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

• ClinicalTrials.gov Identifier: NCT02617446
• Recruitment Status: Unknown
• First Posted: December 1, 2015
• Last Update Posted: September 1, 2017
• Sponsor: Lee's Pharmaceutical Limited
• Collaborator: CVie Therapeutics Co. Ltd.
• Information provided by (Responsible Party): Lee's Pharmaceutical Limited

Study Description

Brief Summary:

To Assess the safety, tolerability and efficacy of two different doses of istaroxime (0.5 and 1.0 µg/kg/min), 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 i. v. for 24 hours in comparison with placebo, in treatment of Chinese and Italian patients with Acute Decompensated Heart Failure. In all the Italian patients and in a subset of Chinese patients pharmacokinetics and metabolism of istaroxime shall also be studied.

Condition or disease	Intervention/treatment	Phase
Acute Decompensated Heart Failure	Drug: placebo; Drug: Istaroxime	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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 Start Date: December 2015
• Estimated Primary Completion Date: August 2018
• Estimated Study Completion Date: October 2018

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; i.v. infusion for 24 hours	Drug: placebo
Active Comparator: treatment; The 2 doses of istaroxime (0.5 and 1.0 µg/kg/min) will be infused i. v. for 24 hours in comparison with placebo, in treatment of Chinese and Italian patients with Acute Decompensated Heart Failure.	Drug: Istaroxime

Outcome Measures

Primary Outcome Measures :

1. Primary efficacy end-point: Change of E/Ea ratio assessed by tissue Doppler. [ Time Frame: 24 hours ]
   Change of E/Ea ratio assessed by tissue Doppler.

Secondary Outcome Measures :

1. Second efficacy endpoint: Change in LV Ejection fraction (EF) (Echo-Doppler parameter) [ Time Frame: 24 hours ]
   Change from baseline to 24 hours in the treatment period Day1 (addressing the differences between the changes at 6 and 24 hours from baseline) of the following Echo-Doppler parameters: LV Ejection fraction (EF)
2. Second efficacy endpoint: Change in Stroke volume index (SVI) (Echo-Doppler parameter) [ Time Frame: 24 hours ]
   Change from baseline to 24 hours in the treatment period Day1 (addressing the differences between the changes at 6 and 24 hours from baseline) of the following Echo-Doppler parameters: Stroke volume index (SVI)
3. Second efficacy endpoint: Change in E, A and E/A ratio (Echo-Doppler parameter) [ Time Frame: 24 hours ]
   Change from baseline to 24 hours in the treatment period Day1 (addressing the differences between the changes at 6 and 24 hours from baseline) of the following Echo-Doppler parameters: E, A and E/A ratio
4. Second efficacy endpoint: Change in LV end systolic and end diastolic volumes (Echo-Doppler parameter) [ Time Frame: 24 hours ]
   Change from baseline to 24 hours in the treatment period Day1 (addressing the differences between the changes at 6 and 24 hours from baseline) of the following Echo-Doppler parameters:LV end systolic and end diastolic volumes
5. Safety endpoint: Incidence of adverse events [ Time Frame: 30 days ]
   Incidence of adverse events
6. Safety endpoint: Change in vital signs (including body temperature and dyspnoea) [ Time Frame: 24 hours ]
   • Change in vital signs (including body temperature and dyspnoea);
7. Safety endpoint: Change in 12-lead ECG parameters [ Time Frame: 24 hours ]
   Change in 12-lead ECG parameters;
8. Safety endpoint: Incidence of clinically or hemodynamically significant episodes of supraventricular or ventricular arrhythmias detected by continuous ECG dynamic monitoring [ Time Frame: 24 hours ]
9. Safety endpoint: Change in laboratory parameters (hematology, blood chemistry and urinalysis) [ Time Frame: 24 hours ]
   Change in laboratory parameters (hematology, blood chemistry and urinalysis);
10. Safety endpoint: Change in in cTnT [ Time Frame: 24 hours ]
11. Safety endpoint: Incidence of cTnT elevation [ Time Frame: 24 hours ]
12. Safety endpoint: Mortality at Day 30 [ Time Frame: 30 days ]
    • Mortality at Day 30
13. Plasma and urine PK profile: AUC [ Time Frame: 24 hours ]
    AUC
14. Plasma and urine PK profile: Cmax [ Time Frame: 24 hours ]
    Cmax

Eligibility Criteria

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

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 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 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 ICD (implantable cardioverter defibrillator) shock within the past month;
14. CRT (cardiac resynchronization therapy), 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,

Contacts and Locations

Locations

China

Fuwai Hospital Chinese Academy of Medical Sciences; Recruiting

Beijing, China, 100037

Contact: Yuhui Zhang, MD 86-10-88322674 yuhuizhangjoy@163.com

Sponsors and Collaborators

Lee's Pharmaceutical Limited

CVie Therapeutics Co. Ltd.

More Information

• Responsible Party: Lee's Pharmaceutical Limited
• ClinicalTrials.gov Identifier: NCT02617446
• Other Study ID Numbers: CVie2015002
• First Posted: December 1, 2015
• Last Update Posted: September 1, 2017
• Last Verified: August 2017

Keywords provided by Lee's Pharmaceutical Limited:

safety; efficacy; istaroxime

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases