allopurinol 300 mg

Subject analysis set type

Full analysis

Subject analysis set description

The FAS population includes all randomized subjects, who received at least one dose of study medication (including placebo) and with at least one assessment after visit 0 (Day 0) of serum urate.

Subject analysis set title

PP Population/Febuxostat 80 mg

Subject analysis set type

Per protocol

Subject analysis set description

Include all subjects in the FAS population without any major protocol violation.

Subject analysis set title

PP Population/Allopurinol 300 mg

Subject analysis set type

Per protocol

Subject analysis set description

Include all subjects in the FAS population without any major protocol violation.

Subject analysis sets values	Modified Safety/Febuxostat 80 mg	Modified Safety/Allopurinol 300 mg	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg	PP Population/Febuxostat 80 mg	PP Population/Allopurinol 300 mg
Number of subjects	167	162	150	148	139	137
Age categorical
Units: Subjects
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	56.17 ± 11.49	57.34 ± 12.28	55.59 ± 11.20	57.14 ± 12.21	55.08 ± 11.20	57.02 ± 12.22
Gender categorical
Units: Subjects
Female	16	18	11	14	9	12
Male	151	144	139	134	130	125

End points

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Reporting group title

Febuxostat 80 mg

Reporting group description

Febuxostat 80 mg given once a day. Dosage form is Oral capsules as result of the over encapsulation of the 80 mg oral tablets. Treatment period of 4 weeks +/- 4 days.

Reporting group title

Allopurinol 300 mg

Reporting group description

Allopurinol 300 mg given once a day. Dosage form is Oral capsules as result of the over encapsulation of three 100 mg oral tablets. Treatment period of 4 weeks +/- 4 days.

Reporting group title

Febuxostat 80 mg/Febuxostat 80 mg

Reporting group description

Reporting group title

Febuxostat 80 mg/Febuxostat 120 mg

Reporting group description

Reporting group title

Allopurinol 300 mg/Allopurinol 300 mg

Reporting group description

Reporting group title

Allopurinol 300 mg/Febuxostat 80 mg

Reporting group description

Reporting group title

Febuxostat 80 mg pure line

Reporting group description

Reporting group title

Febuxostat 80 mg/Febuxostat 120 mg

Reporting group description

Reporting group title

Allopurinol 300 pure line

Reporting group description

Reporting group title

Allopurinol 300 mg/Febuxostat 80 mg

Reporting group description

Reporting group title

Allopurinol 300 mg/Febuxostat 80 mg/Febuxostat 120

Reporting group description

Subject analysis set title

Modified Safety/Febuxostat 80 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Modified Safety/Allopurinol 300 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Full Analysis Set/Febuxostat 80 mg

Subject analysis set type

Full analysis

Subject analysis set description

The FAS population includes all randomized subjects, who received at least one dose of study medication (including placebo) and with at least one assessment after visit 0 (Day 0) of serum urate.

Subject analysis set title

Full Analysis Set/Allopurinol 300 mg

Subject analysis set type

Full analysis

Subject analysis set description

The FAS population includes all randomized subjects, who received at least one dose of study medication (including placebo) and with at least one assessment after visit 0 (Day 0) of serum urate.

Subject analysis set title

PP Population/Febuxostat 80 mg

Subject analysis set type

Per protocol

Subject analysis set description

Include all subjects in the FAS population without any major protocol violation.

Subject analysis set title

PP Population/Allopurinol 300 mg

Subject analysis set type

Per protocol

Subject analysis set description

Include all subjects in the FAS population without any major protocol violation.

Primary: Percentage of subjects with sUA < 6 mg/dL after 4 week treatment

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End point title

Percentage of subjects with sUA < 6 mg/dL after 4 week treatment

End point description

The primary objective of the study was to determine whether Febuxostat 80 mg, given once a day, was more effective than Allopurinol 300 mg/day considering the proportion of subjects, at visit 1 (week 4), whose serum urate concentrations was below 6 mg/dl (357 µmol/L).

End point type

Primary

End point timeframe

4 weeks of treatment, from Visit 0 (randomization visit) to Visit 1 (4 weeks +/- 4 days).

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg	PP Population/Febuxostat 80 mg	PP Population/Allopurinol 300 mg
Number of subjects analysed	150	148	139	137
Units: number of patients SUA < 6	102	94	98	91

Febuxostat 80mg vs Allopurinol300 mg FAS populatio

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg and with Sua levels < 6.0 mg/dl after 4 weeks treatment. Analysis performed in the FAS population

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

298

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.414 ^[1]

Method

Fisher exact

Parameter type

Risk difference (RD)

Point estimate

4.49

Confidence interval

level

95%

sides

2-sided

lower limit

-6.28

upper limit

15.25

Notes
[1] - Not statistically significant (p>0.05)

Febuxostat 80mg vs Allopurinol 300mg PP population

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg and with Sua levels < 6.o mg/dl after 4 weeks treatment. Analysis performed in the PP population

Comparison groups

PP Population/Allopurinol 300 mg v PP Population/Febuxostat 80 mg

Number of subjects included in analysis

276

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.465 ^[2]

Method

Fisher exact

Parameter type

Risk difference (RD)

Point estimate

4.08

Confidence interval

level

95%

sides

2-sided

lower limit

-6.28

upper limit

15.04

Notes
[2] - Not statistically significant (p>0.05)

Secondary: Percentage of subjects with sUA level <6 mg/dL after 8 weeks treatment

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End point title

Percentage of subjects with sUA level <6 mg/dL after 8 weeks treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day vs Allopurinol 300 mg/day, given after a four-week treatment, in lowering serum urate concentration below 6 mg/dl at visit 2 (week 8 after randomization).

End point type

Secondary

End point timeframe

8 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	97	90
Units: number of patients	83	71

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg and with SUA levels < 6.0 mg/dl after 8 weeks of treatment.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.231 ^[3]

Method

Fisher exact

Confidence interval

Notes
[3] - Not statistically significant (p>0.05)

Secondary: Percentage of subjects with sUA < 6 mg/dL after 12 week treatment

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End point title

Percentage of subjects with sUA < 6 mg/dL after 12 week treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day vs Allopurinol 300 mg/day in lowering serum urate concentration below 6 mg/dl at visit 3 (12 weeks after randomization).

End point type

Secondary

End point timeframe

12 weeks treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: number of patients	77	66

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg and with SUA levels < 6.0 mg/dl after 12 weeks of treatment.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.317 ^[4]

Method

Fisher exact

Confidence interval

Notes
[4] - Not statistically significant (p>0.05)

Secondary: Percentage of subjects with sUA < 6 mg/dL after 16 week treatment

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End point title

Percentage of subjects with sUA < 6 mg/dL after 16 week treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day vs Allopurinol 300 mg/day in lowering serum urate concentration below 6 mg/dl at visit 4 (16 weeks after randomization).

