| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Symptomatic heart failure with diastolic dysfunction in diabetic and hypertensive patients |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019279 |
| E.1.2 | Term | Heart failure |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052337 |
| E.1.2 | Term | Diastolic dysfunction |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Determination of NT-proBNP and its correlation to other objective HF-parameters (NYHA-class, SF-36-score, BP-control, kidney function, metabolic state) to generate efficacy data for optimization of therapy in heart failure with a preserved ejection fraction over a 6-month therapy with the angiotensin-II type-I receptor-blocker Candesartan Cilexetil (CC) compared to Placebo. CC or placebo will be administered 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 isolated diastolic dysfunction in diabetic and hypertensive patients. |
|
| E.2.2 | Secondary objectives of the trial |
| Mean change from: V1 to V4 and V4 to V6 for NT-proBNP; V1 to V6 for SF-36-score, Adiponectin, Cystatin C, HbA1C and UAE as well as for the kidney function; V0 to V6 for NYHA-, body weight-, BP- and echocardiographic results. Correlations of NT-proBNP with NYHA-class, SF-36-score and BP-results. Subgroup evaluations: regarding ß-blocker therapyand NYHA-class; in terms of the different possible dosages during the period of constant therapy (V4 to V6); based on different baseline levels of eGFR, Cystatin C and NT-proBNP. Comparison between V1, V4 and V6 concerning the concomitant use of loop diuretics. Evaluation on any new onset or recurrence of atrial fibrillation during the study period. Safety Variables: Development of laboratory parameters; ECG recording and echocardiography at V0 and V6 including appropriate evaluation; development of physical examination parameters and vital signs including monitoring of BW; incidence of Adverse Events. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or female patient of at least 45 years of age
- Diabetes mellitus type 2 - insulin dependent or orally treated or managed by diet for at least
3 months
- Normotension or controlled hypertension with sSBP < 140 mmHg and/or sDBP < 90 mmHg
- Regular sinus rhythm or atrial fibrillation with a medicamentally achieved rate control of less
than 100 bpm as confirmed by ECG-recordings (see also additional criteria 4.4)
- Echocardiographic evidence of a preserved LVEF ≥ 45% (assessed by the modified Simpson-
method) with further doppler-echocardiographic criteria for diastolic dysfunction grade I-IV.
Each grade must be confirmed by 3 of the following 5 parameters
(validated for sinus rhythm):
Grade E/A DT S/D E/E’ VP_
Impaired relaxation (I) ≤0,75 >220 >1 <10 >45
Pseudonormalisation (II) 0,75-1, 5 150-220 <1 ≥10 <45
Restrictive filling (III/IV*) >1,5 ≤150 <<1 ≥10 <45
* The lack of E/A- reversibility under valsalva manoeuvre connotes grade IV
- NYHA-classification of II or III in a stable condition since at least 3 months
- Existing background HF-therapy with an ACEI alone or together with further preparations in a
constant regimen since at least 1 month, in case of β-blockers since at least 3 months
- NT-proBNP ≥ 220 pg/ml measured at screening visit or collected from a dated previous
laboratory document not older than 3 months
- No previous therapy with ARBs during the last 4 weeks prior to the study
- A woman of childbearing potential must have a negative pregnancy test before study start
and must plan not to become pregnant during the study
- A woman of non-childbearing potential can be included if she was surgically sterilized or
hysterectomized at least three months before study start or when the postmenopausal status
was confirmed by a period of amenorrhoe of at least 12 months plus concomitant adequate
hormone levels (i.e., FSH > 40 MIE/ml and estrogen < 30 pg/ml or negative estrogen test)
- Available signed written informed consent
|
|
| E.4 | Principal 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: non-
metastasizing 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)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable will be the mean change from baseline (V1) compared to the final study visit (V6) of the objective primary study endpoint NT-proBNP during the planned 24-week period of study treatment. The change will be calculated as the NT-proBNP value at baseline (V1; day 0) minus the NT-proBNP value at the final visit (V6; day 168±8). The natural logarithmic transformation will be applied to the NT-proBNP values because of their expected skewed distribution.
Patients who terminated treatment before end of week 24 will be considered with their individual last value under study medication (last-observation-carried-forward method; LOCF). In case of missing baseline values for NT-proBNP, results from the screening visit (V0) will be used.
Absolute values and changes from baseline will be presented for NT-proBNP values after 24 weeks of treatment (and at each scheduled time point) using descriptive summary statistics. Moreover percentage changes from baseline will be displayed. Presentation of summary descriptive results will also include display of the untransformed NT-proBNP values.
The confirmatory inferential statistical analysis of the primary study endpoint will be performed with the same test procedure as used for the sample size calculation, i.e. the one-sided t-test for two independent samples. The t-test will be calculated with the parameter estimates of an analysis of covariance (ANCOVA) using the primary target parameter as dependent variable, the treatment group as fixed factor and the baseline NT-proBNP value as covariate. In addition, exploratory ANCOVA will be done using baseline eGFR and Cystatin C values as covariates. Exploration of possible heterogeneity of treatment effects across centers will be provided in a descriptive manner only, e.g. by graphical display of the results of individual centers.
The confirmatory analysis of the primary efficacy variable will be done for the full analysis set. Additional efficacy analyses will be conducted for the per-protocol analysis set. The p-values of these analyses will be interpreted in the exploratory sense only.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 45 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | |
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