CAN‐DHF.

Study characteristics
Methods	Study design: two‐arm, individual, placebo‐controlled RCT Centres: 8 sites in Germany Start of enrolment: January 2008 End of enrolment: December 2008 Follow‐up: 24 weeks Run‐in period: not reported
Participants	Inclusion criteria: "Male or female patients of at least 45 years of age suffering from a non‐insulin dependent diabetes mellitus type 2 orally treated for at least 3 months and showing normotension or controlled hypertension with sitting systolic blood pressure (sSBP) < 140 mmHg and/or sitting diastolic blood pressure (sDBP) < 90 mmHg. Evidence of an abnormal left ventricular relaxation, diastolic distensibility or diastolic stiffness confirmed by echocardiography under the prerequisite of a preserved Left ventricular ejection fraction (LVEF) ≥ 45%. NT‐proBNP ≥ 250 pg/ml at baseline, NYHA class II or III in stable condition since 3 months, and standard HF‐ therapy with an ACE‐inhibitor alone or with further preparations in a constant regimen since at least 1 month (3 months in terms of β‐blockers). Signed written informed consent available." Exclusion criteria: "The following criteria must not be met to enrol a single patient into the study: Impaired renal function (serum creatinine > 2.2 mg/dL or > 194 µmol/l); Known bilateral renal artery stenosis (RAS) or interventional treatment for RAS in the last year; State after kidney transplantation; Serum potassium > 5.5 mmol/l or HbA1C > 9.5 %; Cor pulmonale or primary pulmonary disease with dyspnea at rest; Known disposition to episodes of symptomatic hypotension or sSBP < 95 mmHg at baseline; Acute coronary syndrome or unstable angina pectoris and any coronary artery disease that was not stable during the last 3 months prior to inclusion; CABG or PTCA (incl. stent implantation) within 3 months before inclusion; Myocardial infarction or stroke within 6 months before inclusion; Patients who are dependent on a permanently paced pacemaker (i.e. a patient with a device that is not pacing during the echocardiographic examination can enter the study); Open heart surgery for other reasons than coronary revascularization; Tachycardia at rest > 100 bpm as confirmed by ECG‐recordings; Known clinically relevant rhythm disorders (e.g. tachyarrhythmias, salves of supraventricular or ventricular extrasystoles or atrial fibrillation without ventricular rate control) or symptoms suggesting a significant rhythm disorder (e.g. recurrent syncopes); Primary valvular diseases and/or restrictive or obstructive cardiomyopathy ‐ Existing ventricular assist devices; Relevant liver diseases (cholestasis or ALAT/ASAT > 2xULN or GT > 3xULN); History of primary hyperaldosteronism; of cancer in the last 5 years (exception: nonmetastasizing skin cancer) or of another wasting disease with life expectancy of < 2 years; Known hypersensitivity to Candesartan Cilexetil; Need for maintenance therapy with NSAIDs or Cox‐2‐inhibitors; Use of other ARBs throughout the entire study period; Any history of life‐threatening diseases; History of drug addiction and/or an extensive use of alcohol; Female patients who are pregnant or breast feeding; Sexually active women of childbearing potential not consistently and correctly practicing highly effective birth control with a low failure rate (less than 1% / year) such as implants, injectables, combined oral contraceptives, hormonal intrauterine devices (IUDs), sexual abstinence or vasectomised partner; Psychological and/or emotional problems, which render the informed consent invalid or limit the ability of the patient to comply with the study requirements; Patient is an employee or at least in dependence of the investigator and/or the sponsor or of another institution directly involved in the study or other trials under the investigator's direction; Participation in another clinical investigation within 30 days prior to enrolment or for the course of the present study (incl. studies for compassionate use or experimental medical devices)." Randomised (N): 22 (11 intervention, 11 control) Withdrawn (N): for reasons other than death 14 (intervention: 3 premature study termination, 3 adverse events, 1 randomisation /enrolment error, control: 4 premature study termination, 2 adverse events, 1 randomisation / enrolment error) Lost to follow‐up (N): 0 Analysed (N): 22 (11 intervention, 11 control) Age (years, mean, SD): intervention: 67.0, 16.8; control: 69.0, 7.1 Sex (% men): intervention: 64; control: 55 Ethnicity (%): not reported Systolic blood pressure not reported Heart rate not reported BMI (mean, SD): intervention: 31.4, 5.0; control: 30.0, 5.7 Serum creatinine not reported B‐type natriuretic peptide (pg/mL): not reported NT pro B‐type natriuretic peptide (pg/mL): not reported LVEF not reported NYHA class: not reported Hypertension (%): not reported Diabetes (%): not reported Atrial fibrillation (%): not reported Hospitalisation for heart failure: not reported Myocardial infarction (%): not reported Stroke (%): not reported Diuretic (%): not reported Digoxin (%): not reported Beta‐blocker (%): not reported ACEI (%): not reported ARB (%): study drug MRA (%): not reported
Interventions	Intervention: candesartan. 8‐32mg as tolerated. "The treatment comprised a titration period of 6 weeks and a period of constant study therapy of at least 18 weeks" Comparator: placebo Concomitant medication: "in an "added" regimen to a constant background‐HF‐therapy with at least ACE‐inhibitors (or further drugs) for the treatment of symptomatic heart failure with diastolic dysfunction in diabetic and hypertensive patients" exclusion criteria: use of other ARB
Outcomes	Planned: primary: mean change from baseline for NT‐proBNP, secondary: QoL, kidney function, NYHA, body weight, BP and echocardiographic measures, adverse events, rate of premature withdrawals Reported: as planned except QoL
Notes	This trial was terminated prematurely and the results are available via a clinical trial registry entry only. No outcome data relevant to this review reported (confirmed by sponsor Takeda via Email).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	not reported
Allocation concealment (selection bias)	Unclear risk	not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐blind" but no detail
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	no information
Selective reporting (reporting bias)	Low risk	all outcomes reported as planned except QoL
Other bias	High risk	"the study was terminated prematurely as a whole by the sponsor in December 2008 since randomization of patients was very poor until that date (low and slow recruitment (N = 42) with a high number (N = 20) of screening failures)" Takeda funded the study. The study results are unpublished and only available via the clinical trial registry entry.