End point type

Secondary

End point timeframe

16 week of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: number of patients	79	66

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg and with SUA levels < 6.0 mg/dl after 16 weeks of treatment.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.168 ^[5]

Method

Fisher exact

Confidence interval

Notes
[5] - Not statistically significant (p>0.05)

Secondary: Percentage of subjects with sUA < 6 mg/dL after 20 weeks treatment

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End point title

Percentage of subjects with sUA < 6 mg/dL after 20 weeks treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day vs Allopurinol 300 mg/day in lowering serum urate concentration below 6 mg/dl at visit 5 (20 weeks after randomization).

End point type

Secondary

End point timeframe

20 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: number of patients	75	64

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg and with SUA levels < 6.0 mg/dl after 20 weeks of treatment.

Comparison groups

Full Analysis Set/Allopurinol 300 mg v Full Analysis Set/Febuxostat 80 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.321 ^[6]

Method

Fisher exact

Confidence interval

Notes
[6] - Not statistically significant (p>0.05)

Secondary: Percentage of subjects with sUA < 6 mg/dL after 24 week treatment

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End point title

Percentage of subjects with sUA < 6 mg/dL after 24 week treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day vs Allopurinol 300 mg/day in lowering serum urate concentration below 6 mg/dl at visit 6 (24 weeks after randomization).

End point type

Secondary

End point timeframe

24 week of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: number of patients	75	65

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg and with SUA levels < 6.0 mg/dl after 24 weeks of treatment.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.415 ^[7]

Method

Fisher exact

Confidence interval

Notes
[7] - Not statistically significant (p>0.05)

Secondary: Percentage of patients with last 3 SUA levels < 6 mg/dl at 16,20 and 24 weeks

Top of page

End point title

Percentage of patients with last 3 SUA levels < 6 mg/dl at 16,20 and 24 weeks

End point description

To evaluate the efficacy of Febuxostat 80 mg/day versus Allopurinol 300 mg/day considering the number of subjects with at least 3 serum urate levels (at 16, 20 and 24 weeks from the treatment start) < 6.0 mg/dl within each of the three subgroups of subjects defined by baseline urate concentration (< 9.0 mg/dl, >= 9.0 mg/dl but < 10 mg/dl, >= 10 mg/dl)

End point type

Secondary

End point timeframe

From 16 weeks to 24 weeks after randomization (Visit 0). A total of 8 weeks of timeframe evaluation

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	89	78
Units: number of patients
Baseline SUA levels < 9 mg/dl	31	22
Baseline SUA levels >= 9 and < 10 mg/dl	23	12
Baseline SUA levels >= 10	9	13

Febuxostat vs Allopurinol with SUA < 9 mg/dl

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg having both SUA levels < 9 mg/dl at baseline and at least 3 SUA levels < 6.0 mg/dl at 16,20 and 24 weeks.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.061 ^[8]

Method

Fisher exact

Confidence interval

Notes
[8] - Not statistically significant (p>0.05)

Feb vs Allo with SUA >= 9 and <10 mg/dl

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg having both SUA levels >= 9 and < 10 mg/dl at baseline and at least 3 SUA levels < 6.0 mg/dl at 16,20 and 24 weeks.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.27 ^[9]

Method

Fisher exact

Confidence interval

Notes
[9] - Not statistically significant (p>0.05)

Febuxostat vs Allopurinol with SUA >= 10 mg/dl

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg having both SUA levels >= 10 mg/dl at baseline and at least 3 SUA levels < 6.0 mg/dl at 16,20 and 24 weeks.

Comparison groups

Full Analysis Set/Allopurinol 300 mg v Full Analysis Set/Febuxostat 80 mg

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.525 ^[10]

Method

Fisher exact

Confidence interval

Notes
[10] - Not statistically significant (p>0.05)

Febuxostat 80 mg vs Allopurinol 300 mg overall

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg having at least 3 SUA levels < 6.0 mg/dl at 16,20 and 24 weeks.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.152 ^[11]

Method

Fisher exact

Confidence interval

Notes
[11] - Not statistically significant (p>0.05)

Secondary: Mean values reduction from baseline in SUA levels after 4 weeks treatment

Top of page

End point title

Mean values reduction from baseline in SUA levels after 4 weeks treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day versus Allopurinol 300 mg/day considering, for each treatment arm, the mean decrease from baseline of serum urate levels after 4 weeks (Visit 1) of drug intake.

End point type

Secondary

End point timeframe

4 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	150	148
Units: mg/dl
arithmetic mean (standard deviation)	-4.36 ± 1.72	-3.66 ± 1.65

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean change from baseline values of Sua levels after 4 weelks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

298

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[12]

Method

ANCOVA

Confidence interval

Notes
[12] - Statistically significant (p<0.05)

Secondary: Mean values reduction from baseline in SUA levels after 8 weeks treatment

Top of page

End point title

Mean values reduction from baseline in SUA levels after 8 weeks treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day versus Allopurinol 300 mg/day considering, for each treatment arm, the mean decrease from baseline of serum urate levels after 8 weeks (Visit 2) of drug intake.

End point type

Secondary

End point timeframe

8 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	97	90
Units: mg/dl
arithmetic mean (standard deviation)	-4.66 ± 1.541	-4.26 ± 1.542

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean change from baseline values of Sua levels after 8 weelks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025 ^[13]

Method

ANCOVA

Confidence interval

Notes
[13] - Statistically significant (p<0.05)

Secondary: Mean values reduction from baseline in SUA levels after 12 weeks treatment

Top of page

End point title

Mean values reduction from baseline in SUA levels after 12 weeks treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day versus Allopurinol 300 mg/day considering, for each treatment arm, the mean decrease from baseline of serum urate levels after 12 weeks (Visit 3) of drug intake.

End point type

Secondary

End point timeframe

12 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: mg/dl
arithmetic mean (standard deviation)	-4.79 ± 1.461	-4.14 ± 1.636

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean change from baseline values of Sua levels after 12 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[14]

Method

ANCOVA

Confidence interval

Notes
[14] - Statistically significant (p<0.05)

Secondary: Mean values reduction from baseline in SUA levels after 16 weeks treatment

Top of page

End point title

Mean values reduction from baseline in SUA levels after 16 weeks treatment

End point description

End point type

Secondary

End point timeframe

16 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: mg/dl
arithmetic mean (standard deviation)	-4.75 ± 1.523	-4.12 ± 1.66

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean change from baseline values of Sua levels after 16 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[15]

Method

ANCOVA

Confidence interval

Notes
[15] - Statistically significant (p<0.05)

Secondary: Mean values reduction from baseline in SUA levels after 20 weeks treatment

Top of page

End point title

Mean values reduction from baseline in SUA levels after 20 weeks treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day versus Allopurinol 300 mg/day considering, for each treatment arm, the mean decrease from baseline of serum urate levels after 20 weeks (Visit 5) of drug intake.

