UMIN-CTR Clinical Trial

Basic information
Public title	The acquired von Willebrand syndrome coexisting with cardiovascular diseases Study
Acronym	The AVeC Study
Scientific Title	The acquired von Willebrand syndrome coexisting with cardiovascular diseases Study
Scientific Title:Acronym	The AVeC Study
Region	Japan

Condition
Condition	Various circulatory diseases including aortic stenosis, mitral regurgitation, hypertrophic cardiomyopathy, pulmonary hypertension, acute pulmonary embolism, mechanical circulatory support, congenital heart diseases, and small-intestinal bleeding
Classification by specialty	Medicine in general Gastroenterology Cardiology Hematology and clinical oncology Cardiovascular surgery
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	von Willebrand factors (VWF), produced as huge multimers, are shear stress-dependently cleaved and present as large molecules with molecular weight no more than 20 million dalton. Since larger multimer of VWF has stronger potency for the induction of platelet thrombus, loss of VWF large multimer causes hemorrhagic tendency classified as VWD type II. Recently, bleeding of gastrointestinal tract associated with severe aortic stenosis, called Heydes syndrome, has been found to be caused by the acquired von Willebrand syndreome (aVWS) due to excess cleavage of VWF by high shear stress at the stenotic aortic valve (NEJM, 367, 1954-6, 2012). The clinical feature of the aVWS is similar to that of VWD type II. We evaluated approximately 30 patients with severe aortic stenosis and found that most of patients had aVWS and that 40% of patients exhibited severe or moderate anemia. However, the association between aortic stenosis and gastrointestinal bleeding is not widely known in many clinical settings in Japan. Furthermore, we have found that some of patients with other circulatory diseases possibly associated with high shear stress, such as pulmonary hypertension, (obstructive) hypertrophic cardiomyopathy and acute pulmonary embolism also exhibited aVWS. Then, we have found that patients with severe heart failure treated with mechanical circulatory support such as PCPS and VAD also exhibited aVWS. However, so far, systematic analysis for these pathological/clinical conditions has not been performed, and therefore, the incidence of aVWS and bleeding events in each disease. In this study, we will further expand small studies so far performed and evaluate various circulatory diseases possibly associated with aVWS systematically. Then, we aim to elucidate the clinical features of those diseases associated with aVWS and establish the ways of treatment for each cardiac disease.
Basic objectives2	Safety,Efficacy
Basic objectives -Others
Trial characteristics_1	Exploratory
Trial characteristics_2	Explanatory
Developmental phase	Not applicable

Assessment
Primary outcomes	This study is a prospective observational study to evaluate and elucidate incidence and clinical condition such as values obtained by laboratory examinations of aVWS and related bleeding events in each target circulatory disease by transverse and longitudinal analyses. Further, patients with small intestinal bleeding will be also enrolled and the contribution of cardiovascular disease-related aVWS would be also evaluated in the same way.
Key secondary outcomes	Elucidation of relationship between aVWS or bleeding events and values of blood examination such as ADAMTS13 activity and multiuser analysis of VWF, in each circulatory disease. aVWS-related bleeding sites such as gastrointestinal tract in each circulatory disease. Elucidation of set-up that possibly inducing aVWS under treatment of mechanical circulatory support device

