UMIN-CTR Clinical Trial

Public title

Urate lowering drugs RandomIzed parallel-group Comparison study in the Chronic Kidney Disease patients with hypertension and hyperuricemia

Acronym

URIC-CKD study

Scientific Title

Urate lowering drugs RandomIzed parallel-group Comparison study in the Chronic Kidney Disease patients with hypertension and hyperuricemia

Scientific Title:Acronym

URIC-CKD study

Region

Japan

Condition

Chronic kidney disease with hyperuricemia and hypertension

Classification by specialty

Nephrology

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

To compare the effect of xanthine oxidase inhibitor and urate transporter 1 inhibitor on the renal dysfunction in chronic kidney disease patients with hyperuricemia and hypertension

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Pragmatic

Developmental phase

Not applicable

Primary outcomes

Rate of change in estimated GFR from baseline to 52 week (%/52week and ml/min/1/73m2/52w)

Key secondary outcomes

1) Rate of change in eGFR from the baseline to 8 weeks
2) Rate of change in office blood pressure from the baseline to 8 and 52 weeks
3) Difference in rate of change in estimated GFR before(Visit 1 to 2) and after treatment (Visit 2 to 4)
4) Rate of change in serum uric acid from baseline to 8 and 52 weeks and achievement rate of serum uric acid concentration less than 6 mg/dl at 8 and 52 weeks
5) Rate of change in urinary albumin-to-creatine ratio from baseline to 8 and 52 weeks
6) Rate of change in urinary pH from baseline to 8 and 52 weeks
7) Rate of change in serum xanthine oxidase activity from baseline to 8 and 52 weeks
8) Rate of change in high sensitive C reactive protein from baseline to 8 and 52 weeks
9) Rate of change in 8-OHdG (8-hydroxy-2-deoxyguanosine) from baseline to 8 and 52 weeks
10) Rate of change in urinary angiotensinogen from baseline to 8 and 52 weeks
11) Rate of change in L type free fatty acid binding protein(L-FABP) from baseline to 8 and 52 weeks
12) Rate of change in estimated GFR from baseline to 52 weeks stratified by basal urinary albumin-to-creatinine ratio (300mg/gCr) or estimated GFR (45ml/min/1.73m2)

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -but assessor(s) are blinded

Control

Active

Stratification

YES

Dynamic allocation

YES

Institution consideration

Institution is not considered as adjustment factor.

Blocking

NO

Concealment

Central registration

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Febuxostat group:
Patients take febuxostat by oral administration for 52 weeks (approximately one year).
The beginning dosage of the febuxostat is 10 mg/day. The dose is increased to 20 mg /day after four weeks and is maintained until 8 weeks. The dose will be titrated to maintain serum uric acid levels less than 6mg/dl after 8 weeks until the 52 weeks.

Interventions/Control_2

Benzbromarone group:
Patients take benzbromarone by oral administration for 52 weeks (approximately one year).
The beginning dosage of the benzbromarone is 25 mg/day and is maintained for 8 weeks. The dose will be titrated to maintain serum uric acid levels less than 6 mg/dl after 8 weeks until the 52 weeks. Alkalization of urinewill be initiated if urine is acidic.

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

1) Serum uric acid >7.0 mg/dL
2) Patients with hypertension defined as blood pressure measurements of equal or more than 140 mm Hg systolic and/or equal or more than 90 mm Hg diastolic or treatment with antihypertensive agents. No changes in prescription of antihypertensive agent 8 weeks before initiating the study drug.
3) CKD stage 3a and 3b
4) Age equal to or more than 20 years at obtaining informed consent
5) Outpatient
6) No history of gout
7) Obtained written informed consent from the patient for participation to the study

Key exclusion criteria

1) History of hypersensitivity to febuxostat or benzbromarone
2) AST or ALT is more than twice the upper limit of institutional normal range
3) eGFR <30ml/min/1.73m2 or dialysis patients.
4) Under treatment with thiazide diuretics or loop diuretics
5) History of treatment with urate lowering drugs within 2 weeks before determination of eligibility
6) History of coronary heart disease within 3 month before determination of eligibility
7) Patients with neoplasm, History of neoplasm except for the cured patients without recurrence within 5 years before determination of eligibility
8) Under treatment with the following: mercaptopurine,azathioprine, pyrazinamide, ethanbutol
9) Under treatment with warfarin
10) Women who are or may be pregnant, or brest-feeding
11) Participants of other clinical trials within 6 month before determination of eligibility
12) Urolithiasis
13) A patient who are judged inadequate for enrollment by an attending physician
14) A patient whose serum uric acid level is equal to or less than 7 mg/dl at Visit2 after randomization
15) A patient has been suffered from any of following: acute myocardial infarction, acute coronary syndrome, patients undergoing percutaneous coronary intervention or coronary artery bypass grafting, vetricular tachycarida, mutifocal ventricular arrhythmia and acute heart failure within three months before the eligibility assessment. This exclusion criteria was added since recent study suggested febuxostat may be associated with increased cardiovascular mortality compared with allopurinol among gout patients with major cardiovascular disease (N Engl J Med 2018;378:1200-10)