End point type

Secondary

End point timeframe

20 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: mg/dl
arithmetic mean (standard deviation)	-4.49 ± 1.867	-4.09 ± 1.655

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean change from baseline values of Sua levels after 20 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.075 ^[16]

Method

ANCOVA

Confidence interval

Notes
[16] - Not statistically significant (p>0.05)

Secondary: Mean values reduction from baseline in SUA levels after 24 weeks treatment

Top of page

End point title

Mean values reduction from baseline in SUA levels after 24 weeks treatment

End point description

End point type

Secondary

End point timeframe

24 weeks of treatment (end of study)

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: mg/dl
arithmetic mean (standard deviation)	-4.46 ± 1.97	-4.03 ± 1.764

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean change from baseline values of Sua levels after 24 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.083 ^[17]

Method

ANCOVA

Confidence interval

Notes
[17] - Not statistically significant (p>0.05)

Secondary: Mean percentage reduction from baseline in SUA levels after 4 weeks treatment

Top of page

End point title

Mean percentage reduction from baseline in SUA levels after 4 weeks treatment

End point description

To evaluate the efficacy of Febuxostat 80 mg/day versus Allopurinol 300 mg/day considering, for each treatment arm, the mean percentage decrease from baseline of serum urate levels after 4 weeks (Visit 1) of drug intake.

End point type

Secondary

End point timeframe

4 week of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	150	148
Units: percent change
arithmetic mean (standard deviation)	-45.50 ± 17.50	-38.49 ± 15.45

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean percent change from baseline values of Sua levels after 4 weelks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

298

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003 ^[18]

Method

ANOVA

Confidence interval

Notes
[18] - Statistically significant (p<0.05)

Secondary: Mean percentage reduction from baseline in SUA levels after 8 weeks treatment

Top of page

End point title

Mean percentage reduction from baseline in SUA levels after 8 weeks treatment

End point description

End point type

Secondary

End point timeframe

8 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	97	90
Units: percent change
arithmetic mean (standard deviation)	-49.75 ± 15.317	-44.94 ± 13.715

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean percent change from baseline values of Sua levels after 8 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017 ^[19]

Method

ANOVA

Confidence interval

Notes
[19] - Statistically significant (p<0.05)

Secondary: Mean percentage reduction from baseline in SUA levels after 12 weeks treatment

Top of page

End point title

Mean percentage reduction from baseline in SUA levels after 12 weeks treatment

End point description

End point type

Secondary

End point timeframe

12 weeks treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: percent change
arithmetic mean (standard deviation)	-51.49 ± 14.911	-43.43 ± 14.938

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean percent change from baseline values of Sua levels after 12 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006 ^[20]

Method

ANOVA

Confidence interval

Notes
[20] - Statistically significant (p<0.05)

Secondary: Mean percentage reduction from baseline in SUA levels after 16 weeks treatment

Top of page

End point title

Mean percentage reduction from baseline in SUA levels after 16 weeks treatment

End point description

End point type

Secondary

End point timeframe

16 weeks treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: percent change
arithmetic mean (standard deviation)	-51.13 ± 15.695	-43.45 ± 15.244

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean percent change from baseline values of Sua levels after 16 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[21]

Method

ANOVA

Confidence interval

Notes
[21] - Statistically significant (p<0.05)

Secondary: Mean percentage reduction from baseline in SUA levels after 20 weeks treatment

Top of page

End point title

Mean percentage reduction from baseline in SUA levels after 20 weeks treatment

End point description

End point type

Secondary

End point timeframe

20 weeks treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: percent change
arithmetic mean (standard deviation)	-48.24 ± 19.041	-42.97 ± 15.036

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean percent change from baseline values of Sua levels after 20 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.047 ^[22]

Method

ANOVA

Confidence interval

Notes
[22] - Statistically significant (p<0.05)

Secondary: Mean percentage reduction from baseline in SUA levels after 24 weeks treatment

Top of page

End point title

Mean percentage reduction from baseline in SUA levels after 24 weeks treatment

End point description

End point type

Secondary

End point timeframe

24 weeks of treatment (end of study)

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: percent change
arithmetic mean (standard deviation)	-48.06 ± 20.163	-42.37 ± 16.136

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Comparison between Febuxostat 80 mg and Allopurinol 300 mg in the mean percent change from baseline values of Sua levels after 24 weeks treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.045 ^[23]

Method

ANOVA

Confidence interval

Notes
[23] - Statistically significant (p<0.05)

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 4 week treatment

Top of page

End point title

Percentage of subjects with sUA < 5 mg/dL after 4 week treatment

End point description

To determine whether Febuxostat 80 mg/day, was more effective than Allopurinol 300 mg/day considering the proportion of subjects, at visit 1 (week 4), whose serum urate concentrations was below 5 mg/dl.

End point type

Post-hoc

End point timeframe

4 weeks treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	143	141
Units: number of patients SUA < 5	66	33

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Percentage of patients with serum urate levels <5 mg/dl after 4 weeks of treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

284

Analysis specification

Post-hoc

Analysis type

superiority

P-value

< 0.0001 ^[24]

Method

Fisher exact

Confidence interval

Notes
[24] - Statistically significant (p<0.005)

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 8 week treatment

Top of page

End point title

Percentage of subjects with sUA < 5 mg/dL after 8 week treatment

End point description

To determine whether Febuxostat 80 mg/day, was more effective than Allopurinol 300 mg/day considering the proportion of subjects, at visit 2 (week 8), whose serum urate concentrations was below 5 mg/dl.

End point type

Post-hoc

End point timeframe

8 weeks treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	97	90
Units: number of patients SUA < 5	62	41

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Percentage of subjects with sUA < 5 mg/dL after 8 week treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

187

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0117 ^[25]

Method

Fisher exact

Confidence interval

Notes
[25] - Statistically significant (p<0.05)

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 12 week treatment

Top of page

End point title

Percentage of subjects with sUA < 5 mg/dL after 12 week treatment

End point description

To determine whether Febuxostat 80 mg/day, was more effective than Allopurinol 300 mg/day considering the proportion of subjects, at visit 3 (week 12), whose serum urate concentrations was below 5 mg/dl.

End point type

Post-hoc

End point timeframe

12 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: number of patients SUA < 5	62	39

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Percentage of patients with serum urate levels <5 mg/dl after 12 weeks of treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0042 ^[26]

Method

Fisher exact

Confidence interval

Notes
[26] - Statistically significant (p<0.05)

Post-hoc: Percentage of patients with Sua levels <5 mg/dl after 16 weeks of treatment

Top of page

End point title

Percentage of patients with Sua levels <5 mg/dl after 16 weeks of treatment

End point description

To determine whether Febuxostat 80 mg/day, was more effective than Allopurinol 300 mg/day considering the proportion of subjects, at visit 4 (week 16), whose serum urate concentrations was below 5 mg/dl.

