UMIN-CTR Clinical Trial

Public title

Effect of urate LowEring Agent Febuxostat
in Chronic Heart Failure patients with hyperuricemia

Acronym

LEAF-CHF study

Scientific Title

Effect of urate LowEring Agent Febuxostat
in Chronic Heart Failure patients with hyperuricemia

Scientific Title:Acronym

LEAF-CHF study

Region

Japan

Condition

Chronic heart failure patients with hyperuricemia

Classification by specialty

Cardiology

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

To evaluate the efficacy of Febuxostat, a urate lowering agent, on BNP in patients with chronic heart failure (CHF) (NYHA functional class II and III) and hyperuricemia.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Explanatory

Developmental phase

Not applicable

Primary outcomes

The change of BNP from baseline after 24 week treatment

Key secondary outcomes

(1)LVEF and E/e' from baseline after 24 week treatment
(2)The occurrences of events from 0 to 24 weeks will be evaluated. The details are decided by event evaluation standards defined before staring this study.
According to event evaluation standard, Event Evaluation Committee conducts central review an Investigator's assessment by blind study.
1)Death
2)Cardiovascular event
Cardiovascular death
Hospitalization due to worsening heart failure
Hospitalization due to cardiovascular causes
Enforcement of heart failure treatment
(3) NYHA functional class from baseline after 4, 8, 12, 16, 20 and 24 weeks
(4) Lab data from baseline after 4, 8, 12, 16, 20 and 24 week
1)BNP
2)eGFR
3)Hemoglobin
4)Serum uric acid
(5) Adverse events during the study period
Adverse events from 0 to 24 weeks will be evaluated.

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Active

Stratification

NO

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 administration for 24 weeks

Interventions/Control_2

Follow-up for 24 weeks

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)Male or female patients over 20 years old at time stable chronic heart failure the subjects sign the Informed Consent Form (ICF).
(2)Serum uric acid level >7.0 mg/dL and <=10.0 mg/dL
(3)CHF, NYHA functional class II and III
(4)Serum BNP is >= 100 pg/mL or NT-proBNP >= 400 pg/mL
(Use measured value at each site for confirmation of eligibility)
(5)Systolic dysfunction, LVEF < 40% (Echocardiogram taken within 8 weeks can be used as confirmation of eligibility. However, echocardiogram at examination on admission cannot be used.)
(6)History of hospitalization due to worsening CHF to confirmation of eligibility. Admission only for work up is excluded.
(7) Stable for 4 weeks prior to eligibility test, without changes in NYHA functional class and dose of drugs for heart failure such as angiotensin converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), betablocker,and diuretics.
(8)Written informed consent by his/her own will.

Key exclusion criteria

(1) Drugs for hyperuricemia, within 2 weeks before confirmation of eligibility.
Allopurinol, Benzbromarone, Probenecid, Bucolome, Topiroxostat, Febuxostat
(2) Drugs at the time of confirmation of eligibility.
Mercaptopurinehydrate, Azathioprine, Vidarabine, Dinanosine
(3) Gouty tophus or certain symptom of gouty arthritis within 1 year before eligibility confirmation.
(4) Acute myocardial infarction or coronary arterial revascularization within 3 month before eligibility confirmation.
(5) Planned cardiac surgery such as coronary arterial valve operation, during participation of this study.
(6) Heart failure caused by valvular heart disease or congenital heart disease.
(7) Severe hepatic, or renal dysfunction, dialysis or malignancy disqualified from the study by the investigators.
Severe hepatic dysfunction is defined as twice the upper limit of baseline AST or ALT. Severe renal dysfunction is defined as eGFR <30/mL/min/1.73m2.
eGFR is calculated by formula shown in "CKD diagnostic guideline 2012 by Japanese Society of Nephropathy"
eGFR(mL/min/1.73m2)=194*Cr^(-1.094)*Age^(-0.287)(Female *0.739)
(8) Febuxostat hypersensitivity.
(9) Pregnant, possibly pregnant, brest-feeding, or expecting to conceive.
(10)Participated in other clinical study within 6 months before confirmation of eligibility.
(11)Considered to be inappropriate for the participation in this study by the investigators.

Target sample size

200

Name of lead principal investigator

1st name	Hiroyuki
Middle name
Last name	Tsutsui

Organization

Kyushu University Graduate School of Medicine

Division name

Department of Cardiovascular Medicine

Zip code

812-8582

Address

Umade3-1-1, Higashi-ku, Fukuoka, 812-8582

TEL

092-642-5360

Email

htsutsui@cardiol.med.kyushu-u.ac.jp

Name of contact person

1st name	Mao
Middle name
Last name	Kakinoki

Organization

Hubit genomix, Inc.

