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

Acute Decompensated Heart Failure Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02617446
• Other study ID #: CVT-CV-002
• Secondary ID: 2013-000540-2620
• Status: Completed
• Phase: Phase 2
• Start date: December 2015
• Est. completion date: February 6, 2019

Study information

• Verified date: April 2023
• Source: Windtree Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: February 6, 2019
• Est. primary completion date: August 14, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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,

Related Conditions & MeSH terms

• Acute Decompensated Heart Failure
• Heart Failure

Intervention

Drug:
• Placebo
IV of matching saline solution
• Istaroxime
IV infusion of 0.5 µg/kg/min or 1.0 µg/kg/min istaroxime

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Windtree Therapeutics

Countries where clinical trial is conducted

China,  Italy, 

References & Publications (1)

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 i — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in cTnT	Safety endpoint: Changes in troponin (cTnT)	24 hours
Other	Change in eGFR	Safety endpoint: Change from baseline in estimated glomerular filtration rate (eGFR)	24 Hours
Other	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
Other	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
Other	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
Other	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
Other	All-Cause Mortality at Day 30	Safety endpoint: Mortality at Day 30	30 days
Other	RBC - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in red blood cells (RBC)	Day 3
Other	Hematocrit - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in hematocrit	Day 3
Other	Hemoglobin - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in hemoglobin	Day 3
Other	White Blood Cells (WBC) - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in WBC	Day 3
Other	Platelets - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in platelets	Day 3
Other	Potassium - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in potassium	Day 3
Other	Sodium - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in sodium	Day 3
Other	Calcium - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in calcium	Day 3
Other	BUN - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in blood urea nitrogen (BUN)	Day 3
Other	ALT - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in alanine aminotransferase (ALT)	Day 3
Other	AST - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in aspartate aminotransferase (AST)	Day 3
Other	Total Bilirubin - Shift	Safety endpoint: Baseline normal/abnormal to Day 3 normal/abnormal in total bilirubin	Day 3
Primary	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	Change in LVEF	Change from baseline at 24 hours in LV ejection fraction (LVEF) by tissue Doppler	24 hours
Secondary	Change in SVI	Change from baseline at 24 hours in stroke volume index (SVI) by tissue Doppler	24 hours
Secondary	Change in E/A Ratio	Change from baseline at 24 hours in E/A ratio by tissue Doppler	24 hours
Secondary	Change in LV End Systolic Volume	Change from baseline in left ventricular end systolic volume (LVESV) by tissue Doppler	24 hours
Secondary	Change in LV End Diastolic Volume	Change from baseline in left ventricular end diastolic volume (LVEDV) by tissue Doppler	24 hours
Secondary	Change in Dyspnea	Measured using a visual analog scale (0 to 100). Higher scores indicate less dyspnea.	24 hours