HANGZHOU Solution in Bicuspid AS Undergoing TAVR

Aortic Stenosis Clinical Trial

Official title:

HANGZHOU Solution for Patients With Bicuspid Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement by Using Supra-annular Structure Based Balloon Sizing Strategy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04722796
• Other study ID #: 2021-0007
• Status: Recruiting
• Phase: N/A
• Start date: April 12, 2021
• Est. completion date: April 1, 2028

Study information

• Verified date: January 2021
• Source: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Contact: Jian'an Wang, PhD, MD
• Phone: +86057187783777
• Email: wja[@]zju.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To compare supra-annular sizing and THV implantation technique (Hangzhou solution) versus annular sizing and THV implantation technique (control group) in bicuspid aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR) with self-expanding valves (SEVs): a randomized superiority trial

Description:

Transcatheter aortic valve replacement (TAVR) has emerged as a favorable alternative for severe symptomatic aortic stenosis (AS) patients from low to high surgical risk. BAV patients treated with TAVR had similar 30-day mortality as well as stroke and new pacemaker implantation rates compared to TAV subjects, but carried higher risk of moderate/severe PVL, conversion to surgery and device failure. Event rates significantly decreased with the use of new-generation devices, but TAVR still showed better procedural results in TAV compared to BAV.

Clinical experience in China suggests bicuspid aortic valves and heavy calcium burden are more common among TAVR candidates. Morphological characteristics at supra-annular structure (from annulus to the level of sinotubular junction) are quite complex in bicuspid AS, especially concomitant with heavily calcified leaflets. Because only two leaflet hinge points provide the definition of the annulus plane, current CT-based annulus measurements might not be accurate under these circumstances. From previous single center clinical practice, "waist sign" above the annulus during balloon aortic valvuloplasty in TAVR was often observed in patients with bicuspid AS, indicating that the supra-annular structure may serve a key role in anchoring the THV.

Therefore, we developed a balloon based supra-annular sizing strategy (Hangzhou Solution) for SEV implantation in bicuspid AS. From our single center experience, the device success rate and pacemaker implantation rate were relatively low.

The aim of this study is to compare supra-annular sizing and THV implantation technique (Hangzhou solution) versus annular sizing and THV implantation technique (control group) in bicuspid aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR) with self-expanding valves (SEVs).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 508
• Est. completion date: April 1, 2028
• Est. primary completion date: April 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

• Age = 65 years

• Age <65 years and age = 60 years with high surgical risk after combing STS Risk Estimate, Katz activities of Daily Living, major Organ System Dysfunction and Procedure-Specific Impediment;

• Severe, bicuspid aortic stenosis:

• Mean gradient =40 mmHg

• Maximal aortic valve velocity =4.0 m/sec

• Aortic valve area =1.0 cm2 (or aortic valve area index of =0.6 cm2/m2)

• NYHA classification = II;

• Type 0, type 1 (Sievers classification) by MDCT

• Perimeter-derived annulus diameter ranges from 20.0 mm to 29.0 mm;

• Transfemoral TAVR

• The study patient has been informed of the nature of the study, agrees to its provisions and has provided written informed consent as approved by the Institutional Review Board (IRB)/Ethics Committee (EC) of the respective clinical site.

Exclusion Criteria:

• Any contra-indication for Self-expanding bioprosthetic aortic valve deployment

• Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), Thrombocytopenia (Plt< 50,000 cell/mL).

• Active sepsis, including active bacterial endocarditis with or without treatment;

• Evidence of an acute myocardial infarction = 1 month (30 days) before the intended treatment [(defined as: Q wave MI, or non-Q wave MI with total CK elevation of CK-MB = twice normal in the presence of MB elevation and/or troponin level elevation (WHO definition)].

• Stroke or transient ischemic attack (TIA) within 3 months (90 days) of the procedure.

• Estimated life expectancy < 12 months (365 days) due to carcinomas, chronic liver disease, chronic renal disease or chronic end stage pulmonary disease.

