Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02402478 |
| Other study ID # |
11/LO/1621 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
March 18, 2015 |
| Last updated |
March 24, 2015 |
| Start date |
July 2009 |
| Est. completion date |
January 2014 |
Study information
| Verified date |
March 2015 |
| Source |
University College, London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United Kingdom: Research Ethics CommitteeUnited Kingdom: National Institute for Health ResearchUnited Kingdom: National Health Service |
| Study type |
Observational
|
Clinical Trial Summary
The purpose of this study is to advance research through collaboration, 4C was established
in the United Kingdom (UK) in 2009 as a resource in which deoxyribonucleic acid (DNA) and
biomarker samples were obtained at time of presentation with chest pain linked to detailed
phenotypic data obtained from electronic health records and participant self-completed
questionnaires. The investigators sought to explore and assess the current potential of
setting up a comparable consented research platform by collecting DNA samples and to
quantify the extent to which diverse NHS hospital information systems are accessible for
extracting secondary care data (structured and unstructured) for research purposes at scale.
Description:
Obtaining participant consent Patients were invited to read a study information sheet and
encouraged to ask questions about the research, after which written informed consent was
sought from patients for: a) completion of a baseline health questionnaire; b) provision of
a blood sample for long-term storage and analysis of DNA and biomarkers; c) extraction of
patient data from their medical records; and d) linkage of patient data with national
electronic health record data sources (e.g. coded hospitalisations and procedures, emergency
admissions and cause-specific mortality).
Sample size For sufficient power to detect relative risk differences of 1.2 at a 5%
significance level a minimum of 3000 patients was required.
Baseline data collection and measures Three unique sources of data contributed to the
participant baseline assessment, which took place during patients' scheduled hospital
appointments. Research measures (biological specimens and information not routinely
collected during patients' clinical assessments) included 1) blood samples for DNA and
biomarker analysis and a 2) short health questionnaire completed by participants (usual
completion time 5-10 minutes). Clinical measures were 3) detailed clinical information
collected as part of usual care, extracted from the hospital electronic health record up to
six months after the baseline assessment to allow time for procedure and test results to be
uploaded to hospital electronic systems.
A. Collection of research measures (i) Blood resource Venous blood sampling and processing
of samples Non-fasting blood samples were obtained from consenting participants, including
those in whom a diagnosis of angina was subsequently ruled out, by staff trained in
venepuncture during the hospital appointment. Twenty millilitres of blood was drawn to
enable a wide range of research measures to be obtained. Blood was drawn into five
vacutainers in the following order: 2x 4.0 mL ethylenediaminetetraacetic acid tube (EDTA),
1x 4.5 mL gel-separator lithium heparin tube (plasma separation tube (PST)), 1x 5.0 mL gel
serum separator tube (SST), 2x 4.0 mL, and 1x 2.5 mL PAXgene ribonucleic acid (RNA) blood
tube (PreAnalytiX, Franklin Lakes, NJ). Vacutainers were gently inverted and reverted up to
five times to allow additives to mix with the blood, labelled and temporarily stored at
approximately 5°C until processing. Date and time of collection was recorded. Different
blood fractions were separated by centrifugation at 2500 g for 10 minutes. EDTA and PST
samples were centrifuged within four hours after sampling and the SST sample was left to
clot at room temperature for 25-30 minutes prior to centrifugation.
EDTA plasma, heparinised plasma, serum and white cells (buffy coat) were aliquoted into a
total of nineteen 0.5 mL 2D QR-coded cryovial tubes suitable for long-term cryopreservation.
Each cryovial was individually logged in two un-linked databases using a single-tube QR-code
reader, placed in a 96-position rack and stored locally at -20°C. PAXgene RNA tubes were
stored as whole blood at -20°C.
Buccal swab sample collection Consenting patients who did not provide a venous blood sample
were invited to provide a buccal swab for subsequent DNA extraction. Samples were collected
by rubbing a sterile swab firmly against the inside of the participant's cheek or between
their lips and the gum line for one minute. The swab was stored in a sterile container with
a silica gel capsule (Isohelix Dri-Capsules, Cell Projects Ltd) to stabilise the sample at
room temperature for up to two years.
Samples were transported in temperature-controlled shipping boxes for long-term storage at a
biobank at -80°C.