Target sample size

100

Name of lead principal investigator

1st name	Kentaro
Middle name
Last name	Kohagura

Organization

University hospital of the Ryukyus

Division name

Dialysis Unit

Zip code

9030215

Address

207 Uehara, Nishihara-cho, Nakagami-gun, Okinawa, Japan

TEL

0988951341

Email

kohagura@med.u-ryukyu.ac.jp

Name of contact person

1st name	Kentaro
Middle name
Last name	Kohagura

Organization

University hospital of the Ryukyus

Division name

Dialysis Unit

Zip code

9030215

Address

207 Uehara, Nishihara-cho, Nakagami-gun, Okinawa, Japan

TEL

0988951341

Homepage URL

Email

kohagura@med.u-ryukyu.ac.jp

Institute

Dialysis Unit, University Hospital of the Ryukyus

Institute

Department

Personal name

Organization

TEIJIN Pharma, Co,insp

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Review Board of University of the Ryukyus for Clinical Research

Address

1 Senbaru, Nishihara-cho, Nakagami-gun, Okinawa, Japan

Tel

098-895-8016

Email

knknkyu@to.jim.u-ryukyu.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

琉球大学医学部附属病院、南部病院、海邦病院、首里城下町クリニック、中頭病院

Date of disclosure of the study information

2017

Year

04

Month

10

Day

URL releasing protocol

URL releasing protocol is unpublished

Publication of results

Unpublished

URL related to results and publications

URL related to results is unpublished

Number of participants that the trial has enrolled

88

Results

There were no significant differences in the rate of change in eGFR between the groups by week 52 after initiation of treatment. Febuxostat significantly reduced xanthine oxidase activity compared to benzbromarone. There were no significant differences between the groups in the other secondary endpoints of blood pressure, albuminuria, inflammation, oxidative stress, and renal renin-angiotensin system markers.

Results date posted

2021

Year

04

Month

09

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Baseline data (Benzbromarone, n=48 vs. Febuxostat, n=47) were as followed: age(years); 67.3, 64.6, Male(%); 68.8, 63.8, Systolic blood pressure(mmHg); 132.4, 128.3, Serum uric acid (mg/dl); 8.5, 8.2, eGFR (ml/min/1.73m2); 44.3, 44.4, Albumin creatinine ratio (mg/gCr); 190.1, 204.4

Participant flow

Eligibility was assessed in 137 preenrolled patients.42 patients were found not to meet the eligibility criteria　for serum uric acid levels at visit 2.Finally, because of the scheduled period for enrollment, we ended the enrollment and randomization with 95 patients.Of the 95 patients who were randomized, two patients were excluded from the full analysis set because of protocol violation. Two patients were excluded because they were discontinued the study drugs and other two patients were excluded due to safety information from the full analysis set. Further one patient were excluded due to lost of follow up. Thus, the intention to treat set and the per-protocol set for 52-week outcomes included 88 and 8789 participants, respectively.

Adverse events

Pneumonia and bone fracture were observed in one patient in each group. One case of urinary tract infection was observed in the febuxostat group. There were no deaths, cardiovascular events, or end-stage renal failure.

Outcome measures

[Primary endpoint]
There was no significant differences in changes in estimated GFR from baseline to 52 weeks between the groups.
[Secondary endpoint]
The rate of change in XO activity was significantly greater in the febuxostat group. There was no significant difference in all other secondary endpoints between the two groups.

Plan to share IPD

IPD sharing Plan description

Recruitment status

No longer recruiting

Date of protocol fixation

2016

Year

11

Month

16

Day

Date of IRB

2015

Year

11

Month

18

Day

Anticipated trial start date

2017

Year

11

Month

18

Day

Last follow-up date

2020

Year

01

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Papers are being submitted for publication.

Registered date

2017

Year

04

Month

03

Day

Last modified on

2023

Year

04

Month

08

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000029056