UMIN-CTR Clinical Trial

Basic information
Public title	Safety of canagliflozin in diabetic patients with chronic heart failure: randomized, non-inferiority trial
Acronym	CANDLE trial
Scientific Title	Safety of canagliflozin in diabetic patients with chronic heart failure: randomized, non-inferiority trial
Scientific Title:Acronym	CANDLE trial
Region	Japan

Condition
Condition	Type 2 diabetic patients with chronic heart failure
Classification by specialty	Cardiology Endocrinology and Metabolism
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	Investigation of the safety of canagliflozin in patients with type 2 diabetes complicated with chronic heart failure by using NT-proBNP measurement as an index.
Basic objectives2	Safety,Efficacy
Basic objectives -Others
Trial characteristics_1
Trial characteristics_2
Developmental phase

Assessment
Primary outcomes	Percent change in NT-proBNP from baseline to 24 weeks
Key secondary outcomes	1) Change in NT-proBNP from baseline to 24 weeks 2) Control of blood glucose HbA1c value after 24 weeks (or at discontinuation) and change in HbA1c from baseline to 24 weeks Following values after 24 weeks (or at discontinuation) and change in them from baseline to 24 weeks fasting plasma glucose, insulin, HOMA-R, HOMA-beta 3) Blood pressure, home blood pressure (optional), and body weight Following values after 24 weeks (or at discontinuation) and change in them from baseline to 24 weeks Blood pressure, home blood pressure (early morning), body weight 4) Serum lipid and serum uric acid level Following values after 24 weeks (or at discontinuation) and change in them from baseline to 24 weeks TC, HDL-C, LDL-C, TG, non-HDL-C, uric acid level 5) QOL score QOL (MLHF) score after 24 weeks (or at discontinuation) and change in QOL (MLHF) from baseline to 24 weeks 6) Heart function LVEF and E/e' values after 24 weeks (or at discontinuation) and change in LVEF and E/e' from baseline to 24 weeks Severity and change in NYHA functional classification from baseline to 24 weeks 7) Renal function Following values after 24 weeks (or at discontinuation) and change in them from baseline to 24 weeks Serum creatinine, eGFR, urine albumin excretion (creatinine corrected value), and urine L-FABP 8) Cardiovascular event occurred from baseline to 24 weeks Nonfatal stroke, nonfatal myocardial infarction, hospitalization because of heart failure, exacerbation of heart failure (adding agents or increasing the dose) 9) All-cause mortality 10) Adverse events and adverse drug reaction from baseline to 24 weeks

Base
Study type	Interventional

Study design
Basic design	Parallel
Randomization	Randomized
Randomization unit	Individual
Blinding	Open -but assessor(s) are blinded
Control	Active
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms	2
Purpose of intervention	Treatment
Type of intervention	Medicine
Interventions/Control_1	Group receiving canagliflozin Oral administration of 100 mg canagliflozin once a day, pre or post breakfast
Interventions/Control_2	Group receiving glimepiride Oral administration of glimepiride once or twise a day, before or after breakfast or dinner. Initial dose is 0.5-1mg/day and increased or descreased by investigator's discretion if necessary. Maxmum dose is 6 mg/day.
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	1) 20 years or older at consent (male and female) 2) Is diagnosed with type 2 diabetes and the investigator considered that initiation of administrating antidiabetic agents or change or addition of antidiabetic agent is possible 3) Is diagnosed with chronic heart failure (NYHA class is I-III) 4) NYHA functional classification dosn't change in 4 weeks prior to eligibility qualification and dose of heart failure treatment drugs (such as ACE inhibitor, ARB, beta blocker, diuretic etc.) dosn't change 5) The patient provided written informed consent to participate in the study
Key exclusion criteria	1) Type 1 diabetes 2) Has history of diabetic ketoacidosis, diabetic coma, or hypoglycemic attack within 6 months 3) With severe renal dysfunction (eGRF < 45 mL/min/1.73m 2 or patient undergoing artificial dialysis) 4) With serious liver disfunction (ASTor ALT is 3 times site reference value or more) 5) Heart failure patient whose NYHA functional classification is IV 6) With pituitary gland dysfunction or adrenal gland dysfunction 7) With malnutrition, starvation, irregular eating pattern, lack of dietary intake, debilitaion 8) Excessive alcohol consumption 9) Is pre or post surgery, has severe infection or sirious trauma at eligibility qualification 10) With gastrointestinal disorder such as diarrhea and vomiting 11) BMI < 18.5 kg/m 2 12) Has history of coronary artery disease, coronary revascularization, cardiotomy, stroke and transient ischemic attacks within 3 months before eligibility qualification 13) Has malignancy 14) Has history of hypersensitivity to canagliflozin, glimepiride or sulfonamides 15) Pregnant, possibly pregnant, planned to become pregmant or nursing women 16) Are considered not eligible for the study by the attending doctor due to other reasons
Target sample size	250

Research contact person
Name of lead principal investigator	1st name Koichi Middle name Last name Node
Organization	Saga University
Division name	Department of Cardiovascular Medicine
Zip code	849-8501
Address	5-1-1 Nabeshima, Saga
TEL	0952-34-2364
Email	cardiostudy@ml.cc.saga-u.ac.jp

Public contact
Name of contact person	1st name Koichi Middle name Last name Node
Organization	Saga University
Division name	Department of Cardiovascular Medicine
Zip code	849-8501
Address	5-1-1 Nabeshima, Saga
TEL	0952-34-2364
Homepage URL
Email	cardiostudy@ml.cc.saga-u.ac.jp