• Any Emergent surgery required before TAVR procedure.

• A known hypersensitivity or contraindication to any of the following that cannot be adequately medicated:aspirin or heparin (HIT/HITTS) and bivalirudin, clopidogrel,Nitinol (titanium or nickel),contrast media

• Gastrointestinal (GI) bleeding that would preclude anticoagulation.

• Subject refuses a blood transfusion.

• Severe dementia (resulting in either inability to provide informed consent for the study/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits).

• Other medical, social, or psychological conditions that in the opinion of the investigator precludes the subject from appropriate consent or adherence to the protocol required follow-up exams.

• Currently participating in an investigational drug or another device study (excluding registries).

• Hypertrophic cardiomyopathy (HCM with myocardium more than 1.5cm without an identifiable cause) with obstruction (HOCM).

• Echocardiographic evidence of intracardiac mass, thrombus or vegetation.

• Severe mitral stenosis amenable to surgical replacement or repair.

• Aortic valve type cannot be determined (Sievers classification).

• Significant aortic disease, including marked tortuosity (hyperacute bend), aortic arch atheroma [especially if thick (> 5 mm), protruding or ulcerated] or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe"unfolding" and horizontal aorta(Annular Angulation>70°).

• Ascending aorta diameter > 50 mm.

• Aortic or iliofemoral vessel characteristics that would preclude safe placement of the introducer sheath.

• Patient is considered high risk for TAVR by CT corelab, including coronary obstruction, annular rupture and other severe TAVR-Related complications.

• Previous pacemaker implantation.

Related Conditions & MeSH terms

• Aortic Stenosis
• Aortic Stenosis With Bicuspid Valve
• Aortic Valve Stenosis
• Constriction, Pathologic

Intervention

Device:
• TAVR with Venus A plus using supra-annular sizing and THV implantation technique (Hangzhou solution)
Transcatheter aortic valve replacement (TAVR) with Venus A plus using supra-annular sizing and THV implantation technique (Hangzhou solution)
• TAVR with Venus A plus using annular sizing and THV implantation technique
Transcatheter aortic valve replacement (TAVR) with Venus A plus using annular sizing and THV implantation technique (Traditional sizing strategy)

Locations

Country	Name	City	State
China	The General Hospital of the People's Liberation Army	Beijing	Beijing
China	The First affiliated hospital of bengbu medical college	Bengbu	Anhui
China	The Second XIANGYA Hospital Of Central South University	Changsha	Hunan
China	Fujian Medical University Union Hospital	Fuzhou	Fujian
China	Guangdong People's Hospital	Guangzhou	Guangdong
China	The Second Affiliated Hospital Zhejiang University School of Medicine.	Hangzhou	Zhejiang
China	The First Affiliated Hospital of Nanchang University	Nanchang	Jiangxi
China	The Second Affiliated Hospital of Nanchang University	Nanchang	Jiangxi
China	Ning Bo First Hospital	Ningbo	Zhejiang
China	The Affiliated Hospital of Qingdao University	Qingdao	Shandong
China	Shanxi Cardiovascular Hospital	Taiyuan	Shanxi
China	tianjin Chest Hospital	Tianjing	Tianjing
China	Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology	Wuhan	Hubei
China	Xiamen University Affiliated Cardiovascular Hospital	Xiamen	Fujian
China	Northern Jiangsu People's Hospital	Yangzhou	Jiangsu
China	Hennan Provincial Chest Hospital	Zhengzhou	Hennan
China	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan
China	Zhengzhou Cardiovascular Hospital	Zhengzhou	Henan

Sponsors (19)

