A Study to Evaluate the Feasibility of Screening Relatives of Patients Affected by Non-Syndromic Thoracic Aortic Diseases

Genetic Disease Clinical Trial

— ReST  

Official title:

A Study to Evaluate the Feasibility of Screening Relatives of Patients Affected by Non-Syndromic Thoracic Aortic Diseases: The ReST Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03861741
• Other study ID #: 0676
• Status: Active, not recruiting
• Phase: N/A
• Start date: March 1, 2019
• Est. completion date: May 20, 2022

Study information

• Verified date: April 2021
• Source: University of Leicester
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary hypothesis is that a tailored programme of genetic and imaging screening of first- and second-degree relatives of patients affected by non-syndromic forms of thoracic aortic diseases will identify individuals at risk of death from these conditions. These individuals would constitute specific population of patients, requiring dedicated imaging surveillance and/or earlier prophylactic aortic surgery.

Description:

Diseases involving the thoracic aorta (the major artery in the body) are a major health problem affecting an increasing number of people worldwide.

In particular, a group of these conditions termed Non-Syndromic Aortic Diseases (NS-TAD), can develop without any obvious symptoms or external features which prevents early identification. Unfortunately, if not treated, the aorta may enlarge and lead to dissection, a life-threatening medical emergency. For this reason, the investigators believe it might be helpful to investigate relatives of patients undergoing surgery for thoracic aortic disease to understand if there are tests that could help identify and treat this condition at the right time.

Therefore the investigators propose to conduct a feasibility study to identify the practical issues and challenges that would need to be overcome in order to perform a successful tailored genetic (by collecting a small blood sample) and imaging (with exams such as echocardiography and MRI) screening in such population of individuals.

Moreover, all participants will receive two questionnaires to ask their opinion about the study and to measure their levels of anxiety and depression, to judge whether and how this study has affected their emotional status.

The study will be carried out at the Department of Cardiovascular Sciences Glenfield Hospital, University Hospitals of Leicester NHS Trust.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 70
• Est. completion date: May 20, 2022
• Est. primary completion date: May 20, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

1. NS-TAD probands operated on (n=16).

2. FDR and SDR, aged 16 and above:

1. At least two relatives willing to participate in the screening programme.

2. Relatives able to understand English.

Exclusion Criteria:

1. Probands with syndromic aortopathies, including Marfan Syndrome, Loeys-Dietz Syndrome, Ehlers-Danlos Syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome, arterial tortuosity syndrome, and cutis laxa syndrome.

2. Probands with aortic lesions associated with trauma and infections.

3. Probands/relatives unable to give informed consent

Related Conditions & MeSH terms

• Aneurysm
• Aortic Aneurysm
• Aortic Aneurysm and Dissection
• Aortic Diseases
• Genetic Disease
• Genetic Diseases, Inborn
• Screening

Intervention

Genetic:
• WES
A peripheral venous blood sample will be processed internally, and externally subjected to WES. Only genetic material from relatives of probands in which a mutation has been identified will be sequenced.

Diagnostic Test:
• MRI
A MRI of the thoracic aorta will be performed in all relatives able to attend the Glenfield Hospital and who have no contra-indications to this imaging modality; pulse-wave velocity will be recorded.
• TTE
TTE screening will be performed by a trained physiologist. Aortic diameter will be measured from the parasternal long-axis view at the sinuses of Valsalva and at the widest level of the ascending aorta. All measurements will be made in end-diastole.

Other:
• Questionnaire
Acceptability questionnaires will be submitted to assess a baseline score of depression/anxiety that will be compared with a follow up value at three months

Locations

Country	Name	City	State
United Kingdom	Department of Cardiovascular Sciences	Leicester	Leicestershire

Sponsors (1)

Lead Sponsor	Collaborator
University of Leicester

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

Mariscalco G, Debiec R, Elefteriades JA, Samani NJ, Murphy GJ. Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease. J Am Heart Assoc. 2018 Aug 7;7(15):e009302. doi: 10.1161/JAHA.118.009302. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of genetic diagnosis	Frequency of first and second degree relatives with newly identified genetic loci associated with NS-TADs.	Through study completion, an average of 1 year
Primary	Rate of diagnosis through imaging modalities	Frequency of newly diagnosed TAD through imaging modalities in first- and second-degree relatives of probands affected by NS-TADs.	At the end of recruitment stage, an average of 6 months
Secondary	Genetic variants	Genetic variants associated with NS-TADs, identified from a panel of 55 loci, and rate of identification of each mutation.	Through study completion, an average of 1 year
Secondary	Family rate of genetic carriers	Rate of genetic carriers in each affected family.	Through study completion, an average of 1 year
Secondary	Penetrance	Genetic penetrance of the NS-TADs (proportion of individuals carrying a particular variant of a gene that are also affected by NS-TAD).	Through study completion, an average of 1 year
Secondary	Mode of inheritance	Pattern of inheritance of the NS-TADs.	Through study completion, an average of 1 year
Secondary	Male: female preponderance	Male: female preponderance of NS-TADs.	Through study completion, an average of 1 year
Secondary	Aortic Compliance	Measured as an MRI feature of affected and unaffected thoracic aortas.	Imaging tests completion, an average of 6 months.
Secondary	Aortic Distensibility	Measured as an MRI feature of affected and unaffected thoracic aortas.	Imaging tests completion, an average of 6 months.
Secondary	Rates of concomitant external and cardiovascular characteristics	Rates of concomitant cardiovascular diseases (e.g. patent ductus arteriosus, cerebrovascular aneurysm) and external physical features (e.g. pectus excavates, livedo reticularis).	Baseline clinical assessment
Secondary	Response rate	Response rates (recruitment) among the probands and their relatives.	Baseline clinical assessment
Secondary	Acceptability questionnaires	Semi-quantitative evaluation of the participant experience awareness and acceptability of the screening and consent process, obtained by questionnaires administered to the patients and relatives.; Scales will be composed by 10 items, each can be rated with a score from 1 to 5. No threshold will be preset. Descriptive statistics will be used to present the results.	Baseline and 3 months follow up
Secondary	Depression evaluation	Semi-quantitative evaluation of the impact of the screening process on depression in probands and their relatives (baseline and 3 months), based on Patient Health Questionnaire (PHQ-9) score. Score range goes from 0 to 27, proposed cut-off for active treatment is 15.	Baseline and 3 months follow up
Secondary	Anxiety evaluation	Semi-quantitative evaluation of the impact of the screening process on anxiety in probands and their relatives (baseline and 3 months), based on Generalized Anxiety Disorder (GAD-7) score. Score range goes from 0 to 21, proposed cut-off for further assessment is 10.	Baseline and 3 months follow up
Secondary	Health-related Quality of Life evaluation	Semi-quantitative evaluation of the impact of the screening process on health-related quality of life in probands and their relatives (baseline and 3 months), based on Short Form (36) Health Survey (SF-36) score. Said questionnaire is made up of eight scales, which are the weighted sums of the items for each section; a score of zero corresponds to maximum disability while 100 correlates to no disability.	Baseline and 3 months follow up
Secondary	Resource use of genetic screening	Resource uses in terms of unitary costs of the genetic screening process.	3 months follow up
Secondary	Resource use of imaging screening	Resource uses in terms of unitary costs of the imaging screening process.	3 months follow up
Secondary	Resource use (hospital visits)	Number of participants reaching the research centre.	3 months follow up