Ignite Creation Date:
2024-05-06 @ 7:02 PM
Last Modification Date:
2024-10-26 @ 2:59 PM
Study NCT ID:
NCT05876676
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-05-30
First Post:
2023-05-17
Brief Title:
RDC Biomarker Study
Sponsor:
Royal Marsden NHS Foundation Trust
Organization:
Royal Marsden NHS Foundation Trust
Study Overview
Official Title:
Rapid Diagnostic Centre Biomarker Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Rapid Diagnostic Centres
Rapid Diagnostic Centres RDC were built to diagnose patients who have common symptoms that occur in cancer but it is unclear if they have cancer or not These symptoms include
Weight loss
Fatigue
Cough
GP suspicion
Only 1 in every 10 patients 10 referred to an RDC will have cancer Some of the patients with cancer may have been more likely to develop cancer due to inherited or environmental factors Some of the patients who dont have cancer may also be at higher risk of developing cancer at another time due to inherited or environmental factors
Aims
The goal of this observational study is to develop a new blood or non-blood test that could help doctors at RDC
detect which patients have cancer through a simple and quick blood or non-blood test
detect patients who are at higher risk of having cancer This is so they can be monitored or guided towards cancer-screening programmes
Main End Points
The study will be considered a success if a test or mixture of tests is developed that can correctly sort patients into cancer or non-cancer groups
Also the study will be considered a success if a test or mixture of tests can show what type of cancer a patient has if they have cancer
Tests
To create this new blood or non-blood test the study will take the following samples from 1000 patients in the RDC Biomarker Study
Breath samples around 300 patients - People with cancer have different levels of chemicals in their breath than people without cancer The study hopes to develop a breath test which could show if a patient has cancer or not
Blood samples around 1000 patients - The study hopes to develop a blood test that could show if a patient has cancer or not
Saliva samples around 1000 patients - For many cancers while there is a genetic component there is no one single gene that causes cancer Instead it can be a combination of hundreds of genes that causes the risk of cancer in a person to go up The study hopes to develop a test which could provide a risk score This risk score is called a polygenic risk score which would tell doctors how likely a patient is to get cancer
Method Patients who meet the criteria to be able to join the study will be asked either via telephone before their appointment or face-to-face at an appointment at the RDC if they would like to join the study If they agree to join the study they will read a patient information sheet and sign a consent form to say they understand what the study requires
The patient will then provide blood and saliva samples and in some cases breath samples at their first appointment They will be then asked to provide further samples up to three at their follow-up appointments Please see below for samples that will be asked for at each appointment
First appointment Breath not all sites Blood Saliva not all sites Survey Follow-up 1 Any samples that could not be taken at the first appointment Follow-up 2 Any samples that could not be taken at the first appointment
The patient will be provided with a Study ID to identify their samples This is a unique code to identify each person on the study Only the site that recruited the participant will have access to the personal information that matches which patients is known by which Study ID All organisations external to the site will only know the patient as the Study ID An example of the study ID could be RDCRMH001
A trained clinical member of the research team at the RDC will take the sample and ship it to the relevant laboratory for testing
As well as blood and non-blood tests information about the patients will be collected This includes routinely collected clinical data alongside investigation results No patient identifiable information such as
Name
Address
Date of birth
Contact details
will be collected and a Study ID will be used to identify the data
A patient questionnaire will be sent out to patients to complete for each appointment asking questions about the patients health The RDC doctors treating the patient will see survey answers before the appointment to allow them to act about anything worrying
For a small group of patients anonymised copies of thier scans from their medical records will also be taken
Study Duration Once the study has recruited 1000 patients it will close These patients will then be followed up for 12 months following the date they joined the study
Rapid Diagnostic Centres RDC were built to diagnose patients who have common symptoms that occur in cancer but it is unclear if they have cancer or not These symptoms include
Weight loss
Fatigue
Cough
GP suspicion
Only 1 in every 10 patients 10 referred to an RDC will have cancer Some of the patients with cancer may have been more likely to develop cancer due to inherited or environmental factors Some of the patients who dont have cancer may also be at higher risk of developing cancer at another time due to inherited or environmental factors
