Study to Evaluate the Efficacy and Safety of AZD4831 in Participants With Heart Failure With Left Ventricular Ejection Fraction > 40%
NCT ID: NCT04986202
Last Updated: 2025-08-27
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2/PHASE3
711 participants
INTERVENTIONAL
2021-06-30
2024-03-27
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Part A 2.5 mg
AZD4831 2.5 mg
AZD4831
AZD4831
Part A 5 mg
AZD4831 5 mg
AZD4831
AZD4831
Part A Placebo
Placebo
Placebo
Placebo
Part B Dose based on Part A
AZD4831 Dose based on Part A
AZD4831
AZD4831
Part B Placebo
Placebo
Placebo
Placebo
Interventions
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AZD4831
AZD4831
Placebo
Placebo
Eligibility Criteria
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Inclusion Criteria
1. ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent.
2. Documented stable symptomatic HF (New York Heart Association Class II-IV) for at least 1 month at Screening (Visit 1) (transient HF in the setting of an MI does not qualify), with a medical history of typical symptoms of HF and receiving optimal therapy for HF as determined by the health-care physician.
3. LVEF \> 40% at Screening (Visit 1). All participants will undergo a local echocardiogram at the Screening (Visit 1) with central reading to confirm the LVEF \> 40% eligibility criteria before randomisation.
4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 3). Difference in 6MWD between Screening and Randomisation must be \< 50 meters.
5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 3)
6. NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI ≤30 kg/m2.
NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI \> 30 kg/m2.
The ECG performed at Screening should be used for heart rhythm evaluation.
7.At least one of the following:
1. Structural heart disease, ie, LA enlargement and/or left ventricular hypertrophy at the echocardiogram performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI \> 34 mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or LVMI \> 95 g/m2 in women and \> 115 g/m2 in men.
2. Spectral tissue Doppler echocardiography - E/e' ratio (average of septal and lateral) ≥ 13 at rest at the echocardiogram performed at Screening (Visit 1).
3. Indirectly estimated elevation of PASP by TRmax velocity \> 2.8 m/s (280 cm/s) (PASP \> 35 mmHg) at the echocardiogram performed at Screening (Visit 1) OR directly measured pulmonary capillary wedge pressure \> 15 mmHg at rest within the past 12 months or \> 25 mmHg at exercise documented by right heart catheterisation within 12 months prior to Screening (Visit 1).
4. HF decompensation within 6 months before Randomisation (Visit 3), defined as hospitalisation for HF or IV diuretic treatment for HF during an urgent, unscheduled visit without hospitalisation.
8.Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2
9.Male or female of non-childbearing potential.
Part B
1. Participant must be ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent.
2. Documented diagnosis of symptomatic HF (NYHA class II-IV) at Screening (Visit 1), and a medical history of typical symptoms/signs of heart failure ≥ 6 weeks before Screening (Visit 1), and receiving optimal therapy for HF as determined by the health-care physician, with at least intermittent need for diuretic treatment.
3. LVEF \>40% and evidence of structural heart disease (ie, left ventricular hypertrophy or
left atrial enlargement \[defined by at least one of the following:LA enlargement and/or left ventricular hypertrophy at the echocardiogram
performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width
(diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI \> 34
mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or
LVMI \> 95 g/m2 in women and \> 115 g/m2 in men.\]) documented by the most recent echocardiogram, or cardiac
magnetic resonance imaging within the last 12 months prior to Screening (Visit 1). If no
echocardiogram is available, it can be performed at Screening (Visit 1).
4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 2). Difference in 6MWD between Screening and Randomisation must be \< 50 meters
5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 2).
6. NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI ≤ 30 kg/m2. NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI \> 30 kg/m2. The ECG performed at Screening should be used for heart rhythm evaluation
7. Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2
8. Male or female of non-childbearing potential.
Exclusion Criteria
1 eGFR \< 30 mL/min/1.73m2 (Chronic Kidney Disease-Epidemiology Collaboration formula) at Screening (Visit 1).
2\. Systolic blood pressure \< 90 mmHg or ≥ 160 mmHg if not on treatment with ≥ 3 blood pressure lowering medications or ≥ 180 mmHg irrespective of treatments at Randomisation
3\. Heart rate \> 110 bpm or \< 50 bpm at Randomisation
4\. Life expectancy \< 3 years due to other reasons than cardiovascular disease.
5\. History or ongoing allergy/hypersensitivity reactions to drugs (including but not limited to rash, angioedema, acute urticaria).
6\. Presence of any disease or condition rather than HF constituting the main reason for limiting the ability to exercise/reduced exercise capacity.