End point type

Post-hoc

End point timeframe

16 weeks treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: number of patients SUA < 5	63	40

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Percentage of patients with serum urate levels <5 mg/dl after 16 weeks of treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0043 ^[27]

Method

Fisher exact

Confidence interval

Notes
[27] - Statistically significant (p<0.05)

Post-hoc: Percentage of patients with Sua levels <5 mg/dl after 20 weeks of treatment

Top of page

End point title

Percentage of patients with Sua levels <5 mg/dl after 20 weeks of treatment

End point description

To determine whether Febuxostat 80 mg/day, was more effective than Allopurinol 300 mg/day considering the proportion of subjects, at visit 5 (week 20), whose serum urate concentrations was below 5 mg/dl.

End point type

Post-hoc

End point timeframe

20 weeks of treatment

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: number of patients SUA < 5	54	37

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Percentage of patients with serum urate levels <5 mg/dl after 4 weeks of treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0449 ^[28]

Method

Fisher exact

Confidence interval

Notes
[28] - Statistically significant (p<0.05)

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 24 week treatment

Top of page

End point title

Percentage of subjects with sUA < 5 mg/dL after 24 week treatment

End point description

To determine whether Febuxostat 80 mg/day, was more effective than Allopurinol 300 mg/day considering the proportion of subjects, at visit 6 (week 24), whose serum urate concentrations was below 5 mg/dl.

End point type

Post-hoc

End point timeframe

24 weeks treatment (end of study).

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	94	87
Units: number of patients SUA < 5	61	32

Febuxostat 80 mg vs Allopurinol 300 mg

Statistical analysis description

Percentage of subjects with sUA < 5 mg/dL after 24 week treatment

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

181

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0002 ^[29]

Method

Fisher exact

Confidence interval

Notes
[29] - Statistically significant (p<0.05)

Post-hoc: Percentage of patients with last 3 SUA levels < 5 mg/dl at 16,20 and 24 weeks

Top of page

End point title

Percentage of patients with last 3 SUA levels < 5 mg/dl at 16,20 and 24 weeks

End point description

To evaluate the efficacy of Febuxostat 80 mg/day versus Allopurinol 300 mg/day considering the number of subjects with at least 3 serum urate levels (at 16, 20 and 24 weeks from the treatment start) < 5.0 mg/dl within each of the three subgroups of subjects defined by baseline urate concentration (< 9.0 mg/dl, >= 9.0 mg/dl but < 10 mg/dl, >= 10 mg/dl).

End point type

Post-hoc

End point timeframe

From 16 weeks to 24 weeks after randomization (Visit 0). A total of 8 weeks of timeframe evaluation

End point values	Full Analysis Set/Febuxostat 80 mg	Full Analysis Set/Allopurinol 300 mg
Number of subjects analysed	89	78
Units: number of patients SUA < 5
Baseline Sua levels < 9 mg/dl	22	9
Baseline SUA levels >= 9 and < 10 mg/dl	15	7
Baseline SUA levels >= 10	6	4

Febuxostat vs Allopurinol with SUA < 9 mg/dl

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg having both SUA levels < 9 mg/dl at baseline and at least 3 SUA levels < 5.0 mg/dl at 16,20 and 24 weeks

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

167

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0047 ^[30]

Method

Fisher exact

Confidence interval

Notes
[30] - Statistically significant (p<0.05)

Feb vs Allo with SUA >= 9 and <10 mg/dl

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg having both SUA levels >= 9 and < 10 mg/dl at baseline and at least 3 SUA levels < 5.0 mg/dl at 16,20 and 24 weeks.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

167

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.4032 ^[31]

Method

Fisher exact

Confidence interval

Notes
[31] - Not statistically significant (p>0.05)

Febuxostat vs Allopurinol with SUA >= 10 mg/dl

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg having both SUA levels >= 10 mg/dl at baseline and at least 3 SUA levels < 5.0 mg/dl at 16,20 and 24 weeks.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

167

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.4727 ^[32]

Method

Fisher exact

Confidence interval

Notes
[32] - Not statistically significant (p>0.05)

Febuxostat 80 mg vs Allopurinol 300 mg overall

Statistical analysis description

Difference between number of patients taking Febuxostat 80 mg and patient taking Allopurinol 300 mg having at least 3 SUA levels < 5.0 mg/dl at 16,20 and 24 weeks.

Comparison groups

Full Analysis Set/Febuxostat 80 mg v Full Analysis Set/Allopurinol 300 mg

Number of subjects included in analysis

167

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0026 ^[33]

Method

Fisher exact

Confidence interval

Notes
[33] - Statistically significant (p<0.05)

Adverse events

Top of page

Timeframe for reporting adverse events

From signing of informed consent at Visit -1 (2 weeks before treatment phase) to follow-up period of 2 weeks after the administration of the last treatment dose. Treatment duration was of 24 weeks.

Adverse event reporting additional description

AE were considered any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

Febuxostat 80 mg Modified Safety Poulation

Reporting group description

Febuxostat 80 mg given once a day. Dosage form is Oral capsules as result of the over encapsulation of the 80 mg oral tablets. Treatment period of 4 weeks +/- 4 days.

