The Role of Biomarkers in Inherited Cardiac Conditions
Conditions: Inherited Cardiac Conditions
Sponsor: Manchester University NHS Foundation Trust

 
The Role of Biomarkers in Inherited Cardiac Conditions 
Protocol No. ICC-01 
 
Version 1.1: 13th October 2016 
IRAS Project ID: 217504 
Page 1 of 7 
 
 
 
 
The Role of Biomarkers in Inherited Cardiac Conditions 
 
 
 
STUDY PROTOCOL 
 
 
 
Protocol number:   
ICC-01 
 
Protocol version:  
1.1 
 
Protocol date 
 
13th October 2016 
 
 
Sponsors:  
 
University Hospital of South Manchester NHS Foundation Trust 
Southmoor Road  
Wythenshawe  
MANCHESTER M23 9LT, UK 
 
Chief investigators:  
Dr Chris Miller 
 
 
 
 
University Hospital of South Manchester NHS Foundation Trust 
Southmoor Road  
Wythenshawe  
MANCHESTER M23 9LT, UK 
 
Primary contact:   
Dr Chris Miller 
 
 
 
 
 
 
 
 
 
 
 
 

 
The Role of Biomarkers in Inherited Cardiac Conditions 
Protocol No. ICC-01 
 
Version 1.1: 13th October 2016 
IRAS Project ID: 217504 
Page 2 of 7 
CONTENTS 
1. 
INTRODUCTION ...................................................................................................................... 3 
1.1. 
Study Summary ..................................................................................................................... 3 
1.2. 
Hypothesis ............................................................................................................................ 3 
2. 
BACKGROUND ....................................................................................................................... 3 
3. 
STUDY OBJECTIVES ............................................................................................................. 3 
4. 
STUDY DESIGN ...................................................................................................................... 3 
4.1. 
Overview/Design Summary ................................................................................................... 4 
4.2. 
Inclusion Criteria ................................................................................................................... 4 
4.3. 
Exclusion Criteria .................................................................................................................. 4 
4.4.  
Recruitment .......................................................................................................................... 4 
4.5. 
Consent................................................................................................................................. 4 
4.6. 
Details of Visits...................................................................................................................... 4 
4.6.1. Clinic Visit ............................................................................................................................. 4 
4.6.2. Cardiovascular status ............................................................................................................ 4 
4.7. 
Associated Risks and Benefits .............................................................................................. 5 
5. 
STATISTICAL PLAN ............................................................................................................... 5 
5.1. 
Sample Size and Power Calculation ...................................................................................... 5 
5.2. 
Statistical Analysis ................................................................................................................ 5 
6. 
DATA HANDLING ................................................................................................................... 5 
6.1. 
Confidentiality and Security ................................................................................................... 5 
6.2. 
Training ................................................................................................................................. 5 
6.3. 
Case Report Forms (CRF) and Source Documents .............................................................. 5 
6.4. 
Records Retention ................................................................................................................ 6 
7. 
STUDY ADMINISTRATION ..................................................................................................... 6 
7.1. 
Organisation and Participating Centres ................................................................................. 6 
7.2. 
Funding Source ..................................................................................................................... 6 
7.3. 
Study Timetable .................................................................................................................... 6 
8. 
PUBLICATION POLICY .......................................................................................................... 6 
9. 
REFERENCES ........................................................................................................................ 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
The Role of Biomarkers in Inherited Cardiac Conditions 
Protocol No. ICC-01 
 
Version 1.1: 13th October 2016 
IRAS Project ID: 217504 
Page 3 of 7 
1. 
INTRODUCTION 
1.1. 
Study Summary 
Inherited cardiac conditions (ICC) comprise any hereditary condition, which may affect heart 
muscle, vasculature, or heart electrical conductive system. ICCs represent a major cause of heart 
disease in all age groups, and have significant implications for patients and their families.1 
Symptoms vary considerably, from no symptoms to sudden death. Our understanding of these 
conditions has increased over the past decade, however significant limitations remains in 
diagnosis and risk stratification of these patients and their families. 2,3  
 
