Effects of peroral levosimendan in the prevention of further hospitalisations in patients with chronic heart failure. A randomised, double-blind, placebo-controlled, multi-centre, parallel-group study - PERSIST

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2004-004225-10-EE
• Date of registration: 07/03/2005
• Prospective Registration: Yes
• Primary sponsor: Orion Pharma
• Public title: Effects of peroral levosimendan in the prevention of further hospitalisations in patients with chronic heart failure. A randomised, double-blind, placebo-controlled, multi-centre, parallel-group study - PERSIST
• Scientific title: Effects of peroral levosimendan in the prevention of further hospitalisations in patients with chronic heart failure. A randomised, double-blind, placebo-controlled, multi-centre, parallel-group study - PERSIST
• Date of first enrolment: 07/03/2005
• Target sample size: 300
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2004-004225-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Estonia, Finland, Latvia, Lithuania

Key inclusion & exclusion criteria

Inclusion criteria:
1. Written Informed Consent obtained
2. Male and female patients over 18 years of age. Women of reproductive age and potential must refrain from breastfeeding, must have a negative pregnancy test and must commit to using an acceptable method of barrier or hormonal contraception (e.g. condoms, diaphragms, oral contraceptives and long acting progestin agents) if sexually active during the study and for 1 month after the last dose of the study
treatment. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be of childbearing potential
3. Chronic heart failure diagnosed at least 3 months before screening
4. Treatment for at least 1 month before screening with angiotensin converting enzyme (ACE) inhibitor or beta-blocker and additionally at least one of the following: diuretics, digitalis, aldosterone antagonist or angiotensin II receptor blocker
5. Left ventricular ejection fraction less than or equal to 30% as assessed by echocardiography, radionuclide ventriculography or contrast angiography within 12 months before screening
6. NYHA IIIb-IV symptoms (dyspnoea on minimal exertion or at rest) at screening and at baseline
7. Further evidence of severely compromised heart failure as evidenced by one of the following at screening:
- History of at least one hospitalisation or visit to out-patient clinic for worsening heart failure requiring treatment either with intravenous (i.v.) diuretics, i.v. vasodilators, and/or i.v. inotropic agents within 6 months before screening; the index hospitalisation may be currently on-going at screening but if so, the patient must be ready to be discharged
- Plasma N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) above or equal to 1000 pg/ml at screening
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Severe obstruction of ventricular outflow tracts such as haemodynamically significant uncorrected primary valve disease or hypertrophic cardiomyopathy or impaired ventricular filling such as restrictive cardiomyopathy
2. Cardiac surgery or coronary angioplasty within 30 days before screening
3. Acute myocardial infarction within 30 days before screening
4. Patients who are scheduled to receive a heart transplant or left ventricular assist device or are scheduled for coronary by-pass or angioplasty in the next 6 months
5. History of life-threatening ventricular arrhythmia within 3 months defined as an episode of resuscitated sudden death, ventricular fibrillation or sustained or haemodynamically destabilising ventricular tachycardia (wide complex tachycardia >100/min, either for >15 seconds or accompanied by hypotension,
presyncope or syncope). Patients with one of these three arrhythmias may be enrolled if the episode was followed by placement of an intracardiac cardioverter-defibrillator (ICD) (and the ICD has not fired within 30 days)
6. History of Torsades de Pointes or family history of long QT-syndrome
7. Stroke or transient ischaemic attack within 3 months before screening
8. Systolic blood pressure less than 85 mmHg at screening and baseline
9. Heart rate 100 bpm or greater at screening and baseline
10. Serum potassium less than 3.5 mmol/l at screening
11. Severe renal insufficiency (serum creatinine >450 µmol/l [5.0 mg/dl]) or on dialysis
12. Severe anaemia (blood haemoglobin <10 g/dl) at screening
13. Significant hepatic impairment at discretion of the investigator
14. Hypersensitivity to levosimendan
15. Other serious diseases limiting life expectancy considerably (e.g. end-stage cancer)
16. Participation in a clinical trial with any experimental treatment within 30 days prior to screening or previous participation in the present study
17. Administration of levosimendan within 30 days prior to screening



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Cardiac Failure
MedDRA version: 7.1 Level: LLT Classification code 10007554

Intervention(s)

Product Name: Levosimendan Capsules 0.5 mg
Pharmaceutical Form: Capsule*
INN or Proposed INN: Levosimendan
CAS Number: 141505-33-1
Current Sponsor code: (-)-OR-1259
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Product Name: Levosimendan Capsules 1 mg
Pharmaceutical Form: Capsule*
INN or Proposed INN: Levosimendan
CAS Number: 141505-33-1
Current Sponsor code: (-)-OR-1259
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.0-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: Primary objective is to test the hypothesis that levosimendan is superior to placebo in the composite endpoint called “Patient Journey” during the 60 days following randomisation.

Secondary Objective: Secondary objectives are
• to validate the primary variable (“Patient Journey”) for phase III
• to evaluate the efficacy of levosimendan on mortality, morbidity, symptoms and quality of life compared to placebo
• to compare the efficacy, safety and pharmacokinetics of the two levosimendan doses
• to compare the efficacy, safety and pharmacokinetics of levosimendan in rapid and slow acetylators
• to evaluate the safety of levosimendan compared to placebo

An optional pharmacogenetic substudy will be carried out under a seperate protocol. This substudy will be conducted in order to develop a better understanding of heart failure and to evaluate how patients respond to treatment with levosimendan.

Primary end point(s): “Patient Journey” is a composite end-point consisting of Patient’s Global Assessment,
worsening heart failure and mortality during the 60 days after randomisation.
The 6-point symmetric scale of Patient’s Global Assessment, the days with worsening heart failure and days dead will be converted to numeric scale according to the Table below.
The Global Assessment score at each visit/telephone contact represents the current day. The days between two visits/telephone contacts will be scored carrying forwards and backwards the scores to the mid-point of the two contacts. However, if the patient is experiencing worsening heart failure between two visits/telephone contacts, the Global Assessment score will be overruled and the score will be -0.5 for those days. All days after death (including the day of death) will be counted as -1.0.

Scores of the “Patient Journey”
Patient’s Global Assessment Score
Very good 1.0
Good 0.8
Fairly good 0.6
Fairly bad 0.4
Bad 0.2
Very bad 0.0
Worsening heart failure -0.5
Death -1.0

Secondary ID(s)

3001081

2004-004225-10-FI