| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Renal Function in Subjects with Congestive Heart Failure and Impaired Renal Function who are on Chronic Furosemide Treatment |
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| 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 | 10010684 |
| E.1.2 | Term | Congestive heart failure |
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| 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 |
To compare five SLV320 doses (1, 2.5, 5, 10 and 20 mg orally twice daily) to placebo regarding the change from baseline in cystatin C at endpoint.
Baseline is defined as the last observation prior to the first administration of the study drug.
Endpoint is defined as Visit 8 (Day 85). In the case of a premature discontinuation (less than 77 days on study drug), there will be no endpoint value.
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| E.2.2 | Secondary objectives of the trial |
-To compare five SLV320 doses to placebo regarding the change in the following variables from baseline to all relevant post-baseline treatment visits:
Cystatin C.
Concentration of sodium, potassium, chloride, creatinine, uric acid, adenosine and albumin in a spot urine sample.
The fractional excretion of sodium, potassium, chloride, creatinine, uric acid and albumin in urine.
Estimated glomerular filtration rate.
Total daily dose of furosemide.
Body weight.
Plasma catecholamines, NT-proBNP, angiotensin II, aldosterone and high sensitive C-reactive protein.
Troponin I, glycosylated hemoglobin (HbA1c), fasting glucose, fasting insulin, calcium and magnesium.
Biomarkers for cardiac remodeling.
Clinical Global Impression
Dose-response relationship for cystatin C, sodium and eGFR.
-To evaluate the trough plasma concentrations prior to the morning dose of five SLV320 doses.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
In a sub-set of subjects (at least 20 subjects per group):
-To evaluate, on Visit 1 (Day 1), Visit 5 (Day 43) and Visit 8 (Day 85), the pharmacokinetic (PK) parameters of SLV320: AUC0-t, AUC, Cmax, tmax, CL/F, Vz/F, t1/2 and λz as well as the dose normalized AUC0-t, AUC, and Cmax. On Visit 5 (Day 43) and Visit 8 (Day 85) AUC0-τ will also be determined.
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| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be included in the study:
1.Men and women aged 18 years to 85 years.
2.Informed consent must be obtained from each subject before any study-related procedure is performed.
3.Subjects must have a history of chronic, symptomatic NYHA Class II-III CHF and impaired renal function (baseline eGFR of 20 to 75 mL/min/1.73m2) for at least 3 months before Visit 1 (Day 1).
The Modification of Diet in Renal Disease (MDRD) equation to estimate GFR can be found on page 37 of the protocol (22 Mar 2007)
Cockcroft-Gault equation may be used as an alternative to the MDRD equation if an albumin value is not available, for this inclusion criterion only.
Cockcroft-Gault equation to estimate GFR:
eGFR (ml/min/1.73 qm)=(140-age in years) x (Body weight in kg) x (0,85 if female) / (72 x Serum creatinine in mg / dl).
4.Subjects must be on chronic treatment with furosemide ≥40 mg daily for at least 3 weeks before Visit 1 (Day 1).
5. Subjects should be receiving „disease modifying“ CHF therapy for at least 3 months before Visit 1 (Day 1)
The subject should have been receiving a stable, optimal, dose of such „disease modifying“ CHF therapy for at least 4 weeks before Visit 1 (Day 1).
“Disease modifying” therapy includes an ACE inhibitor, ARB, beta-blocker, aldosterone antagonist (e.g. spironolactone or eplerenone) and the combination of hydralazine and isosorbide dinitrate.
All subjects should be taking both an ACE inhibitor (or ARB) and a beta-blocker, unless there is intolerance or a contraindication or another medical reason, which must be documented.
Subjects treated with amiodarone must also have been taking a stable dose for at least 4 weeks before Visit 1 (Day 1).
6.The subject must be male, female of non-childbearing potential or female of childbearing potential with an accepted birth control method.