Reporting group title

Febuxostat 120 mg Modified Safety Population

Reporting group description

Reporting group title

Allopurinol 300 mg Modified Safety Population

Reporting group description

Serious adverse events	Febuxostat 80 mg Modified Safety Poulation	Febuxostat 120 mg Modified Safety Population	Allopurinol 300 mg Modified Safety Population
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 218 (2.29%)	3 / 68 (4.41%)	3 / 162 (1.85%)
number of deaths (all causes)	1	2	0
number of deaths resulting from adverse events	1	2	0
Investigations
Blood triglycerides increased
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Sudden death
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Parkinsonism
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Tonsillitis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermal cyst
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Febuxostat 80 mg Modified Safety Poulation	Febuxostat 120 mg Modified Safety Population	Allopurinol 300 mg Modified Safety Population
Total subjects affected by non serious adverse events
subjects affected / exposed	205 / 218 (94.04%)	66 / 68 (97.06%)	153 / 162 (94.44%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Parathyroid cyst
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Renal cyst
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Synovial cyst
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Vascular disorders
Contusion
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Diastolic hypertension
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Hypertension
subjects affected / exposed	2 / 218 (0.92%)	2 / 68 (2.94%)	2 / 162 (1.23%)
occurrences all number	2	2	3
Hypertensive crisis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Systolic hypertension
subjects affected / exposed	3 / 218 (1.38%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	3	1	0
Thrombophlebitis superficial
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Surgical and medical procedures
Tophus removal operation
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Weight loss diet
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
General disorders and administration site conditions
Inflammation
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	2
Influenza like illness
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Sense of oppression
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Psychiatric disorders
Libido decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Investigations
Alanine aminotransferase decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Alanine aminotransferase increased
subjects affected / exposed	62 / 218 (28.44%)	18 / 68 (26.47%)	55 / 162 (33.95%)
occurrences all number	68	23	66
Albumin urine present
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Aspartate aminotransferase increased
subjects affected / exposed	41 / 218 (18.81%)	18 / 68 (26.47%)	34 / 162 (20.99%)
occurrences all number	45	26	38
B-lymphocyte count decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Bacterial test
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	1	2	1
Bacterial test positive
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Band neutrophil percentage decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Basophil count decreased
subjects affected / exposed	3 / 218 (1.38%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	3	2	2
Basophil count increased
subjects affected / exposed	8 / 218 (3.67%)	6 / 68 (8.82%)	8 / 162 (4.94%)
occurrences all number	8	6	11
Basophil percentage decreased
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Basophil percentage increased
subjects affected / exposed	7 / 218 (3.21%)	5 / 68 (7.35%)	9 / 162 (5.56%)
occurrences all number	7	7	13
Bilirubin conjugated
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	0	1	1
Bilirubin conjugated increased
subjects affected / exposed	37 / 218 (16.97%)	16 / 68 (23.53%)	31 / 162 (19.14%)
occurrences all number	45	21	36
Bilirubin urine
subjects affected / exposed	3 / 218 (1.38%)	1 / 68 (1.47%)	2 / 162 (1.23%)
occurrences all number	3	1	2
Blood albumin decreased
subjects affected / exposed	6 / 218 (2.75%)	2 / 68 (2.94%)	5 / 162 (3.09%)
occurrences all number	6	2	6
Blood albumin increased
subjects affected / exposed	17 / 218 (7.80%)	6 / 68 (8.82%)	11 / 162 (6.79%)
occurrences all number	19	6	14
Blood alkaline phosphatase
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Blood alkaline phosphatase decreased
subjects affected / exposed	4 / 218 (1.83%)	1 / 68 (1.47%)	2 / 162 (1.23%)
occurrences all number	5	1	3
Blood alkaline phosphatase increased
subjects affected / exposed	14 / 218 (6.42%)	5 / 68 (7.35%)	10 / 162 (6.17%)
occurrences all number	17	5	13
Blood bilirubin
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	0	1	1
Blood bilirubin decreased
subjects affected / exposed	4 / 218 (1.83%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	6	0	2
Blood bilirubin increased
subjects affected / exposed	19 / 218 (8.72%)	10 / 68 (14.71%)	13 / 162 (8.02%)
occurrences all number	22	15	15
Blood bilirubin unconjugated increased
subjects affected / exposed	2 / 218 (0.92%)	8 / 68 (11.76%)	3 / 162 (1.85%)
occurrences all number	2	10	3
Blood calcium decreased
subjects affected / exposed	8 / 218 (3.67%)	6 / 68 (8.82%)	5 / 162 (3.09%)
occurrences all number	9	7	6
Blood calcium increased
subjects affected / exposed	33 / 218 (15.14%)	14 / 68 (20.59%)	17 / 162 (10.49%)
occurrences all number	42	17	21
Blood chloride decreased
subjects affected / exposed	26 / 218 (11.93%)	9 / 68 (13.24%)	18 / 162 (11.11%)
occurrences all number	28	12	21
Blood chloride increased
subjects affected / exposed	32 / 218 (14.68%)	16 / 68 (23.53%)	25 / 162 (15.43%)
occurrences all number	34	20	30
Blood cholesterol increased
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	2	0	2
Blood creatine increased
subjects affected / exposed	3 / 218 (1.38%)	4 / 68 (5.88%)	7 / 162 (4.32%)
occurrences all number	4	5	8
Blood creatine phosphokinase
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Blood creatine phosphokinase MB increased
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	0	1	1
Blood creatine phosphokinase decreased
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	1	1	1
Blood creatine phosphokinase increased
subjects affected / exposed	32 / 218 (14.68%)	9 / 68 (13.24%)	31 / 162 (19.14%)
occurrences all number	34	9	37
Blood creatinine decreased
subjects affected / exposed	3 / 218 (1.38%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	3	1	1
Blood creatinine increased
subjects affected / exposed	34 / 218 (15.60%)	14 / 68 (20.59%)	23 / 162 (14.20%)
occurrences all number	45	16	32
Blood glucose
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Blood glucose decreased
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Blood glucose increased
subjects affected / exposed	58 / 218 (26.61%)	24 / 68 (35.29%)	48 / 162 (29.63%)
occurrences all number	72	25	65
Blood lactate dehydrogenase decreased
subjects affected / exposed	6 / 218 (2.75%)	0 / 68 (0.00%)	4 / 162 (2.47%)
occurrences all number	7	0	8
Blood lactate dehydrogenase increased
subjects affected / exposed	22 / 218 (10.09%)	11 / 68 (16.18%)	20 / 162 (12.35%)
occurrences all number	28	13	24
Blood phosphorus increased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Blood potassium abnormal
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Blood potassium decreased
subjects affected / exposed	7 / 218 (3.21%)	3 / 68 (4.41%)	6 / 162 (3.70%)
occurrences all number	7	3	8
Blood potassium increased
subjects affected / exposed	29 / 218 (13.30%)	14 / 68 (20.59%)	15 / 162 (9.26%)
occurrences all number	32	14	25
Blood pressure ambulatory increased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Blood pressure diastolic increased
subjects affected / exposed	3 / 218 (1.38%)	2 / 68 (2.94%)	2 / 162 (1.23%)
occurrences all number	4	3	2
Blood pressure increased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Blood pressure systolic increased
subjects affected / exposed	6 / 218 (2.75%)	4 / 68 (5.88%)	2 / 162 (1.23%)
occurrences all number	6	5	2
Blood sodium decreased
subjects affected / exposed	15 / 218 (6.88%)	8 / 68 (11.76%)	19 / 162 (11.73%)
occurrences all number	15	11	21
Blood sodium increased
subjects affected / exposed	26 / 218 (11.93%)	17 / 68 (25.00%)	23 / 162 (14.20%)
occurrences all number	30	18	25
Blood thrombin increased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Blood thyroid stimulating hormone decreased
subjects affected / exposed	7 / 218 (3.21%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	7	1	1
Blood thyroid stimulating hormone increased
subjects affected / exposed	15 / 218 (6.88%)	4 / 68 (5.88%)	12 / 162 (7.41%)
occurrences all number	17	4	15
Blood triglycerides increased
subjects affected / exposed	52 / 218 (23.85%)	16 / 68 (23.53%)	41 / 162 (25.31%)
occurrences all number	69	18	58
Blood uric acid decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Blood uric acid increased
subjects affected / exposed	1 / 218 (0.46%)	3 / 68 (4.41%)	1 / 162 (0.62%)
occurrences all number	1	3	1
Blood urine
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Blood urine present
subjects affected / exposed	21 / 218 (9.63%)	15 / 68 (22.06%)	20 / 162 (12.35%)
occurrences all number	25	17	27
C-reactive protein increased
subjects affected / exposed	75 / 218 (34.40%)	27 / 68 (39.71%)	57 / 162 (35.19%)