Division name

Business Promotion Unit

Zip code

104-0045

Address

Tukiji-Ogawa Building 3F, 7-10-2 Tukiji, Chuo-ku, Tokyo 104-0045, Japan

TEL

03-5148-3992

Homepage URL

Email

mkakinoki@hubitgenomix.com

Institute

LEAF-CHF steering committee

Institute

Department

Personal name

Organization

TEIJIN PHARMA LIMITED.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Japan

Co-sponsor

Name of secondary funder(s)

Organization

Kyushu University Hospital Institutional Review Board

Address

3-1-1 Maidashi, Higashi-ward, Fukuoka-city, Fukuoka 812-8582 JAPAN

Tel

092-642-5774

Email

byskenkyu@jimu.kyushu-u.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

北海道大学病院　循環器内科(北海道)、札幌医科大学附属病院　第２内科(北海道)、医療法人社団慈弘会　ハートサウンズもりクリニック　内科・循環器(北海道)、防衛医科大学校病院　循環器内科(埼玉県)、東京医科歯科大学医学部附属病院　循環器内科(東京都)、東京大学医学部附属病院　循環器内科(東京都)、北里大学病院　循環器内科(神奈川県)、聖マリアンナ医科大学病院　循環器内科(神奈川県)、名古屋大学医学部附属病院　循環器内科(愛知県)、西尾市民病院　内科（循環器）(愛知県)、名古屋市立大学病院　循環器内科(愛知県)、大阪大学医学部附属病院　循環器内科(大阪府)、地方独立行政法人大阪府立病院機構大阪府立急性期・総合医療センター　心臓内科(大阪府)、大阪医科大学附属病院　循環器内科(大阪府)、特定医療法人渡辺医学会　桜橋渡辺病院　循環器内科(大阪府)、兵庫医科大学病院　循環器内科(兵庫県)、奈良県立医科大学附属病院　循環器・腎臓・代謝内科(奈良県)、岡山大学病院　循環器内科(岡山県)、広島大学病院　循環器内科(広島県)、鳥取大学医学部附属病院　循環器内科(鳥取県)、山口大学医学部附属病院　第二内科(山口県)、東北大学病院　循環器内科　（宮城県）、自治医科大学附属さいたま医療センター　循環器科　（埼玉県）、東京慈恵会医科大学附属病院　循環器内科　（東京都）、公立陶生病院　循環器内科　（愛知県）、国立循環器病研究センター　心臓血管内科　（大阪府）、公益財団法人日本心臓血圧研究振興会附属　榊原記念病院　循環器内科　（東京都）、国家公務員共済組合連合会　虎の門病院　循環器センター　（東京都）、九州大学病院　循環器内科　（福岡県）、独立行政法人労働者健康福祉機構山陰労災病院　第二循環器科　（鳥取県）、広島鉄道病院　循環器内科　（広島県）、藤井政雄記念病院　循環器内科　（鳥取県）、県立広島病院　循環器内科　（広島県）、社会福祉法人北海道社会事業協会小樽病院　循環器科　（北海道）、昭和大学病院　循環器内科　（東京都）、市立札幌病院　循環器科　（北海道）、徳山中央病院（山口県）、京都大学（京都府）、済生会山口総合病院（山口県）、山口県立総合医療センター（山口県）

Date of disclosure of the study information

2014

Year

03

Month

04

Day

URL releasing protocol

https://www.jstage.jst.go.jp/article/ihj/59/5/59_17-560/_article/-char/ja

Publication of results

Published

URL related to results and publications

https://link.springer.com/article/10.1007/s00380-024-02448-9

Number of participants that the trial has enrolled

108

Results

There was no statistically significant difference between the febuxostat group and the control group in the change in BNP from the start to 24 weeks/discontinuation.

Results date posted

2024

Year

09

Month

12

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

2024

Year

08

Month

19

Day

Baseline Characteristics

A total of 101 cases were analyzed in the full analysis set, of which 51 were in the febuxostat group and 50 in the control group. The female were 14 (13.9%) in total, of which 6 (11.8%) were in the febuxostat group and 8 (16.0%) in the control group, respectively. The ages were 69.5 years were in total, of which 69.7 years were in the febuxostat group, and 69.2 years in the control group, respectively.