Extraction of DNA and single-nucleotide polymorphism (SNP) genotyping DNA was extracted from
2556 individual participant samples and genotyping of 51 CHD-specific SNPs identified in
Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM PlusC4D) was
completed, according to specification, by a company with specialised services for extraction
of DNA and genotyping.
Biomarkers and metabolomic profiling of patients The investigators propose to measure
routinely collected and novel markers that appear most promising for clinical predictive
value, including N-terminal brain natriuretic peptide (NT-BNP), high-sensitivity C-reactive
protein (hs-CRP), apolipoprotein A1 (apoA1), apolipoprotein B (apoB), lipoprotein A (Lp(a)),
and cystatin C.
(ii) Baseline health questionnaire All participants were invited to complete a questionnaire
to ascertain or validate participants' sex, level of education, ethnicity and health.
General health functioning was assessed using the EQ-5D, (http://www.euroqol.org/) a 5-item
standardised measure of health outcome. Functional chest pain was determined using the Rose
angina questionnaire and angina severity using the Canadian Cardiovascular Society (CCS)
classification. Symptoms of depression were assessed using the Patient Health
Questionnaire-9 (PHQ-9), which scores each of the nine Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV 4th Edition, American Psychiatric Association) criteria for
depression in the PRIME-MD (Primary Care Evaluation of Mental Disorders screening
questionnaire for depressive symptoms) diagnostic instrument for common mental disorders.
Anxiety was assessed using the 7-item Generalized Anxiety Disorder (GAD-7) scale, a
self-reported measure for screening and quantifying severity of generalized anxiety
disorder.
(iii) Extended physical examination and measures obtained in sub-study Additional measures
obtained from a subset of participants included a sixty-minute physical examination
(anthropometric measures, lung function, aortic blood pressure, pulse wave [augmentation]
index, pulse wave velocity and ankle brachial index), 31-hour ambulatory ECG, tri-axial
accelerometry and sleep measures. Sub-study participants also completed an extended health
questionnaire which included questions on diet and sleep.
B. Extraction of clinical information from the electronic health record Trained extractors
reviewed hospital databases and recorded detailed clinical information onto standardised
case report forms. Depending on the clinic or hospital, different clinical systems were
searched to manually extract data that could not be downloaded or exported as a data file.
Information included reason(s) for referral, history of chest pain, physician-recorded risk
factors for coronary artery disease, previously diagnosed medical history, current
medication and test results.
All participants underwent a resting 12-lead electrocardiogram (ECG) as part of their
routine clinical assessment. An exercise tolerance test (ETT) was undertaken by an
experienced cardiac electrophysiologist in hospitals that performed ETTs for routine
assessment of chest pain. The ETT followed the modified Bruce protocol (Bruce, RA, 1963) and
was conducted with concurrent 12-lead electrocardiography.
Data were manually entered onto a research database at the study coordinating centre,
cleaned and coded ready for analysis.
Follow-up Postal questionnaire A postal follow-up questionnaire was sent to study
participants after recruitment (mean time to follow-up 469 days) to assess general health
status (EQ-5D), functional status (Rose angina questionnaire, Seattle angina questionnaire),
symptoms of depression (PHQ-2) and anxiety (GAD-7) and use of nitrate medication.
Electronic health record linkages With their consent, the investigators linked participants
to data from Hospital Episode Statistics, a national data warehouse of administrative data
containing ICD-10-coded hospital diagnoses and OPCS4-coded procedures. The investigators
additionally linked participants with ICD-10-coded cause-specific mortality data from the
Office for National Statistics. The linkages were conducted via the NHS Health and Social
Care Information Centre (formerly known as the NHS Information Centre) and patients were
identified using their NHS number (a unique ten digit numeric identifier for the NHS),
gender, date of birth and postcode.
Data collection and management The design, conduct, analysis and reporting of the study
follow the methodological standards set out in the REporting recommendations for tumour
MARKer prognostic studies (REMARK) guidelines. To maintain confidentiality, identifiers were
removed from all sources of data and replaced with a unique participant study number
assigned at the point of enrolment. Researchers were trained to follow standardised
operating procedures to ensure high quality, consistent collection of data. Data were
checked and validated, and inconsistencies in clinical data were resolved by revisiting
hospital data at source.