occurrences all number	88	31	75
CD4 lymphocytes decreased
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	2
Calcium ionised increased
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Cells in urine
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Coagulation test abnormal
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Coagulation time shortened
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Creatinine renal clearance decreased
subjects affected / exposed	37 / 218 (16.97%)	18 / 68 (26.47%)	26 / 162 (16.05%)
occurrences all number	44	22	35
Creatinine renal clearance increased
subjects affected / exposed	21 / 218 (9.63%)	6 / 68 (8.82%)	20 / 162 (12.35%)
occurrences all number	26	6	30
Crystal urine
subjects affected / exposed	1 / 218 (0.46%)	2 / 68 (2.94%)	5 / 162 (3.09%)
occurrences all number	1	2	6
Crystal urine present
subjects affected / exposed	10 / 218 (4.59%)	8 / 68 (11.76%)	10 / 162 (6.17%)
occurrences all number	11	8	12
Electrocardiogram T wave abnormal
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Eosinophil count
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	2
Eosinophil count decreased
subjects affected / exposed	5 / 218 (2.29%)	3 / 68 (4.41%)	4 / 162 (2.47%)
occurrences all number	5	3	4
Eosinophil count increased
subjects affected / exposed	25 / 218 (11.47%)	9 / 68 (13.24%)	17 / 162 (10.49%)
occurrences all number	28	10	23
Eosinophil percentage decreased
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	2	0
Eosinophil percentage increased
subjects affected / exposed	12 / 218 (5.50%)	5 / 68 (7.35%)	10 / 162 (6.17%)
occurrences all number	13	5	12
Gamma-glutamyltransferase increased
subjects affected / exposed	42 / 218 (19.27%)	20 / 68 (29.41%)	41 / 162 (25.31%)
occurrences all number	54	23	52
Glucose urine
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Glucose urine present
subjects affected / exposed	2 / 218 (0.92%)	3 / 68 (4.41%)	3 / 162 (1.85%)
occurrences all number	2	3	3
Haematocrit abnormal
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Haematocrit decreased
subjects affected / exposed	10 / 218 (4.59%)	4 / 68 (5.88%)	21 / 162 (12.96%)
occurrences all number	12	4	26
Haematocrit increased
subjects affected / exposed	21 / 218 (9.63%)	6 / 68 (8.82%)	14 / 162 (8.64%)
occurrences all number	26	7	15
Haemoglobin abnormal
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Haemoglobin decreased
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	10 / 162 (6.17%)
occurrences all number	4	0	16
Haemoglobin increased
subjects affected / exposed	10 / 218 (4.59%)	4 / 68 (5.88%)	8 / 162 (4.94%)
occurrences all number	12	4	9
Haemoglobin urine
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	2 / 162 (1.23%)
occurrences all number	0	1	2
Haemoglobin urine present
subjects affected / exposed	9 / 218 (4.13%)	3 / 68 (4.41%)	7 / 162 (4.32%)
occurrences all number	10	3	7
High density lipoprotein decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
International normalised ratio decreased
subjects affected / exposed	16 / 218 (7.34%)	5 / 68 (7.35%)	12 / 162 (7.41%)
occurrences all number	18	6	15
International normalised ratio increased
subjects affected / exposed	5 / 218 (2.29%)	5 / 68 (7.35%)	5 / 162 (3.09%)
occurrences all number	5	6	7
LDL/HDL ratio increased
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Laboratory test abnormal
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	0	1	2
Low density lipoprotein increased
subjects affected / exposed	44 / 218 (20.18%)	22 / 68 (32.35%)	29 / 162 (17.90%)
occurrences all number	51	23	40
Lymphocyte count
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Lymphocyte count abnormal
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Lymphocyte count decreased
subjects affected / exposed	6 / 218 (2.75%)	0 / 68 (0.00%)	5 / 162 (3.09%)
occurrences all number	6	0	6
Lymphocyte count increased
subjects affected / exposed	9 / 218 (4.13%)	5 / 68 (7.35%)	11 / 162 (6.79%)
occurrences all number	11	5	11
Lymphocyte percentage decreased
subjects affected / exposed	2 / 218 (0.92%)	2 / 68 (2.94%)	3 / 162 (1.85%)
occurrences all number	2	2	3
Lymphocyte percentage increased
subjects affected / exposed	3 / 218 (1.38%)	0 / 68 (0.00%)	3 / 162 (1.85%)
occurrences all number	4	0	4
Mean cell volume decreased
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Monocyte count
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Monocyte count decreased
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	6 / 162 (3.70%)
occurrences all number	2	0	6
Monocyte count increased
subjects affected / exposed	33 / 218 (15.14%)	11 / 68 (16.18%)	29 / 162 (17.90%)
occurrences all number	42	12	31
Monocyte percentage decreased
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	1	1	0
Monocyte percentage increased
subjects affected / exposed	5 / 218 (2.29%)	6 / 68 (8.82%)	8 / 162 (4.94%)
occurrences all number	6	7	8
Neutrophil count decreased
subjects affected / exposed	12 / 218 (5.50%)	3 / 68 (4.41%)	7 / 162 (4.32%)
occurrences all number	16	4	8
Neutrophil count increased
subjects affected / exposed	18 / 218 (8.26%)	5 / 68 (7.35%)	7 / 162 (4.32%)
occurrences all number	20	5	8
Neutrophil percentage decreased
subjects affected / exposed	4 / 218 (1.83%)	2 / 68 (2.94%)	4 / 162 (2.47%)
occurrences all number	6	2	8
Neutrophil percentage increased
subjects affected / exposed	2 / 218 (0.92%)	3 / 68 (4.41%)	3 / 162 (1.85%)
occurrences all number	2	3	3
Nitrite urine present
subjects affected / exposed	4 / 218 (1.83%)	1 / 68 (1.47%)	4 / 162 (2.47%)
occurrences all number	5	1	4
Platelet count decreased
subjects affected / exposed	4 / 218 (1.83%)	1 / 68 (1.47%)	5 / 162 (3.09%)
occurrences all number	5	1	5
Platelet count increased
subjects affected / exposed	10 / 218 (4.59%)	1 / 68 (1.47%)	5 / 162 (3.09%)
occurrences all number	11	1	7
Protein C increased
subjects affected / exposed	0 / 218 (0.00%)	2 / 68 (2.94%)	2 / 162 (1.23%)
occurrences all number	0	2	2
Protein total abnormal
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Protein total decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Protein urine
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	1	1	1
Protein urine present
subjects affected / exposed	17 / 218 (7.80%)	12 / 68 (17.65%)	13 / 162 (8.02%)
occurrences all number	17	12	16
Prothrombin level decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	1	0	2
Prothrombin level increased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Prothrombin time prolonged
subjects affected / exposed	5 / 218 (2.29%)	1 / 68 (1.47%)	2 / 162 (1.23%)
occurrences all number	5	1	2
Prothrombin time shortened
subjects affected / exposed	0 / 218 (0.00%)	2 / 68 (2.94%)	1 / 162 (0.62%)
occurrences all number	0	2	1
Red blood cell count decreased
subjects affected / exposed	20 / 218 (9.17%)	13 / 68 (19.12%)	20 / 162 (12.35%)
occurrences all number	25	15	24
Red blood cell count increased
subjects affected / exposed	15 / 218 (6.88%)	6 / 68 (8.82%)	10 / 162 (6.17%)
occurrences all number	16	7	10
Red blood cell sedimentation rate increased
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Red blood cells urine
subjects affected / exposed	6 / 218 (2.75%)	1 / 68 (1.47%)	4 / 162 (2.47%)
occurrences all number	6	1	4
Red blood cells urine positive
subjects affected / exposed	19 / 218 (8.72%)	11 / 68 (16.18%)	20 / 162 (12.35%)
occurrences all number	23	11	24
Renal function test abnormal
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Specific gravity urine abnormal
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Specific gravity urine decreased
subjects affected / exposed	52 / 218 (23.85%)	26 / 68 (38.24%)	38 / 162 (23.46%)
occurrences all number	60	28	49
Specific gravity urine increased
subjects affected / exposed	34 / 218 (15.60%)	21 / 68 (30.88%)	25 / 162 (15.43%)
occurrences all number	44	24	27
Transaminases increased
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	3	0	1
Urinary casts present
subjects affected / exposed	1 / 218 (0.46%)	3 / 68 (4.41%)	4 / 162 (2.47%)
occurrences all number	2	5	4
Urinary sediment present
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	1	0	3
Urine analysis abnormal
subjects affected / exposed	6 / 218 (2.75%)	4 / 68 (5.88%)	7 / 162 (4.32%)
occurrences all number	8	4	7
Urine bilirubin increased
subjects affected / exposed	8 / 218 (3.67%)	5 / 68 (7.35%)	5 / 162 (3.09%)
occurrences all number	8	5	6
Urine ketone body
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	1	1	0
Urine ketone body present
subjects affected / exposed	15 / 218 (6.88%)	13 / 68 (19.12%)	5 / 162 (3.09%)
occurrences all number	16	14	7
Urine leukocyte esterase
subjects affected / exposed	3 / 218 (1.38%)	5 / 68 (7.35%)	1 / 162 (0.62%)
occurrences all number	3	6	1
Urine leukocyte esterase positive
subjects affected / exposed	10 / 218 (4.59%)	6 / 68 (8.82%)	13 / 162 (8.02%)
occurrences all number	11	6	15
Urine osmolarity decreased
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	2
Urine output decreased
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Urine oxalate
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Urine protein, quantitative
subjects affected / exposed	2 / 218 (0.92%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	2	1	1
Urine protein/creatinine ratio increased
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Urine transitional cells present
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	0	1	1
Urobilinogen urine
