UMIN-CTR Clinical Trial

Public title

An exploratory study of dapagliflozin for the attenuation of albuminuria in patients with heart failure and type 2 diabetes mellitus

Acronym

DAPPER study

Scientific Title

An exploratory study of dapagliflozin for the attenuation of albuminuria in patients with heart failure and type 2 diabetes mellitus

Scientific Title:Acronym

DAPPER study

Region

Japan

Condition

Type 2 Diabetes Mellitus patients with Chronic Heart Failure

Classification by specialty

Cardiology

Endocrinology and Metabolism

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

To elucidate whether dapagliflozin improves the magnitude of urinary albumin creatinine ratio from the baseline in Type 2 Diabetes Mellitus patients with chronic heart failure compared with other anti-diabetic agents except sodium-dependent glucose transporter-2 inhibitors after 2 years observation

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

The magnitude of the change in urinary albumin creatinine ratio after 2 years observation from the baseline

Key secondary outcomes

(1) The proportion of the number of patients presenting with an albuminuria category shift in each group (dapagliflozin group and control group)
Improvement test
A shift to a better category
Prevention test
No shift to a worse category
Categories
Category 1 (less than 30 mg/g Cr)
Category 2 (from 30 to 299 mg/g Cr)
Category 3 (more than 300 mg/g Cr)
(2) Changes of eGFR during a 2-year period
(3) The proportion of the number of patients presenting with an eGFR category shift in each group
Improvement test
A shift to a better category
Prevention test
No shift or a shift to a worse category
Categories
Category 1 (more than 90 ml/min/1.73m2)
Category 2 (from 89 to 60 ml/min/1.73m2)
Category 3 (from 59 to 45 ml/min/1.73m2)
(4) The changes of urinary kidney injury molecule-1 (KIM-1) from the baseline after a 2-year observation
(5) The changes in the plasma aldosterone concentration, plasma NT-pro BNP concentration, serum FGF23 concentration, and plasma alpha-Klotho concentration from the baseline after a 2-year observation
(6) The composite endpoint, which is defined as CV death or hospitalization for CV events in a 2-year observation
(7) The composite endpoint, which is defined as CV death or the hospitalization for HF in a 2-year observation
(8) The onset of CV events in a 2-year observation
(9) Hospitalization for CV events in a 2-year observation
(10) Hospitalization for HF in a 2-year observation
(11) Death from all causes in a 2-year observation
(12) Hospitalization for all causes in a 2-year observation
(13) An additional change in prescriptions for HF in a 2-year observation
(14) The changes in echocardiographic parameters, including left ventricular end-diastolic and end-systolic dimensions, the left atrial volume index, left atrial dimension, (15) ejection fraction, and (16) fractional shortening from the baseline after a 2-year observation
(17) The category of the New York Heart Association (NYHA) classification in a 2-year observation
etc.

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Active

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

2

Purpose of intervention

Prevention

Type of intervention

Medicine

Interventions/Control_1

dapagliflozin, 5 mg or 10 mg, 2 years observation

Interventions/Control_2

anti-diabetic drugs except for SGLT-2 inhibitors, 2 years observation

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

85

years-old

>=

Gender

Male and Female

Key inclusion criteria

1) Patients with type 2 diabetes at 20 years-old or older and less than or equal to 85 years-old at the time of informed consent
2) Patients necessary to start the treatment using anti-diabetic agent(s) or to change the anti-diabetic agent(s)
3) Patients with plasma HbA1C levels < 10% with or without anti-diabetic agent(s)
4) Patients who fall into any of the following items are defined as those with chronic heart failure:
1. NYHA Functional Class II, III or IV within 3 months before informed consent;
2. Plasma BNP levels of 100 pg/mL or plasma NT-pro BNP levels of 400 pg/mL within 3 months before informed consent; or previous diagnosis of heart failure that was treated including drug therapy.
5) The value of eGFR should be more than 45 ml/min/1.73m2
6) Agreement of written informed consent

Key exclusion criteria

1) Patients with insulin treatment
2) Patients with an allergic history of dapagliflozin
3) Patients with a history of severe diabetic ketoacidosis, diabetic coma or pre-coma
4) Patients using mechanical circulatory support devices
5) Patients waiting for heart transplant
6) Patients waiting for cardiac surgery
7) Patients who may easily show dehydration, including a history of dehydration, highly frequent change of diuretics, extreme thinness
8) Patients with hepatic dysfunction with AST or ALT 3-fold of upper limit of normal (ULN) at screening (However, if increased AST or ALT is determined to be attributable to cardiac diseases, patients do not meet this exclusion criterion as long as total bilirubin levels are < 3.0 mg/dL.)
9) Patients with bilateral renal artery stenosis or renal artery stenosis in a solitary kidney
10) Patients in a serious clinical condition and who are expected to live for < 3 years
11) Patients with possible alcohol or drug abuse
12) Patients who are pregnant or possibly pregnant
13) Patients with breast feeding
14) Patients who have been enrolled in other clinical studies at the same time with this study (excluding observational studies such as registry studies)
15) Patients who are judged by the investigator or subinvestigators to be not suitable for participation in the study