Females with childbearing potential may be enrolled providing that:
-She is routinely using a medically accepted method of birth control. Medically accepted methods of birth control are defined as the use of either a contraceptive implant, a contraceptive injection, an intra-uterine device or an oral contraceptive for at least 3 months before Visit 1 (Day 1), and which she agrees to continue using during the study, or a double-barrier method which has to consist of a combination of any two of the following: diaphragm, cervical cap, condom, or spermicide.
-She agrees not to attempt at becoming pregnant during the study.
-A female of non-childbearing potential is defined as one who has been post-menopausal for at least 24 months, was surgically sterilized (bilateral tubal ligation) or had a hysterectomy prior to screening.
7. Subjects with an implantable cardioverter defibrillator (ICD) must have had their device implanted at least 3 months before Visit 1 (Day 1).
8. Subjects with a biventricular pace maker (cardiac resynchronization therapy) must have had their device implanted at least 6 months before Visit 1 (Day 1).
9. Subjects undergoing coronary revascularization (percutaneous or surgical) or any other cardiac surgical procedure or device implantation should have had this performed at least 6 months before Visit 1 (Day 1). |
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| E.4 | Principal exclusion criteria |
1.Any female of childbearing potential without adequate contraception. Any female who is pregnant or breastfeeding.
2.The subject's condition is so unstable that he / she may require hospitalization (for cardiovascular disease) or adjustment of background medications for CHF.
3.Hospitalization within 7 days before Visit 1 (Day 1).
NB:A subject who was recently discharged from the hospital (less than 7 days) may not be randomized at that time, but may be reconsidered for Visit 1 (Day 1), after he / she is stabilized for at least 7 days.
4.Evidence of any significant respiratory, urogenital, gastro-intestinal, hepatic, hematological, immunologic, head, ears, eyes, nose, throat (HEENT), dermatologic, connective tissue, musculoskeletal, metabolic, nutritional, endocrine, neurological, psychiatric diseases, allergy, major surgery or other relevant diseases as revealed by history, physical examination and / or laboratory assessments which might limit participation in or completion of the study.
5.Recent or chronic gastro-intestinal, hepatic, or biliary disorder that could impair absorption, metabolism, or excretion of orally administered medication.
6.Subjects with malignant tumors with a short life expectancy and / or severe infection.
7.Concomitant use of other investigational drugs or use of any investigational agent within 30 days before Visit 1 (Day 1), and within at least 10 half-life times of that agent before Visit 1 (Day 1).
8.Any history of a severe abnormal medication reaction.
9.Subjects with fever of ≥ 38˚C.
10.Subjects with significant liver disease or with serum transaminase concentrations (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) more than three times the upper limit of the normal reference range.
11.Subjects with uncontrolled diabetes (fasting serum glucose > 11 mmol/L [> 197 mg/dL]).
12.Subjects with eGFR < 20 mL/min/1.73m2 calculated by the MDRD equation.
The MDRD equation to estimate GFR can be found on page 38 of the Protocol (Date: 22 Mar 2007)
13.Subjects with serum potassium < 3.5 mmol/L or > 5.5 mmol/L.
14.Subjects with hemoglobin of < 9 g/dL (< 90 g/L) or hematocrit of < 30%.
15.Subjects with bilateral renal artery stenosis (from medical history).
16.Any history of a convulsive disorder or pre-convulsive state and any risk for a convulsive disorder or pre-convulsive state (for example any past brain trauma, abuse of alcohol etcetera).
17.Subjects may not be related to the Investigator in any way (family relation, practice workers etcetera).
18.Inability to return for scheduled visits.
19.Any condition associated with poor compliance including alcoholism, mental illness or medication dependence. Inability of the subject to understand and follow the requirements of the protocol in the language of the Investigator.
20.Any other reason, in the Investigator’s opinion, that prohibits inclusion of the subject into the study.
21.Subjects receiving selective inhibitors of serotonin reuptake (such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) or other drugs that could produce hyponatremia
22.Subjects receiving Ciprofloxacin within 14 days before visit 1 (day 1). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change from baseline to endpoint in cystatin C. Endpoint is defined as Visit 8 (Day 85). |
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| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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