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	2 / 162 (1.23%)
occurrences all number	0	1	2
Urobilinogen urine increased
subjects affected / exposed	10 / 218 (4.59%)	3 / 68 (4.41%)	5 / 162 (3.09%)
occurrences all number	12	3	5
Weight decreased
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Weight increased
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
White blood cell agglutination present
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
White blood cell analysis abnormal
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	5 / 162 (3.09%)
occurrences all number	1	0	5
White blood cell count decreased
subjects affected / exposed	9 / 218 (4.13%)	4 / 68 (5.88%)	4 / 162 (2.47%)
occurrences all number	11	4	5
White blood cells urine
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	2	0	2
White blood cells urine positive
subjects affected / exposed	27 / 218 (12.39%)	12 / 68 (17.65%)	21 / 162 (12.96%)
occurrences all number	37	15	31
Wound healing normal
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
pH urine decreased
subjects affected / exposed	67 / 218 (30.73%)	31 / 68 (45.59%)	49 / 162 (30.25%)
occurrences all number	92	42	57
pH urine increased
subjects affected / exposed	8 / 218 (3.67%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	9	0	2
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Joint injury
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	2
Atrial fibrillation
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Atrial flutter
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Bradycardia
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Dyspnoea
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Extrasystoles
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Sinus bradycardia
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	1	1	1
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Polyneuropathy
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 218 (0.46%)	2 / 68 (2.94%)	3 / 162 (1.85%)
occurrences all number	1	2	4
Haemoglobinaemia
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Leukocytosis
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	0	1	1
Leukopenia
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Lymphocytosis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Neutropenia
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	4	0	1
Normochromic normocytic anaemia
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Polycythaemia
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
White blood cell disorder
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 218 (0.92%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	3	1	1
Abdominal pain lower
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Diarrhoea
subjects affected / exposed	12 / 218 (5.50%)	0 / 68 (0.00%)	6 / 162 (3.70%)
occurrences all number	13	0	6
Dry mouth
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Flatulence
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Gastritis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Gastroenteritis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Mouth cyst
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Nausea
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Vomiting
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Hepatobiliary disorders
Biliary cyst
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Hepatic steatosis
subjects affected / exposed	2 / 218 (0.92%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	2	1	1
Liver disorder
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Erythema
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Pruritus
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Rash generalised
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Nodule
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Renal and urinary disorders
Bacteriuria
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	1	1	0
Bilirubinuria
subjects affected / exposed	4 / 218 (1.83%)	2 / 68 (2.94%)	8 / 162 (4.94%)
occurrences all number	4	3	9
Bladder dysfunction
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Crystalluria
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	2 / 162 (1.23%)
occurrences all number	0	1	3
Haematuria
subjects affected / exposed	3 / 218 (1.38%)	0 / 68 (0.00%)	5 / 162 (3.09%)
occurrences all number	3	0	6
Haemoglobinuria
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Ketonuria
subjects affected / exposed	6 / 218 (2.75%)	3 / 68 (4.41%)	4 / 162 (2.47%)
occurrences all number	6	3	4
Leukocyturia
subjects affected / exposed	6 / 218 (2.75%)	3 / 68 (4.41%)	3 / 162 (1.85%)
occurrences all number	7	3	3
Nephrolithiasis
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	1	1	1
Proteinuria
subjects affected / exposed	14 / 218 (6.42%)	8 / 68 (11.76%)	11 / 162 (6.79%)
occurrences all number	16	9	12
Renal colic
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Strangury
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Urinary tract infection bacterial
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Urine abnormality
subjects affected / exposed	4 / 218 (1.83%)	3 / 68 (4.41%)	4 / 162 (2.47%)
occurrences all number	4	3	5
Endocrine disorders
Diabetes mellitus
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Glucose tolerance impaired
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Goitre
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	2
Impaired fasting glucose
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Thyroid cyst
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	5 / 218 (2.29%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	7	0	2
Back pain
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Gout
subjects affected / exposed	6 / 218 (2.75%)	1 / 68 (1.47%)	7 / 162 (4.32%)
occurrences all number	8	1	8
Gouty arthritis
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Joint ankylosis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Ligament sprain
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Lower limb fracture
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Meniscal degeneration
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	2	0	0
Metatarsalgia
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Muscle spasms
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Myalgia
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Neck pain
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Pain in extremity
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	2	0	1
Rotator cuff syndrome
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Spondylitis
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Tendonitis
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Gastroenteritis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Influenza
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Laryngitis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Mastitis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Nasopharyngitis
subjects affected / exposed	2 / 218 (0.92%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	2	1	1
Otitis media acute
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	2
Pharyngitis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Sinusitis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Tracheitis
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	2 / 162 (1.23%)
occurrences all number	1	1	2
Urinary tract infection
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	3 / 162 (1.85%)
occurrences all number	2	0	3
Viral upper respiratory tract infection
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	3	0	0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Dyslipidaemia
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	2	0	1
Glucose tolerance impaired
subjects affected / exposed	2 / 218 (0.92%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	2	0	0
Gout
subjects affected / exposed	10 / 218 (4.59%)	7 / 68 (10.29%)	10 / 162 (6.17%)
occurrences all number	18	14	16
Gouty tophus
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Hyperalbuminaemia
subjects affected / exposed	1 / 218 (0.46%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	1	1	1
Hypercalcaemia
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	2
Hyperchloraemia
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	1
Hypercholesterolaemia
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	2 / 162 (1.23%)
occurrences all number	1	0	2
Hyperkalaemia
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Hypernatraemia
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Hypertriglyceridaemia
subjects affected / exposed	6 / 218 (2.75%)	1 / 68 (1.47%)	1 / 162 (0.62%)
occurrences all number	6	1	1
Hypoalbuminaemia
subjects affected / exposed	0 / 218 (0.00%)	1 / 68 (1.47%)	0 / 162 (0.00%)
occurrences all number	0	1	0
Hypokalaemia
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Hyponatraemia
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Osteopenia
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Overweight
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Sodium retention
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1
Type 2 diabetes mellitus
subjects affected / exposed	1 / 218 (0.46%)	0 / 68 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0
Type I hyperlipidaemia
subjects affected / exposed	0 / 218 (0.00%)	0 / 68 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1