7\. Current decompensated HF and/or NT-proBNP \> 5000 pg/mL at Screening (Visit 1)
8\. Documented history of ejection fraction ≤ 40%.i.e. HF with recovered ejection fraction. Transient ejection fraction decrease e.g. in the setting of an MI does not apply
9\. Any planned cardiovascular procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery, etc).
10\. Any cardiac event (eg, myocardial infarction, unstable angina), coronary revascularisation (percutaneous coronary intervention or coronary artery bypass grafting), ablation of atrial fibrillation/flutter, valve repair/replacement, implantation of a cardiac resynchronisation therapy device within 12 weeks prior to Screening (Visit 1) or between Screening and Randomisation. Patients who underwent a successful atrial fibrillation/flutter cardioversion, can be enrolled in the study after 4 weeks.
14\. Hb \< 110 g/L (male) and \< 100 g/L (female) or iron-deficiency with/without anaemia requiring ongoing or planned IV iron treatment.
15\. Participants with hyperthyroidism, uncontrolled hypothyroidism (including but not limited to TSH ≥10 mIU/mL), or any clinically significant thyroid disease as judged by the investigator.
18\. ALT or AST ≥ 2 × ULN at Screening (Visit 1).
19\. Pulmonary arterial hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD (ie, requiring home oxygen, chronic nebulizer therapy or chronic oral steroid therapy, or hospitalization for exacerbation of COPD requiring ventilatory support within 12 months prior to Screening (Visit 1).
20\. Any active infection requiring oral, intravenous or intramuscular treatment at Screening (Visit 1) and/or at Randomisation.
23 Any signs or confirmation of COVID-19 infection:
* Suspected (as judged by PI) or confirmed COVID-19 within the last 2 weeks prior to Screening (Visit 1) or at Randomisation.
* Hospitalisation for COVID-19 within the last 12 weeks prior to Screening (Visit 1).
24\. Any concomitant medications known to be a potent CYP3A4 inducers or inhibitors, eg, itraconazole, rifampicin, clarithromycin, or propylthiouracil
29\. Previous enrolment and randomisation in the present study. (Participants who where screened and screen failed and not randomised in Part A can be screened for possible entry to Part B).
4\. Life expectancy \< 2 years due to other reasons than cardiovascular disease.
11\. HF due to any of the following: known infiltrative cardiomyopathy (eg, amyloid, sarcoid, lymphoma, endomyocardial fibrosis), active myocarditis, constrictive pericarditis, cardiac tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), or uncorrected primary valvular disease.
18\. Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD (ie, requiring home oxygen, chronic nebulizer therapy or chronic oral steroid therapy, or hospitalization for exacerbation of COPD requiring ventilatory support within 12 months prior to Screening \[Visit 1\]).
40 Years
85 Years
ALL
No
Sponsors
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AstraZeneca
INDUSTRY
Responsible Party
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Locations
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Research Site
Alexander City, Alabama, United States
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Little Rock, Arkansas, United States
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Sacramento, California, United States
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Miami, Florida, United States
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Miami Beach, Florida, United States
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Ocala, Florida, United States
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Evanston, Illinois, United States
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Hazel Crest, Illinois, United States
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Shreveport, Louisiana, United States
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Baltimore, Maryland, United States
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St Louis, Missouri, United States
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Buffalo, New York, United States
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New York, New York, United States
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Rosedale, New York, United States
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Chapel Hill, North Carolina, United States
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Pinehurst, North Carolina, United States
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Cleveland, Ohio, United States
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Philadelphia, Pennsylvania, United States
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Knoxville, Tennessee, United States
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Tullahoma, Tennessee, United States
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Norfolk, Virginia, United States
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Bedford Park, , Australia
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Chermside, , Australia
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Concord, , Australia
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Frankston, , Australia
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Aalst, , Belgium
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Dendermonde, , Belgium
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Hasselt, , Belgium
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Huy, , Belgium
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Kortrijk, , Belgium
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Leuven, , Belgium
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Roeselare, , Belgium
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Brasília, , Brazil
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Campina Grande do Sul, , Brazil
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Campinas, , Brazil
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Campinas, , Brazil
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Canoas, , Brazil
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Curitiba, , Brazil
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Porto Alegre, , Brazil
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Ribeirão Preto, , Brazil
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Ribeirão Preto, , Brazil
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Rio de Janeiro, , Brazil
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São Paulo, , Brazil
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Blagoevgrad, , Bulgaria
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Pleven, , Bulgaria
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Plovdiv, , Bulgaria
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Sofia, , Bulgaria
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Sofia, , Bulgaria
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Sofia, , Bulgaria
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Sofia, , Bulgaria
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Sofia, , Bulgaria
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Sofia, , Bulgaria
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Sofia, , Bulgaria
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Varna, , Bulgaria
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Guelph, Ontario, Canada
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Newmarket, Ontario, Canada
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North York, Ontario, Canada
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Ottawa, Ontario, Canada
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Toronto, Ontario, Canada
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Waterloo, Ontario, Canada
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Chicoutimi, Quebec, Canada
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Trois-Rivières, Quebec, Canada
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Brno, , Czechia
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Broumov, , Czechia
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Jaroměř, , Czechia
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Kolín, , Czechia
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Louny, , Czechia
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Pilsen, , Czechia
