Safety and Efficacy Study to Evaluate the Effect of SLV320 on Renal Function in Patients With Worsening Heart Failure

The purpose of this study is to determine the efficacy and safety of IV SLV320 in acute heart failure patients with renal dysfunction.

• SLV320 (Drug): 1.25mg i.v. bid
• SLV320 (Drug): 3.75mg i.v. bid
• SLV320 (Drug): 7.5mg i.v. bid
• SLV320 (Drug): 15.0mg i.v. bid
• Placebo (Drug)

Primary outcomes

• Change in serum creatinine from baseline to Day 14 [Day 14]

Secondary outcomes

• To compare four SLV320 doses to placebo on the change in the following variables: Dyspnea (Likert Scale and PDA scale), eGFR (MDRD Formula), Subject Global Clinical Assessment Score, Urine Osmolality, Serum Osmolality [Up to Day 3 (Dyspnea); Up to Day 4 (Urine Osmolality); Up to Day 60 (eGFR, Subject Global Clinical Assessment Score, Serum Osmolality)]
• To compare the effect of four I.V. doses of SLV320 with placebo using the trichotomous endpoint of treatment success, treatment failure, or no change [Up to Day 14]
• To compare the effect of four I.V. doses of SLV320 with placebo on top of diuretic use [Up to Day 3]
• To compare the effect of four I.V. doses of SLV320 with placebo using a composite endpoint of all-cause mortality, cardiovascular hospitalization or hospitalization for worsening renal function, in time to event and frequency [Up to Day 180]
• To determine the pharmacokinetic profile of I.V. SLV320 [Up to Day 3]

Sex: All, ages: 18 Years to any

Inclusion Criteria Renal dysfunction defined as estimated eGFR of 20-80 mL/min; history of systolic or diastolic chronic heart failure of at least 14 days duration for which loop diuretic therapy has been prescribed; clinical evidence for volume overload; BNP ≥ 500 pg/mL or NT-pro-BNP > 2000 pg/mL; hospitalization.

Exclusion Criteria Have low output syndrome, defined as having the need for treatment with I.V. inotropes or vasopressors; Need mechanical ventilation; Have significant stenotic valvular disease (severe aortic or mitral stenosis); Have myocardial infarction or hemodynamically destabilizing significant arrythmias (ventricular tachycardia, bradyarrythmias with slow ventricular rate \[<45 bpm\] or atrial fibrillation/flutter with a rapid ventricular response of >120 bpm), or electrocardiographic evidence of 2nd degree heart block (Mobitz Type II) or 3rd degree AV-block in the absence of a pacemaker, within 30 days of screening; Have acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy

5 more sites not listed.

• Results publication: Pang PS, Mehra M, Maggioni AP, Filippatos G, Middlebrooks J, Turlapaty P, Kazei D, Gheorghiade M; RENO-DEFEND Investigators. Rationale, design, and results from RENO-DEFEND 1: a randomized, dose-finding study of the selective A1 adenosine antagonist SLV320 in patients hospitalized with acute heart failure. Am Heart J. 2011 Jun;161(6):1012-23.e3. doi: 10.1016/j.ahj.2011.03.004. PMID 21641345

• Robyn Bethany, Study director, Solvay Pharmaceuticals

NIH grants: 2008