Target sample size

288

Name of lead principal investigator

1st name	Fumiki
Middle name
Last name	Yoshihara

Organization

National Cerebral and Cardiovascular Center

Division name

Division of Nephrology

Zip code

5648565

Address

6-1, Kishibeshinmachi, Suita, Osaka

TEL

0661701070

Email

fyoshi@ncvc.go.jp

Name of contact person

1st name	Fumiki
Middle name
Last name	Yoshihara

Organization

National Cerebral and Cardiovascular Center

Division name

Division of Nephrology

Zip code

5648565

Address

6-1, Kishibeshinmachi, Suita, Osaka

TEL

0661701070

Homepage URL

Email

fyoshi@ncvc.go.jp

Institute

Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 5658565, Japan

Institute

Department

Personal name

Organization

Astra Zeneka KK and Ono Pharmaceutical Co., Ltd.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Hyogo College Of Medicine

Address

1-1, Mukogawacho, Nishinomiya, Hyogo

Tel

0798-45-6066

Email

rinken@hyo-med.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

Date of disclosure of the study information

2016

Year

12

Month

15

Day

URL releasing protocol

https://www.thelancet.com/cms/10.1016/j.eclinm.2023.102334/attachment/c4916883-d96b-4f59-bf15-ee05a2

Publication of results

Published

URL related to results and publications

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00511-4/fulltext

Number of participants that the trial has enrolled

294

Results

The primary outcome did not significantly differ between the dapagliflozin and control groups.

Results date posted

2024

Year

06

Month

10

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

The baseline characteristics of patients were similar in both groups. The mean age of patients was 72.1 years and 29% were female. The mean glycated hemoglobin value was 6.9%, mean NT-pro BNP was 429.1pg/mL, mean eGFR was 65.7 mL/min/1.73 m2, and median UACR was 25.0 (8.8-74.6) mg/g Cr in the dapagliflozin group and 25.6 (8.2-95.0) mg/g Cr in the control group. The distributions of UACR categories in each group were 56 and 59% for category 1 (<30 mg/g Cr), 37 and 29% for category 2 (30-300 mg/g Cr), and 7 and 12% for category 3 (>300 mg/g Cr), respectively. The distributions of NYHA functional classes in each group were 9 and 12% for class I, 87 and 83% for class II, and 4 and 6% for class III, respectively.

Participant flow

Between 12 May 2017 and 31 March 2020, 294 patients were randomly assigned to the dapagliflozin (n = 146) or control (n = 148) group at 18 medical facilities in Japan. Among the 146 patients in the dapagliflozin group, 122 completed the study, and 107 (87.7%) were taking 5 mg daily of dapagliflozin at the end of the observation period.

Adverse events

The recorded number of patients with serious adverse events was 26 (17.8%) in the dapagliflozin group and 40 (29.0%) in the control group. Serious adverse events are listed in Supplementary Table S1 as Supplementary Material (https://www.thelancet.com/cms/10.1016/j.eclinm.2023.102334/attachment/b5e5c352-8db7-4673-940d-4c76d33162b4/mmc1.pdf).

Outcome measures

The primary outcome was changes in UACR from baseline after a two-year observation. Secondary endpoints were (1) the percentage of patients presenting with an albuminuria category shift in each group (dapagliflozin and control groups), (2) changes in eGFR during a two-year period, (3) the percentage of patients presenting with an eGFR category shift in each group, (4) changes in urinary kidney injury molecule-1 from baseline after a two-year observation, (5) changes in plasma aldosterone, plasma NT-pro BNP, serum fibroblast growth factor 23, and plasma alpha-Klotho concentrations from baseline after a two-year observation, (6) the composite endpoint, defined as CV death or hospitalization for CV events in a two-year observation, (7) the composite endpoint, defined as CV death or hospitalization for HF in a two-year observation, (8) the onset of CV events in a two-year observation, (9) hospitalization for CV events in a two-year observation, (10) hospitalization for HF in a two-year observation, (11) death from all causes in a two-year observation, (12) hospitalization for all causes in a two-year observation, (13) an additional change in prescriptions for HF in a two-year observation, (14) changes in echocardiographic parameters, including left ventricular end-diastolic dimensions and end-systolic dimensions, the left atrial volume index, and left atrial dimensions, (15) the ejection fraction, (16) fractional shortening from baseline after a two-year observation, (17) the category of the NYHA classification in a two-year observation, (18) changes in the echocardiographic parameters of the mitral peak E wave (E) from baseline after a two-year observation, (19) changes in the echocardiographic parameters of early diastolic mitral annular velocity by tissue doppler echocardiography (e) from baseline after a two-year observation, (20) changes in the echocardiographic parameters of the E/mitral peak A velocity (A) ratio from baseline after a two-year observation, (21) changes in the echocardiographic parameters of the E/e ratio from baseline after a two-year observation, (22) changes in the echocardiographic parameters of the E velocity deceleration time from baseline after a two-year observation, and (23) new-onset atrial fibrillation and/or atrial flutter in a two-year observation. Items (18)-(22) were added after the initiation of the study because we found that the items collected on echocardiographic findings were missing from the secondary endpoints and again received approval by the Ethics Committee.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Main results already published

Date of protocol fixation

2016

Year

09

Month

06

Day

Date of IRB

2016

Year

10

Month

25

Day

Anticipated trial start date

2017

Year

03

Month

01

Day

Last follow-up date

2022

Year

03

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2016

Year

12

Month

01

Day

Last modified on

2024

Year

06

Month

10

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028509