Aims
The goal of this observational study is to develop a new blood or non-blood test that could help doctors at RDC
detect which patients have cancer through a simple and quick blood or non-blood test
detect patients who are at higher risk of having cancer This is so they can be monitored or guided towards cancer-screening programmes
Main End Points
The study will be considered a success if a test or mixture of tests is developed that can correctly sort patients into cancer or non-cancer groups
Also the study will be considered a success if a test or mixture of tests can show what type of cancer a patient has if they have cancer
Tests
To create this new blood or non-blood test the study will take the following samples from 1000 patients in the RDC Biomarker Study
Breath samples around 300 patients - People with cancer have different levels of chemicals in their breath than people without cancer The study hopes to develop a breath test which could show if a patient has cancer or not
Blood samples around 1000 patients - The study hopes to develop a blood test that could show if a patient has cancer or not
Saliva samples around 1000 patients - For many cancers while there is a genetic component there is no one single gene that causes cancer Instead it can be a combination of hundreds of genes that causes the risk of cancer in a person to go up The study hopes to develop a test which could provide a risk score This risk score is called a polygenic risk score which would tell doctors how likely a patient is to get cancer
Method Patients who meet the criteria to be able to join the study will be asked either via telephone before their appointment or face-to-face at an appointment at the RDC if they would like to join the study If they agree to join the study they will read a patient information sheet and sign a consent form to say they understand what the study requires
The patient will then provide blood and saliva samples and in some cases breath samples at their first appointment They will be then asked to provide further samples up to three at their follow-up appointments Please see below for samples that will be asked for at each appointment
First appointment Breath not all sites Blood Saliva not all sites Survey Follow-up 1 Any samples that could not be taken at the first appointment Follow-up 2 Any samples that could not be taken at the first appointment
The patient will be provided with a Study ID to identify their samples This is a unique code to identify each person on the study Only the site that recruited the participant will have access to the personal information that matches which patients is known by which Study ID All organisations external to the site will only know the patient as the Study ID An example of the study ID could be RDCRMH001
A trained clinical member of the research team at the RDC will take the sample and ship it to the relevant laboratory for testing
As well as blood and non-blood tests information about the patients will be collected This includes routinely collected clinical data alongside investigation results No patient identifiable information such as
Name
Address
Date of birth
Contact details
will be collected and a Study ID will be used to identify the data
A patient questionnaire will be sent out to patients to complete for each appointment asking questions about the patients health The RDC doctors treating the patient will see survey answers before the appointment to allow them to act about anything worrying
For a small group of patients anonymised copies of thier scans from their medical records will also be taken
Study Duration Once the study has recruited 1000 patients it will close These patients will then be followed up for 12 months following the date they joined the study
Detailed Description:
Background
The proposed research will focus on Rapid Diagnostic Centres RDCs already established across multiple sites in England Since 2019-2020 RDCs have begun rolling out nationally across all cancer alliances They are a single point of access for cancer diagnostics to allow personalised and rapid diagnosis of patients presenting with non-specific but concerning symptoms of cancer NSCS
Cancer patients with NSCS typically have a longer interval in primary care to referral and have more advanced disease once a diagnosis is made yet approximately 50 of cancer patients present with NSCS These patients are poorly served by existing cancer referral pathways which can be circuitous when a clear pattern of symptoms is not present
The objectives of RDCs are to
Support earlier and faster cancer diagnosis
Create increased capacity through more efficient diagnostic pathways
Deliver a better personalised diagnostic experience for patients
Reduce unwarranted variation in referral for access to and in the reliability of relevant diagnostic tests
RDCs Limitations
Although patients seen in RDCs are presumed to receive faster diagnosis and treatment there is still very little known about how their vague symptoms developed over time and how these are linked to underlying health conditions diagnosis health outcomes and RDC effectiveness