Participant flow

The target number of cases was 200, but the results of the post-marketing surveillance of febuxostat reported to the FDA that "febuxostat caused more deaths than allopurinol," and this was reported to the independent data monitoring committee, which confirmed the continuation of the study. The independent data monitoring committee decided that "since no adverse events have been observed in the cases to date, the study will continue until all registered cases are completed, and as a safety measure, no additional cases will be added," so the study stopped enrolling patients midway. As a result, 108 cases were assigned to enroll, 7 cases dropped out at week 0, no cases were excluded from the full analysis set , and the full analysis set analysis population was 101 cases (51 cases in the febuxostat group, 50 cases in the control group), 9 cases were excluded from the per protocol set (4 cases in the febuxostat group, 5 cases in the control group), and the per protocol set analysis population was 92 cases (47 cases in the febuxostat group, 45 cases in the control group). The safety analysis set of 101 patients (51 in the febuxostat group and 50 in the control group), excluding 7 patients who dropped out at week 0.

Adverse events

The incidence of adverse events was 27.5% in the febuxostat group and 28.0% in the control group, with no statistically significant difference between the assigned groups. The incidence of side effects was 17.6%. No distinctive events were observed in either group, except for events related to worsening heart failure (heart failure, worsening heart failure, exacerbation of heart failure, etc.).

Outcome measures

<Primary endpoint>
No statistically significant differences were observed between the assigned groups in the change in BNP from the start to 24 weeks or at discontinuation.
<Secondary endpoints>
1.No statistically significant differences were observed between the assigned groups in the overall changes in LVEF and E/e' from the start of treatment to 24 weeks / at discontinuation, or at 24 weeks. For LVEF, the febuxostat group showed significantly lower values than the control group in aged 65 years or older at both evaluation points. For E/e', no statistically significant differences were observed between the assigned groups.
2. Regarding events, there were no deaths. There was no statistically significant difference between the allocation groups in the cumulative incidence of "hospitalization due to worsening heart failure," "hospitalization due to cardiovascular causes," and "intensification of treatment for heart failure." No significant hazard ratio was observed, and no interaction with the allocation group was observed in each stratum.

3. Regarding the NYHA classification, there was no statistically significant difference between the assigned groups in the overall change from the start of the study to each observation point. Although there were some points where there was a significant difference in distribution within the group, no major changes were observed.

<laboratory test values>
1. Regarding changes in BNP at each observation point, the febuxostat group showed lower values overall than the control group. From 4 to 20 weeks, the febuxostat group showed significantly lower values than the control group. In stratified analysis, differences in changes were observed for age (</> 65 years), serum uric acid level (</> 8.0 mg/dL), LVEF (</> 30%), and eGFR (</> 60 mL/min/1.73 m2).
2.Regarding the change in eGFR at each observation point, data showed variability in both groups, with the febuxostat group showing lower values than the control group, but this reversed at 24 weeks and at discontinuation. The febuxostat group showed significantly lower values than the control group at 8 weeks. In stratified analysis, the febuxostat group showed significantly lower values than the control group at 8 weeks in patients aged 65 years or older, with hypertension, with anemia, without renal dysfunction, with serum uric acid levels of less than 8.0 mg/dL, at 12 weeks in women, at 4 weeks in LVEF less than 30%, and at 16 weeks in LVEF 30% or more.
3. Regarding changes in hemoglobin levels at each observation point, the febuxostat group was found to have lower hemoglobin levels than the control group overall. The febuxostat group showed significantly lower values than the control group at 20 weeks. In stratified analysis, the febuxostat group showed significantly lower values than the control group at 20 weeks in patients with diabetes, dyslipidemia, BNP 200pg/mL or higher at 20 weeks and 24 weeks, without chronic obstructive pulmonary disease, without renal dysfunction, LVEF 30% or higher, and eGFR less than 60mL/min/1.73m2 at 20 weeks.
4. Regarding the change in serum uric acid level at each observation time point, the febuxostat group showed significantly lower values than the control group at all time points. In stratified analysis, the febuxostat group showed significantly lower values than the control group at all time points except for those with chronic obstructive pulmonary disease.

Plan to share IPD

NONE

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2014

Year

07

Month

14

Day

Date of IRB

2014

Year

02

Month

17

Day

Anticipated trial start date

2014

Year

08

Month

01

Day

Last follow-up date

2018

Year

06

Month

30

Day

Date of closure to data entry

2018

Year

06

Month

30

Day

Date trial data considered complete

2018

Year

12

Month

28

Day

Date analysis concluded

2019

Year

02

Month

21

Day

Other related information

Registered date

2014

Year

03

Month

04

Day

Last modified on

2024

Year

09

Month

12

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000015556