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Were there any global substantial amendments to the protocol? Yes

21 Feb 2013

Changes introduced were the following: -CPK and C-reactive protein were added among the blood chemistry parameters -Clarifications on procedures for reporting gout flares as AEs were given; -Clarifications on the definition of SUSAR were given; -The specification of the baseline visit for the inclusion criterion of serum uric acid ≥ 8.0mg/dl was removed; -The procedures for the criteria for eligibility at the end of the 2-week run-in period relative to gout flares and availability of the results of laboratory tests at Visit 0 were better clarified; -The requirement for the availability of the results of laboratory tests at Visits 1 and 2 was better clarified; -The study flow-chart, the description of visit plan and the study design diagram were modified according to the changes in procedures for the management of gout flares and the availability of the results of laboratory tests; -A clarification of the time of definition of the baseline time point was given; -The two distinctive sets for the analysis of efficacy endpoints were defined; -The dosage of Allopurinol was better clarified.

21 Mar 2014

Changes introduced were the following: -Names of responsible persons of the sponsor and CRO were changed; -Following an EMA request, a form was introduced for collecting additional information in case of serious hepatic and cutaneous reactions; -The sample size was recalculated according to changes in statistical power; -The study timelines were prolonged; -The inclusion criterion of the American Rheumatism Association for the classification of the acute arthritis of primary gout was applied to medical history; -The exclusion criterion on lactose intolerance was clarified as a required known criterion; -The method of calculation of creatinine clearance (Cockroft-Gault formula) was specified; -Procedures for the repetition of laboratory tests in case the randomization visit was postponed due to gout flare were given; -Procedures to be followed in case of study discontinuation were better clarified; -Methods of calculation of compliance for prophylaxis therapy were added; -The timelines required between Visit -1 and Visit 0 were modified; -The blood sample and urine collection at Visit 0 were deleted, except in case the visit was postponed due to gout flare; -The baseline time point for safety and efficacy evaluations was redefined and was better clarified; -The safety population was redefined as inclusive of all enrolled subjects (not only randomised subjects); -The reference person of the sponsor in charge of keeping the copies of the randomization envelopes for emergency unblinding was changed from the medical expert to a generic sponsor personnel.

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.

No limitations or caveats are applicable to this summary

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Clinical trials

Clinical Trial Results: A multicentre, randomised, double-blind, parallel group study on the therapeutic efficacy and safety of Febuxostat (taken once daily) and the therapeutic efficacy and safety of Allopurinol on serum urate concentration in subjects suffering from hyperuricemia and gout.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects with sUA < 6 mg/dL after 4 week treatment

Primary: Percentage of subjects with sUA < 6 mg/dL after 4 week treatment

Secondary: Percentage of subjects with sUA level <6 mg/dL after 8 weeks treatment

Secondary: Percentage of subjects with sUA level <6 mg/dL after 8 weeks treatment

Secondary: Percentage of subjects with sUA < 6 mg/dL after 12 week treatment

Secondary: Percentage of subjects with sUA < 6 mg/dL after 12 week treatment

Secondary: Percentage of subjects with sUA < 6 mg/dL after 16 week treatment

Secondary: Percentage of subjects with sUA < 6 mg/dL after 16 week treatment

Secondary: Percentage of subjects with sUA < 6 mg/dL after 20 weeks treatment

Secondary: Percentage of subjects with sUA < 6 mg/dL after 20 weeks treatment

Secondary: Percentage of subjects with sUA < 6 mg/dL after 24 week treatment

Secondary: Percentage of subjects with sUA < 6 mg/dL after 24 week treatment

Secondary: Percentage of patients with last 3 SUA levels < 6 mg/dl at 16,20 and 24 weeks

Secondary: Percentage of patients with last 3 SUA levels < 6 mg/dl at 16,20 and 24 weeks

Secondary: Mean values reduction from baseline in SUA levels after 4 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 4 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 8 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 8 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 12 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 12 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 16 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 16 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 20 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 20 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 24 weeks treatment

Secondary: Mean values reduction from baseline in SUA levels after 24 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 4 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 4 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 8 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 8 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 12 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 12 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 16 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 16 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 20 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 20 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 24 weeks treatment

Secondary: Mean percentage reduction from baseline in SUA levels after 24 weeks treatment

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 4 week treatment

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 4 week treatment

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 8 week treatment

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 8 week treatment

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 12 week treatment

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 12 week treatment

Post-hoc: Percentage of patients with Sua levels <5 mg/dl after 16 weeks of treatment

Post-hoc: Percentage of patients with Sua levels <5 mg/dl after 16 weeks of treatment

Post-hoc: Percentage of patients with Sua levels <5 mg/dl after 20 weeks of treatment

Post-hoc: Percentage of patients with Sua levels <5 mg/dl after 20 weeks of treatment

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 24 week treatment

Post-hoc: Percentage of subjects with sUA < 5 mg/dL after 24 week treatment

Post-hoc: Percentage of patients with last 3 SUA levels < 5 mg/dl at 16,20 and 24 weeks

Post-hoc: Percentage of patients with last 3 SUA levels < 5 mg/dl at 16,20 and 24 weeks

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A multicentre, randomised, double-blind, parallel group study on the therapeutic efficacy and safety of Febuxostat (taken once daily) and the therapeutic efficacy and safety of Allopurinol on serum urate concentration in subjects suffering from hyperuricemia and gout.