Most RDC patients will not have cancer Therefore accurate and rapid triage will be essential and depend upon improved methods of risk stratification and cancer detection There is both a significant need and opportunity to integrate quantitative research into RDCs to develop and validate novel diagnostic assays and risk scores based on this unique population of patients These patients both represent a primary care community but the enriched cancer prevalence within RDCs could be utilised to facilitate more efficient biomarker development
Rationale
Developing pathways to streamline care in this population group is important not only due to the importance of timely detection and treatment but most patients in these pathways both with and without cancer are more likely to be from more deprived backgrounds or prone to being less engaged with healthcare provision The implementation specification from NHS England highlights the need for RDCs to tackle health inequalities in their roll out This study will allow us to generate a sample set and database to examine the potential to
i discover high risk groups in RDC populations and ii to detect cancer-specific signals in symptom profiling data routine clinical and imaging data and blood and non-blood biomarker tools
The primary aims focus on using descriptive analysis to identify the following
1 The number and clinical traits of Benign versus Malignant Diagnoses
2 The number and clinical traits of cancer subtypes eg lung vs ovarian or other cancer The primary aims also focus on describing how the variability between participants can delineate cancer versus benign pathology using molecular germline risk symptom-profiling and clinical data from each of the four main work packages independently or in combination using AI-based multi-parametric analysis of these traits Descriptive analyses will provide feasibility data to develop and validate models using i Peripheral blood and non-blood eg breath and saliva molecular signatures that can delineate between cancer and benign pathology
ii Patient symptome signatures delineating between cancer and benign pathology
iii Digital health record signature from routinely collected clinical electronic health record EHR andor imaging data andor the standard RDC dataset that delineate between cancer and benign pathology
iv Risk stratification tools eg epidemiological and geneticPRS that inform risk of cancer in RDC attendees and primary care
Patient Selection
Overall we expect an initial sample size of 1000 patients that will allow several exploratory analyses and simple model developmentvalidation in distinct datasets within an observational platform study design The target recruitment will be increased by the Trial Steering Group TSG if new relevant assays are identified and extended funding is secured This is supported by previous work which suggests that 1000 patients are more than sufficient to identify candidate biomarkers for further studies it is a pragmatic approach and is not the result of power calculations A target goal will be for 75 of cancer cases to have histological confirmation ie ground truth of final diagnosis to help power diagnostic accuracy and reliability for any future use of histopathological data Patients recruited will be removed from analysis where ground truth cannot be established by the time of completion of initial investigations or a period of clinical surveillance not to exceed 12 months of surveillance after initial diagnostic pathway completed
The local Principal Investigator PI or members of the delegated clinical care team at participating trusts eg Consultant physicians nurse specialists clinical fellows or admin staff will identify suitable patients via RDC clinic appointments RDC multidisciplinary team MDT lists or by RDC service evaluations supported where necessary by clinical informatics approaches eg structured query language searches or local research team
We estimate that each participating hospital will see approximately 20-50 new RDC patients per week thus we expect that we could recruit large numbers of patients from a small number of RDCs This estimation may evolve considering the number of participating sites as well as the evolving nature of how RDCs are utilised particularly given the impact of the COVID-19 pandemic on cancer diagnosis Recruitment will be consecutive in the order in which patients are seen within each respective RDC Allocation of participants to a particular sample typeassay will be pragmatic based on site geographycapability of the RDC at which the patient is recruited
Study Duration
The study will end when complete outcome or surveillance data is available for all participants or after 12 months following recruitment completion of clinical assessment of the last patient whichever occurs sooner This duration is necessary to ensure confirmation of diagnosis or stability after discharge and therefore ground truth It is expected that recruitment will complete within two years Patient data and samples will be stored for a total of ten years The ten-year duration of storage is necessary to allow us to utilise more advanced laboratory and data analysis techniques which may become available with evolving technology Newer approaches may require very large datasets and this timeframe would allow for a protocol amendment for expansion of our data and further research to be performed as the field evolves Upon completion of the study we will establish a research database for future work and will store patient data for a total of ten years