The NIH has defined a biomarker as “a characteristic that is objectively measured and 
evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic 
responses to a therapeutic intervention”.4  
This study aims to investigate the utility of biomarkers in a large cohort of patients with 
inherited cardiac conditions with the aim of improving diagnosis and risk stratification. Biomarkers 
will be related to the presence and severity of cardiovascular disease and other markers of cardiac 
disease. 
As part of this study, all patients with or with suspected ICCs attending clinics in 
Manchester (University Hospital of South Manchester (UHSM) and Central Manchester University 
Hospitals (CMFT)) will be approached over a 5 year period. The expectation is to recruit 1000 
patients. Patients will undergo their clinic appointments in the usual manner. As part of the study, 
clinical parameters collected as part of routine care (e.g. clinical history, imaging findings, blood 
test results, genetic information) will be assessed in relation to each other and in relation to patient 
outcome over subsequent 10 year follow-up. In addition, a peripheral blood sample of up to 
approximately 20mL will be taken and stored to allow measurement of blood biomarkers relating to 
the heart, including genetic analysis, which will be related to the clinical parameters and outcome.
 
  
 
1.2. 
Hypothesis 
We hypothesise that biomarkers will provide important diagnostic and prognostic information in 
patients with inherited cardiac conditions. 
 
2. 
BACKGROUND 
 
Inherited cardiac conditions (ICC) comprise any hereditary condition, which may affect heart 
muscle, vasculature, or conductive system. More than 50 ICCs have now been recognised as our 
diagnostic capabilities improve. However, whilst our understanding of ICCs and their molecular 
basis has increased, diagnosis and management of these conditions remains challenging owing to 
their heterogeneity, both genetically and phenotypically. 1-3 
 
Sudden death may be the first presentation of ICC, and a new diagnosis has significant 
implications for patients and family members. Risk may be augmented by a multitude of clinical 
and genetic factors, which we do not fully understand. There is an urgent need for tools for 
clinicians to identify patients with ICCs, and identify those with ICCs at increased risk of adverse 
outcome. Biomarkers, including blood, imaging, genetic and clinical biomarkers may be help 
diagnosis patients with ICCs, improve prognostication/risk stratification and monitor treatment and 
disease progression 
 
3. 
STUDY OBJECTIVES 
To investigate the diagnostic and prognostic utility of biomarkers in a large cohort of patients with, 
or with suspected, ICCs. 
 
4. 
STUDY DESIGN 

 
The Role of Biomarkers in Inherited Cardiac Conditions 
Protocol No. ICC-01 
 
Version 1.1: 13th October 2016 
IRAS Project ID: 217504 
Page 4 of 7 
4.1. 
Overview/Design Summary 
This is an observational study of patients attending hospital clinics that specialise in the 
management of patients with ICCs.  
 
4.2. 
Inclusion Criteria  
Any adult patient attending a hospital clinic that specialises in the management of patients with 
ICCs at UHSM or CMFT.  
 
4.3. 
Exclusion Criteria 
Age < 16 years, imprisonment, inability to provide informed consent.  
 
4.4.  Recruitment 
Patients due to attend hospital clinics that specialise in the management of patients with ICCs are 
sent appointment information regarding their clinic appointment as part of usual clinical practice. 
As part of the study, we will include the study Letter of Invitation and Participant Information Sheet 
with the information that is sent out and any questions patients have about the study will be 
answered during their clinic visit. When patients attend a member of the research team will ask 
them if they are willing to take part, discuss any aspects of the study that they wish and answer 
any questions. If they are willing to take part a member of the research team will ask them to sign 
the consent form. 
Occasionally patients will attend clinic at short notice in which case the clinical information is not 
sent out in advance. Given the low risk nature of this study, and the large distances that patients 
can potentially travel to attend these clinics (tertiary service), in this situation a member of the 
research team will give patients the Letter of Invitation and Participant Information Sheet while they 
are in the waiting area. A member of the research team will discuss any aspects of the study that 
they wish and answer any questions. If they feel that they have had sufficient time to understand 
the study and what participation involves, and are willing to take part, a member of the research 
team will ask them to sign the consent form. 
 
