Clinical trial NCT02617446: The Clinical Study of the Safety and Efficacy of Istaroxime in Treatment of Acute Decompensated Heart Failure
Official title: The Clinical Study of the Safety and Efficacy of Istaroxime in Treatment of Acute Decompensated Heart Failure - A Multicenter, Randomized, Double-blind, Placebo Controlled, Parallel Group Clinical Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Decompensated Heart Failure
Keywords: safety
efficacy
istaroxime
Lead sponsor: Windtree Therapeutics
Sponsor class: INDUSTRY
First posted: 2015-12-01
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Cohort I: Participants enrolled in a 2:1 ratio to istaroxime 0.5 µg/kg/min or placebo.

Cohort II: Participants enrolled in a 2:1 ratio to istaroxime 1.0 µg/kg/min or placebo.

Cohort I was enrolled first, followed by Cohort II.
Primary purpose: TREATMENT

Brief summary: To assess the safety, tolerability and efficacy of two different doses of istaroxime, a new agent with lusitropic and inotropic activities that improves the cardiac contraction-relaxation cycle. The 2 doses of istaroxime (0.5 and 1.0 µg/kg/min) will be infused via i. v. for 24 hours in comparison with placebo, in treatment of Chinese and Italian patients with Acute Decompensated Heart Failure.

Detailed description: To assess the safety, tolerability and efficacy of two different doses of istaroxime (0.5 and 1.0 µg/kg/min) in comparison with placebo, including cardiovascular and renal tolerability, as well as changes in biological markers such as N-terminal prohormone brain natriuretic peptide (NT-proBNP) and troponin T (cTnT). The study will be conducted in 96 Chinese and Italian patients with Acute Decompensated Heart Failure. This is a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel group study. Patients were randomly assigned to one of two doses of istaroxime or placebo in a 2:1 ratio within two sequential cohorts of 60 patients each. This 31-day study includes a screening period (Days -1), a treatment period (Day 1), a post-treatment period (Days 2-4), and a follow-up period (which includes one patient visit on Day 30).

In all the Italian patients and in a subset of Chinese patients pharmacokinetics and metabolism of istaroxime shall also be studied.

Eligibility criteria: Inclusion Criteria:

Patients who fulfill the following inclusion criteria at screening will be considered for the study:

1. Signed informed consent;
2. Male or female patients 18-85 years (inclusive);
3. Admission for a recurrent acute decompensated heart failure (ADHF) episode with dyspnea at rest or minimal exertion and need of intravenous diuretic therapy (≥40 mg iv. furosemide);
4. Systolic blood pressure between 90 and 125 mmHg (limits included) without signs or symptoms of hypoperfusion including cardiogenic shock, cold extremities and peripheral vasoconstriction, oliguria/anuria, signs of cerebral hypo perfusion such as confusion;
5. Left ventricular (LV) Ejection fraction (EF) ≤ 40 % measured by 2D-Echocardiography
6. E/Ea ratio \>10
7. BNP ≥ 350pg/mL or NT-pro-BNP ≥1400 pg/mL
8. Adequate echocardiography window (defined as visualization of at least 13/16 segment of the left ventricle);

Exclusion Criteria:

Any of the following criteria established at screening would render a patient ineligible for the study:

1. Pregnant or breast-feeding women (women of child bearing potential must have the results of a negative pregnancy test recorded prior to study drug administration)
2. Current (within 12 hours prior to screening) or planned (through the completion of study drug infusion) treatment with any iv. therapies, including vasodilators (including nitrates or nesiritide), positive inotropic agents and vasopressors
3. Current or need of mechanical support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device),
4. Ongoing treatment with oral digoxin. Patient treated with digoxin within the last week, can be randomised if the plasma concentration of digoxin is tested before randomization and its value will be less than 0.5 ng/ml.
5. History of hypersensitivity to the study medication or any related medication
6. Diagnosis of cardiogenic shock within the past month;
7. Acute coronary syndrome or stroke within the past 3 months;
8. Coronary artery bypass graft or percutaneous coronary intervention within the past month or planned in the next month;
9. Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be associated with infiltrative heart disease;
10. Cor pulmonale or other causes of right-sided heart failure (HF) not related to left ventricular dysfunction;
11. Pericardial constriction or active pericarditis;
12. Atrial fibrillation with marked irregularities of heart rhythm;
13. Life threatening ventricular arrhythmia or implantable cardioverter-defibrillator (ICD) shock within the past month;
14. Cardiac resynchronization therapy (CRT), ICD, or pacemaker implantation within the past month;
15. Valvular disease as primary cause of HF;
16. Heart rate \>120 bpm or \< 50 bpm
17. Acute respiratory distress syndrome or ongoing sepsis;
18. Fever \>38°
19. History of bronchial asthma or porphyria;
20. Donation or loss of blood equal to or exceeding 500 mL, during the 8 weeks before administration of study medication;
21. Positive testing for HIV, Hepatitis B and/or Hepatitis C;
22. Participation in another interventional study within the past 30 days;
23. The following laboratory exclusion criteria, verified based on results obtained within the last 24 hours of hospitalization:

    1. Serum creatinine \> 3.0 mg/dl (\> 265 µmol/L);
    2. Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) \> 3 x upper limit of normal,
    3. Hemoglobin (Hb) \< 10 g/dL,
    4. Platelet count \< 100,000/µL,
    5. Serum potassium \> 5.3 mmol/L or \< 3.8 mmol/L,

Primary outcomes:
measure: Change in E/Ea Ratio
timeFrame: 24 hours
Secondary outcomes:
measure: Change in LVEF
timeFrame: 24 hours
measure: Change in SVI
timeFrame: 24 hours
measure: Change in E/A Ratio
timeFrame: 24 hours
measure: Change in LV End Systolic Volume
timeFrame: 24 hours
measure: Change in LV End Diastolic Volume
timeFrame: 24 hours
measure: Change in Dyspnea
timeFrame: 24 hours
Other outcomes:
measure: Change in cTnT
timeFrame: 24 hours
measure: Change in eGFR
timeFrame: 24 Hours
measure: Participants With Clinically or Hemodynamically Significant Episodes of Arrhythmias
timeFrame: 24 hours
measure: PR Interval
timeFrame: 24 Hours
measure: QRS Duration
timeFrame: 24 hours
measure: QTc Interval
timeFrame: 24 Hours
measure: All-Cause Mortality at Day 30
timeFrame: 30 days
measure: RBC - Shift
timeFrame: Day 3
measure: Hematocrit - Shift
timeFrame: Day 3
measure: Hemoglobin - Shift
timeFrame: Day 3
measure: White Blood Cells (WBC) - Shift
timeFrame: Day 3
measure: Platelets - Shift
timeFrame: Day 3
measure: Potassium - Shift
timeFrame: Day 3
measure: Sodium - Shift
timeFrame: Day 3
measure: Calcium - Shift
timeFrame: Day 3
measure: BUN - Shift
timeFrame: Day 3
measure: ALT - Shift
timeFrame: Day 3
measure: AST - Shift
timeFrame: Day 3
measure: Total Bilirubin - Shift
timeFrame: Day 3
Locations:
city: Lanzhou
country: China
facility: Lanzhou University No.2 Hospital
state: Gansu
city: Lanzhou
country: China
facility: The First Hospital of Lanzhou University
state: Gansu
city: Wuhan
country: China
facility: Renmin Hospital of Wuhan University
state: Hubei
city: Nanjing
country: China
facility: Jiangsu Province People's Hospital
state: Jiangsu
city: Shenyang
country: China
facility: The General Hospital Of Shenyang Military Region
state: Liaoning
city: Xi'an
country: China
facility: The First Affiliated Hospital Of Xi'an Jiaotong University
state: Shaanxi
city: Beijing
country: China
facility: Fuwai Hospital Chinese Academy of Medical Sciences
city: Beijing
country: China
facility: Beijing Chao Yang Hospital
city: Beijing
country: China
facility: The 307th Hospital of Chinese People's Liberation Army
city: Brescia
country: Italy
facility: University and Civil Hospital of Brescia
city: Milan
country: Italy
facility: University of Milano-Bicocca
Study officials:
affiliation: Windtree Therapeutics, Inc.
name: Giuseppe Bianchi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Carubelli V, Zhang Y, Metra M, Lombardi C, Felker GM, Filippatos G, O'Connor CM, Teerlink JR, Simmons P, Segal R, Malfatto G, La Rovere MT, Li D, Han X, Yuan Z, Yao Y, Li B, Lau LF, Bianchi G, Zhang J; Istaroxime ADHF Trial Group. Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: a randomised, placebo-controlled trial. Eur J Heart Fail. 2020 Sep;22(9):1684-1693. doi: 10.1002/ejhf.1743. Epub 2020 Jan 23.