Lead Sponsor

Collaborator

Second Affiliated Hospital, School of Medicine, Zhejiang University

Central South University, Chinese PLA General Hospital, First Affiliated Hospital Bengbu Medical College, Fujian Medical University Union Hospital, Guangdong People's Hospital, Hennan Provincial Chest Hospital, Ning Bo First Hospital, Northern Jiangsu Province People's Hospital, Second Affiliated Hospital of Nanchang University, Shanxi cardiovascular hospital, The Affiliated Hospital of Qingdao University, The First Affiliated Hospital of Nanchang University, The First Affiliated Hospital of Zhengzhou University, Tianjin Chest Hospital, Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, Venus MedTech (HangZhou) Inc., Xiamen University Affiliated Cardiovascular Hospital, Zhengzhou Cardiovascular Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of all-cause mortality rate, disabling stroke rate, new permanent pacemaker implantation rate and moderate or severe prosthetic valve regurgitation rate at 1 month	Composite of all-cause mortality, disabling stroke, new permanent pacemaker implantation and moderate or severe prosthetic valve regurgitation at 1 month (per Valve Academic Research Consortium-2 [VARC-2] criteria)	1 month
Secondary	Deaths (all-cause mortality) at 1 month	Number of deaths from any cause mortality at 1 month	1 month
Secondary	Deaths (all-cause mortality) at 1 year		1 year
Secondary	Deaths (all-cause mortality) at 2 years		2 years
Secondary	Deaths (all-cause mortality) at 3 years		3 years
Secondary	Deaths (all-cause mortality) at 4 years		4 years
Secondary	Deaths (all-cause mortality) at 5 years		5 years
Secondary	All Stroke (disabling and non-disabling) at 1 month	duration of a focal or global neurological deficit >24 h; OR <24 h if available neuroimaging documents a new haemorrhage or infarct; OR the neurological deficit results in death	1 month
Secondary	All Stroke (disabling and non-disabling) at 1 year		1 year
Secondary	All Stroke (disabling and non-disabling) at 2 years		2 years
Secondary	All Stroke (disabling and non-disabling) at 3 years		3 years
Secondary	All Stroke (disabling and non-disabling) at 4 years		4 years
Secondary	All Stroke (disabling and non-disabling) at 5 years		5 years
Secondary	Rate of New permanent pacemaker implantation at 1 month	Rate of New permanent pacemaker implantation (e.g. defibrillator, single vs. dual chamber, biventricular)	1 month
Secondary	Rate of New permanent pacemaker implantation at 1 year		1 year
Secondary	Rate of New permanent pacemaker implantation at 2 years		2 years
Secondary	Rate of New permanent pacemaker implantation at 3 years		3 years
Secondary	Rate of New permanent pacemaker implantation at 4 years		4 years
Secondary	Rate of New permanent pacemaker implantation at 5 years		5 years
Secondary	Rate of Moderate or severe prosthetic valve regurgitation at 1 month	Moderate or severe prosthetic valve regurgitation by transthoracic echocardiography, VARC-2 definition	1 month
Secondary	Rate of Moderate or severe prosthetic valve regurgitation at 1 year		1 year
Secondary	Rate of Moderate or severe prosthetic valve regurgitation at 2 years		2 years
Secondary	Rate of Moderate or severe prosthetic valve regurgitation at 3 years		3 years
Secondary	Rate of Moderate or severe prosthetic valve regurgitation at 4 years		4 years
Secondary	Rate of Moderate or severe prosthetic valve regurgitation at 5 years		5 years
Secondary	Re-hospitalization for signs and symptoms of aortic valve disease and/or THV related complications at 1 month	Re-hospitalization for signs and symptoms of aortic valve disease and/or THV related complications by VARC-2 definition	1 month
Secondary	Re-hospitalization for signs and symptoms of aortic valve disease and/or THV related complications at 1 year		1 year
Secondary	Re-hospitalization for signs and symptoms of aortic valve disease and/or THV related complications at 2 years		2 years
Secondary	Re-hospitalization for signs and symptoms of aortic valve disease and/or THV related complications at 3 years		3 years
Secondary	Re-hospitalization for signs and symptoms of aortic valve disease and/or THV related complications at 4 years		4 years
Secondary	Re-hospitalization for signs and symptoms of aortic valve disease and/or THV related complications at 5 years		5 years
Secondary	Rate of alternating valve of prosthetic valve size during TAVR	Alternating valve of prosthetic valve size during TAVR (up size or down size)	peri-procedural