Assessment of imaging data quality and integrity and suitability of research specimens for laboratory analysis will be contemporaneous to patient recruitmentsample receipt and ongoing thereafter Analysis will typically be performed on patients with confirmed ground truth by biopsy or sufficient clinical surveillance if benign eg 12 months see above but scans performed after this period may be accessed if future relevant data become available
Enrolment and Consent
Patient enrolment into the study will occur once consent is taken and eligibility criteria is met A trial number will be allocated to each patient for the identification research samples
In most cases patients will donate a blood specimen on one visit Baseline Where recurrent visits to the hospital for surveillance CT scans are made over a longer period then up to 3 blood specimens will be collected in total with a minimum of 21 days between each research specimen collection or a treatment intervention This will allow the consideration of evolution of the biomarker signal in question as a determinant of cancer presence or absence using the logic that a given signal is likely to increase alongside tumour growth and therefore be easier to detect in comparison with samples from patients without malignancy
All participants are free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing further treatment The patient can request that any remaining samples donated are destroyed All members of the delegated research team will ensure that patient confidentiality is maintained in compliance with the UK Data Protection Act 2018 and General Data Protection Regulation
Patient Samples Acquisition and Processing
The laboratory manual will provide further details of the collection processing and storage of specimens
Study Oversite
A Trial Steering Group TSG will meet on a regular basis to provide overall study oversight and clinical or scientific steer - particularly for academicresearch considerations
In addition a Trial Management Group TMG will meet quarterly to discuss patient recruitment data collection data management data analysis reporting for adverse events and change management The minutes of these meetings will be made available and a rolling agenda will highlight any ongoing actions or concerns
In addition the trial management team will provide day-to-day support for trial administration including all rules and regulations concerning research studies in the UK This includes UK Policy Framework for Health and Social Care Research Data Protection Act 2018 and UK General Data Protection Regulations
Data Analysis and Statistical Considerations
Statistical guidance and study design oversight will be provided by RM-ICR guided by the CI and Lead StatisticianData Scientist and will be undertaken in partnership with academic partner institutions named in the protocol support from other academic centres Data sharing agreements will be in place in each case A full Data Analysis Plan will be assembled and ratified by the Trial Steering Group at its creation and on any subsequent amendment
Clinical Data analysis
The main analysis including clinical data values will be descriptive and will be focused to inform future prospective studies For continuous variables the mean and standard deviation will be presented together with the mean between-group difference and 95 confidence interval For binary outcomes the percentage and frequency of patients in the outcome category of interest will be presented When necessary intracluster correlation coefficients will be reported together with 95 confidence interval Where appropriate p-values will be presented
Baseline characteristics collected at the time of commencing the study will provide an overview of the study population both at the RDC and site level It is expected that patients may differ based on which RDC they are recruited at and described with summary statistics including the index of multiple deprivation score for the RDC postcode percentage of patients with comorbidities and the cancer type At the individual patient level variables can include gender age at baseline data collection individual Index of Multiple Deprivation IMD values baseline measures of all physiological measurements comorbidity Baseline characteristics will be summarised as the mean standard deviation and range for continuous approximately symmetric variables medians interquartile range and range for continuous skewed variables frequenciespercentages of patientsRDC in each category for categorical variables
Laboratory Data Analysis
Analysis of laboratory data will lie in the first instance with the clinical and scientific lead for each work package with further details provided in the laboratory manual and local laboratory protocols The assays will give a read out for each patient that will be assessed using receiver operating characteristic curve analysis against each endpoint Firstly this will be performed using a single biological parameter for cancer versus non-cancer or most likely cancer subtype and then in combination with other laboratory and clinical endpoints as a multiparametric signature for the same endpoints as outlined in the protocol
