E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure with preserved ejection fraction |
Hartfalen met intacte ejectiefractie |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10069211 |
E.1.2 | Term | Diastolic heart failure |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | Heart failure |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of cardiovascular death and total (first and recurrent) heart failure (HF) hospitalizations, in HF patients (NYHA Class II-IV) with preserved EF (LVEF ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response. |
Het primaire doel van deze studie is het vergelijken van LCZ696 met valsartan in de reductie van het samengestelde eindpunt van cardiovasculair overlijden en alle ziekenhuisopnames vanwege hartfalen bij patienten met hartfalen (NYHA klasse II-IV) met intacte ejectiefractie (LVEF ≥ 45%). De behandelarm met een lager aantal eindpunten geldt als een succesvol respons. |
|
E.2.2 | Secondary objectives of the trial |
- To compare LCZ696 to valsartan on changes in the clinical summary
score for HF symptoms and physical limitations (as assessed by Kansas
City Cardiomyopathy Questionnaire [KCCQ]) at 8 months.
- Evaluation of change from baseline to Month 8 in NYHA functional class
- To compare LCZ696 to valsartan in delaying the time to first occurrence
of a composite renal endpoint.
- Evaluation of the time to all cause death. |
- Evaluatie van de verandering van klinische beoordeling HF symptomen en fysieke beperkingen (beoordeeld middels KCCQ vragelnlijst) op maand 8 t.o.v. baseline.
- Evaluatie van de verandering van de NYHA klasse op maand 8 t.o.v. de baseline.
- Evaluatie van de tijd tot aan eerste samengestelde renale eindpunt.
- Evaluatie van de tijd tot overlijden door welke oorzaak dan ook. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Biomarker substudy. A part of the Dutch sites will participate.
- Pharmacokinetic substudy. Netherlands won't participate in this substudy.
- Pharmacogenomic/Pharmacogenetic sub study. All sites will partcipate but is optional for patients.
- Cardiac monitoring substudy. It is possible, in a later phase of this trial, that Netherlands will partcipate in this substudy. |
- Biomarker sub studie. Een deel van de Nederlandse sites zullen hieraan deelnemen.
- Farmacokinetiek sub studie. Nederland zal niet deelnemen aan deze sub studie.
- Pharmacogenomische / pharmacogenetische sub studie. Alle sites zullen hieraan deelnemen maar is optioneel voor de patiënten.
- Holter monitoring sub studie. Het is mogelijk, in een latere fase van dit onderzoek, dat Nederland zal deelnemen aan deze sub studie. |
|
E.3 | Principal inclusion criteria |
- ≥ 55 years of age, male or female.
- Left ventricular ejection fraction (LVEF) ≥45% by echo during the screening epoch, or within 6 months prior to Visit 1.
- Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF ≥30 days prior to Visit 1.
- Current symptom(s) of HF (NYHA Class II-IV) at Visit 1.
- Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
- A HF hospitalization within 9 months prior to Visit 1 and/or an elevated NT-proBNP at Visit 1.
- See protocol for details and more inclusion criteria. |
- ≥ 55 jaar, mannen en vrouwen.
- Linker ventrikel ejectiefractie (LVEF) ≥ 45% op echocardiogram tijdens de screening of binnen 6 maanden voorafgaand aan visite 1.
- Symptomen van hartfalen (HF) waarvoor diuretica nodig ≥ 30 dagen voorafgaand aan visite 1.
- Huidige symptomen van HF (NYHA klasse II-IV) op moment van visite 1.
- Structurele hartziekte gesteund door echobevindingen vergroting linker atrium en/of linker ventrikel hypertrofie).
- Een ziekenhuisopname vanwege hartfalen binnen 9 maanden voor visite 1 en / of een verhoogde NT-proBNP op moment van visite 1.
- Zie protocol voor details en meer inclusie criteria. |
|
E.4 | Principal exclusion criteria |
- Any prior echocardiographic measurement of LVEF < 40%.
- Acute coronary syndrome (including myocardial infarction (MI)), cardiac surgery, other major cardiovascular surgery within 3 months, or urgent percutaneous coronary intervention (PCI) within 30 days of Visit 1.
- Any clinical event within 6 months that could have reduced the LVEF
(e.g., MI, coronary artery bypass graft [CABG]), unless an echo
measurement was performed after the event confirming the LVEF to be ≥
45%.
- Current acute decompensated HF requiring therapy.
- Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB) or a renin inhibitor.
- Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.
- Hyper- or hypotension.
- See protocol for details and more exclusion criteria. |
- Eerdere echocardiografische meting van LVEF <40%.
- Acuut coronair syndroom (waaronder myocardinfarct (MI)), hartchirurgie, andere relevante cardiovasculaire chirurgie binnen 3 maanden, of urgente percutane coronaire interventie (PCI) binnen 30 dagen voorafgaand aan visite 1.
- Enig klinisch event binnen de 6 maanden voorafgaand aan visite 1 dat LVEF zou kunnen hebben verminderd (bijv. MI, coronaire bypass (CABG)), tenzij een echo meting nadien uitgevoerd met een LVEF ≥ 45%.
- Acuut gedecompenseerd HF waarvoor behandeling nodig.
- Patiënten die behandeling nodig hebben met 2 of meer van de volgende middelen: ACE-remmer (ACE-remmers), angiotensine receptor blokker (ARB) of renine-remmer.
- Andere oorzaak voor voor kortademigheid zoals: Significante longziekte of ernstige COPD, hemoglobine (Hb) <10 g / dl of body mass index (BMI) > 40 kg/m2.
- Hyper- or hypotensie.
- Zie protocol voor details en meer exclusie criteria. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Cumulative number of primary composite events of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations. |
Cumulatief aantal primair samengestelde eindpunten van cardiovasculair (CV) overlijden en (eerste en recidiverende) ziekenhuisopnames vanwege hartfalen.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Total follow up time (up to 57 months) |
Einde totale follow up (tot 57 maanden). |
|
E.5.2 | Secondary end point(s) |
- Change in KCCQ clinical summary score from baseline to Month 8.
- Change from baseline to Month 8 in New York Heart Association (NYHA) functional class.
- Time to composite renal endpoint.
- Time to all-cause mortality. |
- Verandering van KCCQ, klinische score op maand 8 t.o.v. de baseline.
- Verandering van de NYHA klasse op maand 8 t.o.v. de baseline.
- Tijd tot het ontstaan van samengesteld renaal eindpunt.
- Tijd tot overlijden, door welke oorzaak dan ook. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Total follow up time (up to 57 months).
- 8 months for the NYHA functional class.
- 8 months for KCCQ clinical summary score. |
- Einde totale follow up (tot 57 maanden).
- Voor NYHA klasse 8 maanden.
- Voor KCCQ klinische score 8 maanden. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 324 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
China |
Colombia |
Croatia |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Guatemala |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Democratic People's Republic of |
Mexico |
Netherlands |
Norway |
Peru |
Philippines |
Poland |
Romania |
Russian Federation |
Serbia |
Singapore |
Slovakia |
Slovenia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Turkey |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS (15-May-2019) |
LVLS (15-mei-2019) |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 9 |