4.5. 
Consent 
Patients are required to read the Patient Information Sheet. Fully informed written and verbal 
consent will be gained from patients before they elect to participate. 
 
4.6. 
Details of Visits 
There will be no visits in addition to standard clinical care. 
 
4.6.1. Clinic Visit 
Patients will attend clinic, and any additional clinically indicated hospital appointments, in the usual 
manner. A peripheral blood sample of up to approximately 20mL will be taken for blood markers of 
cardiac disease and genetic analysis. Clinical data, including that relating to any imaging, blood 
test or functional investigations, will be recorded.  
 
4.6.2. Cardiovascular status 
Follow-up information regarding cardiovascular disease status, demographics and concurrent 
medical conditions and treatments will be obtained over the 10 year period following the clinic visit 
using the following methods: 
1. GP and hospital medical records. 
2. Central UK bodies, registries, audits and databases (e.g. HSCIC, ONS, NICOR, MINAP) and 
local health bodies e.g. clinical commissioning groups. 
3. Phone call to patients 
 

 
The Role of Biomarkers in Inherited Cardiac Conditions 
Protocol No. ICC-01 
 
Version 1.1: 13th October 2016 
IRAS Project ID: 217504 
Page 5 of 7 
None of these follow-up procedures will occur more than once yearly. 
 
4.7. 
Associated Risks and Benefits 
The study is associated with negligible risk. The blood sample will be taken peripherally by an 
experienced member of the research team. There is a rare potential risk associated with 
confidentiality of medical record information, however this risk will be minimised by running the 
study in accordance with the Trust guidelines on Confidentiality and Security and the NHS code of 
practice for confidential patient information. 
 
The use of information collected for this research study may be of future benefit to patients with 
cardiovascular diseases. 
 
5. 
STATISTICAL PLAN 
5.1. 
Sample Size and Power Calculation 
We will ask each adult patient scheduled to attend hospital clinics that specialise in the 
management of patients with ICCs at UHSM and CMFT to participate in this research study. The 
expectation is that over a 5 year period, approximately 200 participants per year may be enrolled in 
this study. Due to the diversity of the variables being collected, all patients who sign consent will 
provide meaningful information for this study. 
 
5.2. 
Statistical Analysis  
Multivariable regression modelling will be used to examine relationships between cardiac 
biomarkers and cardiovascular disease while adjusting for baseline differences of subjects. Chi 
square or Fisher exact tests will be used to compare categorical variables between patients with 
different marker levels. Independent samples t tests or Mann Whitney U tests will be used to 
compare continuous variables between patients with differing marker levels. Survival analysis will 
use logrank testing and Cox regression. 
 
6. 
DATA HANDLING 
6.1. 
Confidentiality and Security 
Data collected during the study will be stored on a secure database on an NHS computer with 
restricted access and password entry. A unique identifier made up of numbers and letters will be 
allocated. All personal data collected during the study will be handled in accordance with the NHS 
code of practice for confidential patient information. 
 
6.2. 
Training 
It will be ensured that all members of the research team who handle the data are familiar with the 
policies governing the confidentiality and security of the data collected during the study and SOPs 
specific to the study will be adhered to. Training records for all members of the research team will 
be maintained. 
 
6.3. 
Case Report Forms (CRF) and Source Documents 
Source documents are original documents, data, and records from which participants’ CRF data 
are obtained. These include, but are not limited to, hospital records (from which medical history 
and previous and concurrent medication may be summarised into the CRF), clinical and office 
charts, laboratory and pharmacy records, diaries, radiographic images and results, and 
correspondence. CRF entries will be considered source data in this study. 
 