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Prague, , Czechia
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Prague, , Czechia
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Příbram, , Czechia
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Zlín, , Czechia
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Århus N, , Denmark
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Copenhagen, , Denmark
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Copenhagen O, , Denmark
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Hvidovre, , Denmark
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København NV, , Denmark
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Roskilde, , Denmark
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Viborg, , Denmark
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Bayonne, , France
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Dijon, , France
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La Tronche, , France
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Le Coudray, , France
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Montauban, , France
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Montpellier, , France
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Paris, , France
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Paris, , France
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Pierre-Bénite, , France
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Rennes, , France
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Saint-Brieuc, , France
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Toulon, , France
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Toulouse, , France
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Tourcoing, , France
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Balatonfüred, , Hungary
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Budapest, , Hungary
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Budapest, , Hungary
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Nyíregyháza, , Hungary
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Fukui-shi, , Japan
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Higashiohmi-shi, , Japan
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Iwakuni-shi, , Japan
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Kanazawa, , Japan
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Kasugai-shi, , Japan
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Kishiwada-shi, , Japan
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Kure-shi, , Japan
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Kyoto, , Japan
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Matsumoto-shi, , Japan
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Minamiku, , Japan
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Nagano, , Japan
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Naha, , Japan
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Otaru-shi, , Japan
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Ōita, , Japan
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Ōmihachiman, , Japan
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Sagamihara-shi, , Japan
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Toshima-ku, , Japan
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Ueda-shi, , Japan
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Uwajima-shi, , Japan
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Yokohama, , Japan
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's-Hertogenbosch, , Netherlands
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Amsterdam, , Netherlands
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Deventer, , Netherlands
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Heerlen, , Netherlands
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The Hague, , Netherlands
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Bydgoszcz, , Poland
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Lublin, , Poland
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Rzeszów, , Poland
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Skierniewice, , Poland
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Tarnów, , Poland
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Tczew, , Poland
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Tychy, , Poland
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Warsaw, , Poland
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Warsaw, , Poland
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Warsaw, , Poland
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Wołomin, , Poland
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Aramil, , Russia
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Kemerovo, , Russia
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Moscow, , Russia
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Moscow, , Russia
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Moscow, , Russia
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Novosibirsk, , Russia
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Perm, , Russia
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Saint Petersburg, , Russia
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Tver', , Russia
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Banská Bystrica, , Slovakia
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Bratislava, , Slovakia
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Brezno, , Slovakia
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Košice, , Slovakia
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Košice, , Slovakia
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Nitra, , Slovakia
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Prešov, , Slovakia
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Gothenburg, , Sweden
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Jönköping, , Sweden
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Lund, , Sweden
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Norrköping, , Sweden
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Örebro, , Sweden
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Stockholm, , Sweden
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Stockholm, , Sweden
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Stockholm, , Sweden
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Kaohsiung City, , Taiwan
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Kaohsiung City, , Taiwan
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Kaohsiung City, , Taiwan
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Taichung, , Taiwan
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Taichung, , Taiwan
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Taichung, , Taiwan
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Tainan City, , Taiwan
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Tainan City, , Taiwan
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Taipei, , Taiwan
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Taipei, , Taiwan
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Taipei, , Taiwan
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Taoyuan District, , Taiwan
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Eskişehir, , Turkey (Türkiye)
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Izmir, , Turkey (Türkiye)
Countries
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References
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Lund LH, Lam CSP, Pizzato PE, Gabrielsen A, Michaelsson E, Nelander K, Ericsson H, Holden J, Folkvaljon F, Mattsson A, Collen A, Aurell M, Whatling C, Baldus S, Drelich G, Goudev A, Merkely B, Bergh N, Shah SJ. Rationale and design of ENDEAVOR: A sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction. Eur J Heart Fail. 2023 Sep;25(9):1696-1707. doi: 10.1002/ejhf.2977. Epub 2023 Aug 22.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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Other Identifiers
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2020-005844-47
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
D6580C00010
Identifier Type: -
Identifier Source: org_study_id
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