Sponsor
Institute	Department of Cardiovascular Medicine, Saga University
Institute
Department

Funding Source
Organization	Mitsubishi Tanabe Pharma Corporation
Organization
Division
Category of Funding Organization	Profit organization
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Institutional Review Board,Saga University Hospital
Address	5-1-1 Nabeshima, Saga
Tel	0952-34-3400
Email	kenkyu-shinsei@ml.cc.saga-u.ac.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions

Institutions

佐賀大学医学部附属病院（佐賀県） 名古屋大学医学部附属病院（愛知県） 徳島大学病院（徳島県） 新潟大学医歯学総合病院（新潟県） 福島県立医科大学附属病院（福島県） 獨協医科大学病院（栃木県） 獨協医科大学埼玉医療センター（埼玉県） 日本医科大学付属病院（東京都） 東京医科大学病院（東京都） 亀田総合病院（千葉県） 北里大学病院（神奈川県） 名古屋第一赤十字病院（愛知県） 名古屋市立大学病院（愛知県） 藤田保健衛生大学病院（愛知県） 平光ハートクリニック（愛知県） 三重大学病院（三重県） 大西内科ハートクリニック（三重県） 大阪大学医学部附属病院（大阪府） 大阪府急性期・総合医療センター（大阪府） 関西ろうさい病院（兵庫県） 大阪労災病院（大阪府） 大分大学医学部附属病院（大分県） 済生会熊本病院（熊本県） 三井記念病院（東京都） 自治医科大学附属病院（栃木県） 医療法人旭和会　東京駅センタービルクリニック（東京都） 浦添総合病院（沖縄県） 国際医療福祉大学病院（栃木県） 済生会二日市病院（福岡県） 佐賀県医療センター好生館（佐賀県） 大阪医科大学（大阪府） 桜橋渡辺病院（大阪府） JR広島病院（広島県） 関野病院（東京都） 公立陶生病院（愛知県） 春日井市民病院（愛知県） 関西電力病院（大阪府） 伊万里有田共立病院（佐賀県） 聖マリアンナ医科大学（神奈川県） 石川島記念病院（東京都） 横浜市立大学附属市民総合医療センター（神奈川県）

Other administrative information
Date of disclosure of the study information	2015 Year 05 Month 25 Day

Related information
URL releasing protocol	https://cardiab.biomedcentral.com/articles/10.1186/s12933-016-0381-x
Publication of results	Published

Result
URL related to results and publications	https://onlinelibrary.wiley.com/doi/full/10.1002/ehf2.12707
Number of participants that the trial has enrolled	249
Results	This study did not meet the predefined primary endpoint of non-inferiority of canagliflozin vs. glimepiride, pre-defined as a margin of 1.1 in the upper limit of the two-sided 95% confidence interval for the group ratio of percentage change in NT-proBNP at 24 weeks.
Results date posted	2020 Year 07 Month 29 Day
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics	The mean age was 68.3+-9.8 years old in the canagliflozin group (female n=25 [22.1%]), and the mean age was 68.9+-10.4 years old in the glimepiride group (female n=34 [28.3%]).
Participant flow	A total of 249 patients were enrolled and 245 patients were randomized either the canagliflozin group (122) or glimepiride group (123). Among them, 118 cases (canagliflozin group) and 123 cases (glimepiride group) were included in the safety analysis set, and 113 cases (canagliflozin group) and 120 cases (glimepiride group) were included in the full analysis set.
Adverse events	In the canagliflozin group, two patients had the prespecified and adjudicated clinical events, one non-fatal stroke and one investigator-reported worsening of HF; in the glimepiride group, five patients experienced those events, three investigator-reported worsening of HF events, leading to hospitalization in one patient, and two all-cause deaths. Regarding other major adverse events, we observed osmotic diuresis-related symptom (n=1), hypovolemia-related symptom (n=1), worsening glycemic control (n=2), and non-urinary tract or non-genital infection (n=2) in the canagliflozin group; hypoglycemia (n=2) and non-urinary tract or non-genital infection (n=2) in the glimepiride group.
Outcome measures	Primary endpoint Percentage changes in NT-proBNP were 10.4% (95% CI, -0.54 to 21.26) in the canagliflozin group and 21.5% (95% CI, 7.18 to 35.77) in the glimepiride group, and its group ratio was 0.48 (95% CI, -0.13 to 1.59, P = 0.226). Major secondary endpoint Change volumes of NT-proBNP (baseline-adjusted) were -78.7 pg/mL (95% CI, -139.9 to -17.5) in the canagliflozin group and -4.5 pg/mL (95% CI, -63.4 to 54.4) in the glimepiride group, and its group difference was -74.7 pg/mL (95% CI, -159.3 to 10.9, P = 0.087).
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Main results already published
Date of protocol fixation	2015 Year 03 Month 20 Day
Date of IRB	2015 Year 04 Month 06 Day
Anticipated trial start date	2015 Year 06 Month 01 Day
Last follow-up date	2018 Year 01 Month 31 Day
Date of closure to data entry	2018 Year 01 Month 31 Day
Date trial data considered complete	2018 Year 09 Month 20 Day
Date analysis concluded

Other
Other related information

Management information
Registered date	2015 Year 05 Month 25 Day
Last modified on	2020 Year 07 Month 29 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000020483

Research Plan
Registered date	File name

Research case data specifications
Registered date	File name

Research case data
Registered date	File name

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