The Clinical Study of the Safety and Efficacy of Istaroxime in Treatment of Acute Decompensated Heart Failure

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Decompensated Heart Failure
• Intervention / Treatment: Drug: Placebo; Drug: Istaroxime

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Beijing Chao Yang Hospital
  • Beijing, China, 100037
    • Fuwai Hospital Chinese Academy of Medical Sciences
  • Beijing, China
    • The 307th Hospital of Chinese People's Liberation Army
  • Gansu
    • Lanzhou, Gansu, China
      • The First Hospital of Lanzhou University
    • Lanzhou, Gansu, China
      • Lanzhou University No.2 Hospital
  • Hubei
    • Wuhan, Hubei, China
      • Renmin Hospital of Wuhan University
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Jiangsu Province People's Hospital
  • Liaoning
    • Shenyang, Liaoning, China
      • The General Hospital Of Shenyang Military Region
  • Shaanxi
    • Xi'an, Shaanxi, China
      • The First Affiliated Hospital of Xi'an Jiaotong University
• Italy
  • Brescia, Italy
    • University and Civil Hospital of Brescia
  • Milan, Italy
    • University of Milano-Bicocca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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,

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; IV infusion of placebo for 24 hours	Drug: Placebo; IV of matching saline solution
Experimental: Istaroxime 0.5 µg/kg/min; The istaroxime treatment dosed at 0.5 µg/kg/min via IV infusion for 24 hours	Drug: Istaroxime; IV infusion of 0.5 µg/kg/min or 1.0 µg/kg/min istaroxime
Experimental: Istaroxime 1.0 µg/kg/min; The istaroxime treatment dosed at 1.0 µg/kg/min via IV infusion for 24 hours	Drug: Istaroxime; IV infusion of 0.5 µg/kg/min or 1.0 µg/kg/min istaroxime

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in E/Ea Ratio	Change from baseline at 24 hours in the unitless ratio of E (cm/sec) to Ea (or e') (cm/sec) as measured by echocardiogram. The endpoint is the Tissue Doppler echocardiography showing measurement of mitral E/Ea ratio for assessment of diastolic dysfunction. Initially mitral E wave is measured. After that, color Tissue Doppler (tissue velocity imaging or TVI) mode is switched on to assess tissue Doppler. The cursor is placed over the medial mitral annulus and tissue Doppler tracing obtained. This allows Ea velocity to be measured. Higher values are suggestive of a worse outcome; less than 8 is normal.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in LVEF	Change from baseline at 24 hours in LV ejection fraction (LVEF) by tissue Doppler	24 hours
Change in SVI	Change from baseline at 24 hours in stroke volume index (SVI) by tissue Doppler	24 hours
Change in E/A Ratio	Change from baseline at 24 hours in E/A ratio by tissue Doppler	24 hours
Change in LV End Systolic Volume	Change from baseline in left ventricular end systolic volume (LVESV) by tissue Doppler	24 hours
Change in LV End Diastolic Volume	Change from baseline in left ventricular end diastolic volume (LVEDV) by tissue Doppler	24 hours
Change in Dyspnea	Measured using a visual analog scale (0 to 100). Higher scores indicate less dyspnea.	24 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cTnT	Safety endpoint: Changes in troponin (cTnT)	24 hours
Change in eGFR	Safety endpoint: Change from baseline in estimated glomerular filtration rate (eGFR)	24 Hours
Participants With Clinically or Hemodynamically Significant Episodes of Arrhythmias	Safety endpoint: Number of participants with incidence of clinically or hemodynamically significant episodes of supraventricular or ventricular arrhythmias detected by continuous ECG dynamic monitoring	24 hours
PR Interval	Safety Endpoint: The PR interval, measured in milliseconds, extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex (the onset of ventricular depolarization).	24 Hours
QRS Duration	Safety endpoint: The quasi-random signal (QRS) duration represents the time for ventricular depolarization, normally 0.06 to 0.10 seconds.	24 hours
QTc Interval	Safety Endpoint: The corrected QT interval (QTc) on an ECG represents the duration in milliseconds of the ventricular action potential, which physiologically correlates with the duration of the ventricular depolarization and repolarization.	24 Hours
All-Cause Mortality at Day 30	Safety endpoint: Mortality at Day 30	30 days
RBC - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in red blood cells (RBC)	Day 3
Hematocrit - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in hematocrit	Day 3
Hemoglobin - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in hemoglobin	Day 3
White Blood Cells (WBC) - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in WBC	Day 3
Platelets - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in platelets	Day 3
Potassium - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in potassium	Day 3
Sodium - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in sodium	Day 3
Calcium - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in calcium	Day 3
BUN - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in blood urea nitrogen (BUN)	Day 3
ALT - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in alanine aminotransferase (ALT)	Day 3
AST - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in aspartate aminotransferase (AST)	Day 3
Total Bilirubin - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in total bilirubin	Day 3

Collaborators and Investigators

• Sponsor: Windtree Therapeutics
• Collaborators: CVie Therapeutics Co. Ltd.
• Investigators: Principal Investigator: Giuseppe Bianchi, MD, Windtree Therapeutics, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Actual): August 14, 2018
• Study Completion (Actual): February 6, 2019

Study Registration Dates

• First Submitted: July 9, 2015
• First Submitted That Met QC Criteria: November 25, 2015
• First Posted (Estimate): December 1, 2015

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: April 27, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: safety; efficacy; istaroxime
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CVT-CV-002; 2013-000540-26 (EudraCT Number); 2015L00219 (Other Identifier: National Medical Products Administration (China))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No