Secondary	Rate of valve malposition	Valve malposition (migration, embolization, and ectopic deployment)	peri-procedural
Secondary	Rate of TAV-in-TAV deployment	TAV-in-TAV deployment (An additional valve prosthesis is implanted within a previously implanted prosthesis because of suboptimal device position and/or function, during the index procedure)	peri-procedural
Secondary	Rate of device recapture or retrieval	Device recapture or retrieval peri-procedural	peri-procedural
Secondary	Rate of conversion to open surgery	Conversion to open surgery (Conversion to open sternotomy during the TAVR procedure secondary to any procedure-related complications)	peri-procedural
Secondary	Rate of unplanned use of cardiopulmonary bypass (CPB) for hemodynamic support at any time during the TAVR procedure	Unplanned use of cardiopulmonary bypass (CPB) for hemodynamic support at any time during the TAVR procedure	peri-procedural
Secondary	Rate of coronary obstruction	Coronary obstruction (Angiographic or echocardiographic evidence of a new, partial or complete, obstruction of a coronary ostium, either by the valve prosthesis itself, the native leaflets, calcifications, or dissection, occurring during the TAVR procedure)	peri-procedural
Secondary	Major vascular complications (VARC 2)	Major vascular complications by VARC 2 definition	peri-procedural
Secondary	Rate of annulus rupture	Procedural-related injuries occur in the region of the aortic root and the left ventricular outflow tract during transcatheter aortic valve replacement.	peri-procedural
Secondary	Rate of structural valve deterioration at 1 month	Structural valve deterioration (2017 EAPCI/ESC/EACTS definition)	1 month
Secondary	Rate of structural valve deterioration at 1 year		1 year
Secondary	Rate of structural valve deterioration at 2 years		2 years
Secondary	Rate of structural valve deterioration at 3 years		3 years
Secondary	Rate of structural valve deterioration at 4 years		4 years
Secondary	Rate of structural valve deterioration at 5 years		5 years
Secondary	New onset complete LBBB before discharge	New onset complete LBBB, by 2009 AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part III definition	before discharge
Secondary	New onset complete LBBB at 1 month		1 month
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ) QoL Scores at Baseline	The Kansas City Cardiomyopathy Questionnaire is a 23-item, self administered instrument that quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores: KCCQ Symptom Domain, KCCQ Physical Function Domain, KCCQ Quality of Life Domain, KCCQ Social Limitation Domain, KCCQ Self-efficacy Domain, KCCQ Symptom Stability Domain, Clinical Summary Score and Overall Summary Score. Clinical Summary Score includes total symptom and physical function scores to correspond with NYHA Classification. Overall Summary Score includes the total symptom, physical function, social limitations and quality of life scores.	Baseline
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ) QoL Scores at 1 month	The Kansas City Cardiomyopathy Questionnaire is a 23-item, self administered instrument that quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores: KCCQ Symptom Domain, KCCQ Physical Function Domain, KCCQ Quality of Life Domain, KCCQ Social Limitation Domain, KCCQ Self-efficacy Domain, KCCQ Symptom Stability Domain, Clinical Summary Score and Overall Summary Score. Clinical Summary Score includes total symptom and physical function scores to correspond with NYHA Classification. Overall Summary Score includes the total symptom, physical function, social limitations and quality of life scores.	1 month
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ) QoL Scores at 1 year	The Kansas City Cardiomyopathy Questionnaire is a 23-item, self administered instrument that quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores: KCCQ Symptom Domain, KCCQ Physical Function Domain, KCCQ Quality of Life Domain, KCCQ Social Limitation Domain, KCCQ Self-efficacy Domain, KCCQ Symptom Stability Domain, Clinical Summary Score and Overall Summary Score. Clinical Summary Score includes total symptom and physical function scores to correspond with NYHA Classification. Overall Summary Score includes the total symptom, physical function, social limitations and quality of life scores.	1 year