 
The Role of Biomarkers in Inherited Cardiac Conditions 
Protocol No. ICC-01 
 
Version 1.1: 13th October 2016 
IRAS Project ID: 217504 
Page 6 of 7 
All documents will be stored safely in confidential conditions. On all study-specific documents, 
other than the signed consent, the participant will be referred to by the study participant number, 
not by name. Data will be stored in a database on an NHS computer, with restricted access and 
password entry. Patients’ NHS number and date of birth will be recorded in the database. Other 
identifiable information will be separated from the rest and stored with the associated study 
number on a separate computer under password protection in a locked office. This will be used for 
contacting patients and will not be kept with the study data. A back up copy will be made 
periodically and stored on a password-protected disk in a secure place. 
 
6.4. 
Records Retention 
Records will be retained in accordance with the UHSM SOP11: ‘End of Study Document Storage’. 
The Principal Investigator (PI) or a nominated deputy will be responsible for all research related 
documents. Individuals responsible for data who leave the Trust must inform the Research and 
Development (R&D) Directorate of who will be acting as the custodian of that data. 
 
After an end of study has been declared and acknowledged by the Ethics Committee and, where 
appropriate the MHRA, the following procedures will be adhered to: 
Research documents less than 10 years old will be kept on-site by the PI to facilitate access for 
audit, information, etc. Where it is not possible to store the documents on-site the PI will arrange 
for off-site storage via the R&D Directorate. It will be ensured that the documents can be accessed, 
with short notice if required. A log will be kept by the PI of the documents stored, which will include 
the following information: box number (1 of 1 etc.), Trial ID, study name, PI, date of storage, date 
to be destroyed, emergency contact details, Sponsor and contact details. 
 
Research documents over 10 but less than 20 years old will be stored off-site. A log will be kept by 
the PI of the documents stored. 
 
Any research documents over 20 years old will be destroyed, but prior to destruction, a log will be 
made, and kept by the PI, of all the documents that are being destroyed. This log will include the 
following information: Trial ID, Study name, Patient ID, date of destruction, name and signature of 
authorised person. 
 
7. 
STUDY ADMINISTRATION 
7.1. 
Organisation and Participating Centres 
This is a single-centre study. The study will be conducted at UHSM, which will act as sponsor. 
 
7.2. 
Funding Source 
The study is funded by an external grant from Singulex, who will provide the assays and analysis.  
 
7.3. 
Study Timetable 
Subject to obtaining a favourable opinion from the Research Ethics Committee, we aim to start the 
study from 1st January 2017. 
 
8. 
PUBLICATION POLICY 
Our expectation is that after data analysis, information from this study will be widely disseminated 
in the medical and scientific community. This will be achieved through a series of peer-reviewed 
publications and meeting abstracts at local, national and international events. Anonymised raw 
data will be shared with the scientific community. 
9. 
REFERENCES 
 

 
The Role of Biomarkers in Inherited Cardiac Conditions 
Protocol No. ICC-01 
 
Version 1.1: 13th October 2016 
IRAS Project ID: 217504 
Page 7 of 7 
 
 
 
 
1. 
Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. N Engl J Med. 
2011;364:1643–1656.  
2. 
Arbustini E, Narula N, Tavazzi L, Serio A, Grasso M, Favalli V, Bellazzi R, Tajik JA, Bonow 
RO, Bonow RD, Fuster V, Narula J. The MOGE(S) classification of cardiomyopathy for 
clinicians. Journal of the American College of Cardiology. 2014;64:304–318.  
3. 
Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kühl U, 
Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren 
A. Classification of the cardiomyopathies: a position statement from the European Society Of 
Cardiology Working Group on Myocardial and Pericardial Diseases. European Heart Journal. 
2008;29:270–276.  
4. 
Strimbu K, Tavel JA. What are biomarkers? Current Opinion in HIV and AIDS. 2010;5:463–
466.