Base
Study type	Observational

Study design
Basic design
Randomization
Randomization unit
Blinding
Control
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms
Purpose of intervention
Type of intervention
Interventions/Control_1
Interventions/Control_2
Interventions/Control_3
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Eligibility
Age-lower limit	Not applicable
Age-upper limit	Not applicable
Gender	Male and Female
Key inclusion criteria	This research is consisted following A and B lines. Research A: When patients undergo bleeding events and surgical therapy during follow-up period, they are evaluated for laboratory examination including VWF multimer analysis several times after the evemts. 1. Aortic stenosis with peak pressure gradients more than 30 mmHg evaluated with Doppler ultrasound cardiography (UCG), 500cases. 2. Mitral regargitation more than II degree at B-mode UCG, 500 cases. 3. Hypertrophic obstractive cardiomyopathy with intraventricular pressure gradient more than 20 mmHg, 200 caases. 4. Pulmonary hypertension (PH) more than 40 mmHg maximal trans-tricuspid valve pressure gradient estimated by Doppler UCG including primary pulmonary hypertension, collagen-disease-related PH, CTEPH, PH caused by congenital heart diseases, 500 cases. 5. Acute pulmonary embolism, 100 cases. 6. Patients with mechanical circulatory support 195 cases (percutaneous cardiopulmonary support 150 cases, extracorponeal left ventricular assist device (VAD) 15 cases, implantable left ventricular VAD) 7. Patients congenital heart diseases with possible high shear stress within bodies including grown-ups and those after surgical repair, 200 cases. Research B: patients with intestinal bleeding in following (a) and (b ) categories are enrolled, 200 cases: a: definite small-intestinal bleeding from angiodysplasia evaluated with capsule endoscopy or baloon-type small-intestinal endoscopy b: suspected small-intestinal bleeding compatible with following categories. (i) apparent gastrointestinal bleeding. No causative origin observed by upper and lower endoscopic examination. clinically considered small-intestinal bleeding. (ii) tumor lesion, inflammatory bowel diseases, infectious colitis, and drug-induced colitis are excluded by capsule endoscopy or baloon-type small-intestinal endoscopy
Key exclusion criteria	none
Target sample size	2300

Research contact person
Name of lead principal investigator	1st name Hisanor Middle name Last name i Horiuchi
Organization	Tohoku University
Division name	Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer
Zip code	980-8575
Address	4-1 Seiryomachi, Sendai, 980-8575, Japan
TEL	+81-22-717-8463
Email	hisanori.horiuchi.e8@tohoku.ac.jp

Public contact
Name of contact person	1st name Hisanori Middle name Last name Horiuchi
Organization	Tohoku University
Division name	Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer
Zip code	980-8575
Address	4-1 Seiryomachi, Sendai, 980-8575, Japan
TEL	+81-22-717-8463
Homepage URL	http://www2.idac.tohoku.ac.jp/avec2/
Email	hisanori.horiuchi.e8@tohoku.ac.jp

Sponsor
Institute	The Research Group for the AVec Study (Main Offiece at IDAC,Tohoku University)
Institute
Department

Funding Source
Organization	AMED
Organization
Division
Category of Funding Organization	Japanese Governmental office
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Tohoku University
Address	2-1 Seiryomachi, Sendai, 980-8575, Japan
Tel	022-717-8007
Email	rinri-esct@proj.med.tohoku.ac.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2015 Year 07 Month 01 Day

Related information
URL releasing protocol
Publication of results	Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Open public recruiting
Date of protocol fixation	2015 Year 06 Month 20 Day
Date of IRB	2014 Year 10 Month 29 Day
Anticipated trial start date	2015 Year 07 Month 15 Day
Last follow-up date	2023 Year 03 Month 31 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other

Other related information

It is known that various cardiovascular diseases with high shear stress sometimes cause acquired von Willebrand factor syndrome (aVWS) and bleedings. However, many things such as incidences of aVWS and bleeding events, and risk factors for aVWS and bleedings in each disease remain unclear. In this study, patients with various cardiovascular diseases possibly causing high shear stress are enrolled and the incidence of aVWS and bleedings and their relationship in each disease are evaluated by transverse and longitudinal analyses. The aVWS-associated gastrointestinal bleeding often occurs in small-intestine. In the study, patients with bleeding in the small intestine are also enrolled and evaluated for aVWS and cardovascular diseases. It would uncover the contribution of aVWS in the small-intestinal bleeding.

Management information
Registered date	2015 Year 06 Month 30 Day
Last modified on	2021 Year 07 Month 05 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000019166