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ) QoL Scores at 2 years	The Kansas City Cardiomyopathy Questionnaire is a 23-item, self administered instrument that quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores: KCCQ Symptom Domain, KCCQ Physical Function Domain, KCCQ Quality of Life Domain, KCCQ Social Limitation Domain, KCCQ Self-efficacy Domain, KCCQ Symptom Stability Domain, Clinical Summary Score and Overall Summary Score. Clinical Summary Score includes total symptom and physical function scores to correspond with NYHA Classification. Overall Summary Score includes the total symptom, physical function, social limitations and quality of life scores.	2 years
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ) QoL Scores at 3 years	The Kansas City Cardiomyopathy Questionnaire is a 23-item, self administered instrument that quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores: KCCQ Symptom Domain, KCCQ Physical Function Domain, KCCQ Quality of Life Domain, KCCQ Social Limitation Domain, KCCQ Self-efficacy Domain, KCCQ Symptom Stability Domain, Clinical Summary Score and Overall Summary Score. Clinical Summary Score includes total symptom and physical function scores to correspond with NYHA Classification. Overall Summary Score includes the total symptom, physical function, social limitations and quality of life scores.	3 years
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ) QoL Scores at 4 years	The Kansas City Cardiomyopathy Questionnaire is a 23-item, self administered instrument that quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores: KCCQ Symptom Domain, KCCQ Physical Function Domain, KCCQ Quality of Life Domain, KCCQ Social Limitation Domain, KCCQ Self-efficacy Domain, KCCQ Symptom Stability Domain, Clinical Summary Score and Overall Summary Score. Clinical Summary Score includes total symptom and physical function scores to correspond with NYHA Classification. Overall Summary Score includes the total symptom, physical function, social limitations and quality of life scores.	4 years
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ) QoL Scores at 5 years	The Kansas City Cardiomyopathy Questionnaire is a 23-item, self administered instrument that quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores: KCCQ Symptom Domain, KCCQ Physical Function Domain, KCCQ Quality of Life Domain, KCCQ Social Limitation Domain, KCCQ Self-efficacy Domain, KCCQ Symptom Stability Domain, Clinical Summary Score and Overall Summary Score. Clinical Summary Score includes total symptom and physical function scores to correspond with NYHA Classification. Overall Summary Score includes the total symptom, physical function, social limitations and quality of life scores.	5 years
Secondary	New York Heart Association (NYHA) Functional Class at baseline	Measure Description: The New York Heart Association (NYHA) Classification provides a simple way of classifying the extent of heart failure. It classifies patients in one of four categories based on their limitations during physical activity:Class I: No symptoms and no limitation in ordinary physical activity Class II: Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity Class III: Marked limitation in activity due to symptoms Class IV: Severe limitations	Baseline
Secondary	New York Heart Association (NYHA) Functional Class at 1 month		1 month
Secondary	New York Heart Association (NYHA) Functional Class at 1 year		1 year
Secondary	New York Heart Association (NYHA) Functional Class at 2 years		2 years
Secondary	New York Heart Association (NYHA) Functional Class at 3 years		3 years
Secondary	New York Heart Association (NYHA) Functional Class at 4 years		4 years
Secondary	New York Heart Association (NYHA) Functional Class at 5 years		5 years
Secondary	Six Minute Walk Test (6MWT Distance or 6MWD) at baseline	Six-Minute Walk Test is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes. The 6-minute walk test distance (6 MWD) provides a measure for integrated global response of multiple cardiopulmonary and musculoskeletal systems involved in exercise.	Baseline
Secondary	Six Minute Walk Test (6MWT Distance or 6MWD) at 1 month		1 month
Secondary	Six Minute Walk Test (6MWT Distance or 6MWD) at 1 year		1 year
Secondary	Six Minute Walk Test (6MWT Distance or 6MWD) at 2 years		2 years
Secondary	Six Minute Walk Test (6MWT Distance or 6MWD) at 3 years		3 years
Secondary	Six Minute Walk Test (6MWT Distance or 6MWD) at 4 years		4 years
Secondary	Six Minute Walk Test (6MWT Distance or 6MWD) at 5 years		5 years
Secondary	Mini-Mental State Examination score at baseline	The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written; 8 points), and visuospatial function (1 point)	baseline
Secondary	Mini-Mental State Examination score at 1 month	The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written; 8 points), and visuospatial function (1 point)	1 month
Secondary	Mini-Mental State Examination score at 1 year	The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written; 8 points), and visuospatial function (1 point)	1 year
Secondary	Mini-Mental State Examination score at 2 years	The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written; 8 points), and visuospatial function (1 point)	2 years
Secondary	Mini-Mental State Examination score at 3 years	The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written; 8 points), and visuospatial function (1 point)	3 years
Secondary	Mini-Mental State Examination score at 4 years	The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written; 8 points), and visuospatial function (1 point)	4 years
Secondary	Mini-Mental State Examination score at 5 years	The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written; 8 points), and visuospatial function (1 point)	5 years
Secondary	Modified Rankin Scale Score at baseline	MODIFIED RANKIN SCALE SCORE DESCRIPTIONS: 0- No symptoms at all; 1- No significant disability despite symptoms; able to carry out all usual duties and activities; 2- Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- Moderate disability; requiring some help, but able to walk without assistance; 4- Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5- Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- Dead	baseline
Secondary	Modified Rankin Scale Score at 1 month	MODIFIED RANKIN SCALE SCORE DESCRIPTIONS: 0- No symptoms at all; 1- No significant disability despite symptoms; able to carry out all usual duties and activities; 2- Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- Moderate disability; requiring some help, but able to walk without assistance; 4- Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5- Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- Dead	1 month
Secondary	Modified Rankin Scale Score at 1 year	MODIFIED RANKIN SCALE SCORE DESCRIPTIONS: 0- No symptoms at all; 1- No significant disability despite symptoms; able to carry out all usual duties and activities; 2- Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- Moderate disability; requiring some help, but able to walk without assistance; 4- Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5- Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- Dead	1 year
Secondary	Modified Rankin Scale Score at 2 years	MODIFIED RANKIN SCALE SCORE DESCRIPTIONS: 0- No symptoms at all; 1- No significant disability despite symptoms; able to carry out all usual duties and activities; 2- Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- Moderate disability; requiring some help, but able to walk without assistance; 4- Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5- Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- Dead	2 years
Secondary	Modified Rankin Scale Score at 3 years	MODIFIED RANKIN SCALE SCORE DESCRIPTIONS: 0- No symptoms at all; 1- No significant disability despite symptoms; able to carry out all usual duties and activities; 2- Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- Moderate disability; requiring some help, but able to walk without assistance; 4- Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5- Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- Dead	3 years
Secondary	Modified Rankin Scale Score at 4 years	MODIFIED RANKIN SCALE SCORE DESCRIPTIONS: 0- No symptoms at all; 1- No significant disability despite symptoms; able to carry out all usual duties and activities; 2- Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- Moderate disability; requiring some help, but able to walk without assistance; 4- Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5- Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- Dead	4 years
Secondary	Modified Rankin Scale Score at 5 years	MODIFIED RANKIN SCALE SCORE DESCRIPTIONS: 0- No symptoms at all; 1- No significant disability despite symptoms; able to carry out all usual duties and activities; 2- Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- Moderate disability; requiring some help, but able to walk without assistance; 4- Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5- Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- Dead	5 years