The proposed research will focus on Rapid Diagnostic Centres RDCs already established across multiple sites in England Since 2019-2020 RDCs have begun rolling out nationally across all cancer alliances They are a single point of access for cancer diagnostics to allow personalised and rapid diagnosis of patients presenting with non-specific but concerning symptoms of cancer NSCS
Cancer patients with NSCS typically have a longer interval in primary care to referral and have more advanced disease once a diagnosis is made yet approximately 50 of cancer patients present with NSCS These patients are poorly served by existing cancer referral pathways which can be circuitous when a clear pattern of symptoms is not present
The objectives of RDCs are to
Support earlier and faster cancer diagnosis
Create increased capacity through more efficient diagnostic pathways
Deliver a better personalised diagnostic experience for patients
Reduce unwarranted variation in referral for access to and in the reliability of relevant diagnostic tests
RDCs Limitations
Although patients seen in RDCs are presumed to receive faster diagnosis and treatment there is still very little known about how their vague symptoms developed over time and how these are linked to underlying health conditions diagnosis health outcomes and RDC effectiveness
Most RDC patients will not have cancer Therefore accurate and rapid triage will be essential and depend upon improved methods of risk stratification and cancer detection There is both a significant need and opportunity to integrate quantitative research into RDCs to develop and validate novel diagnostic assays and risk scores based on this unique population of patients These patients both represent a primary care community but the enriched cancer prevalence within RDCs could be utilised to facilitate more efficient biomarker development
Rationale
Developing pathways to streamline care in this population group is important not only due to the importance of timely detection and treatment but most patients in these pathways both with and without cancer are more likely to be from more deprived backgrounds or prone to being less engaged with healthcare provision The implementation specification from NHS England highlights the need for RDCs to tackle health inequalities in their roll out This study will allow us to generate a sample set and database to examine the potential to
i discover high risk groups in RDC populations and ii to detect cancer-specific signals in symptom profiling data routine clinical and imaging data and blood and non-blood biomarker tools
The primary aims focus on using descriptive analysis to identify the following
1 The number and clinical traits of Benign versus Malignant Diagnoses
2 The number and clinical traits of cancer subtypes eg lung vs ovarian or other cancer The primary aims also focus on describing how the variability between participants can delineate cancer versus benign pathology using molecular germline risk symptom-profiling and clinical data from each of the four main work packages independently or in combination using AI-based multi-parametric analysis of these traits Descriptive analyses will provide feasibility data to develop and validate models using i Peripheral blood and non-blood eg breath and saliva molecular signatures that can delineate between cancer and benign pathology
ii Patient symptome signatures delineating between cancer and benign pathology
iii Digital health record signature from routinely collected clinical electronic health record EHR andor imaging data andor the standard RDC dataset that delineate between cancer and benign pathology
iv Risk stratification tools eg epidemiological and geneticPRS that inform risk of cancer in RDC attendees and primary care
Patient Selection
Overall we expect an initial sample size of 1000 patients that will allow several exploratory analyses and simple model developmentvalidation in distinct datasets within an observational platform study design The target recruitment will be increased by the Trial Steering Group TSG if new relevant assays are identified and extended funding is secured This is supported by previous work which suggests that 1000 patients are more than sufficient to identify candidate biomarkers for further studies it is a pragmatic approach and is not the result of power calculations A target goal will be for 75 of cancer cases to have histological confirmation ie ground truth of final diagnosis to help power diagnostic accuracy and reliability for any future use of histopathological data Patients recruited will be removed from analysis where ground truth cannot be established by the time of completion of initial investigations or a period of clinical surveillance not to exceed 12 months of surveillance after initial diagnostic pathway completed
The local Principal Investigator PI or members of the delegated clinical care team at participating trusts eg Consultant physicians nurse specialists clinical fellows or admin staff will identify suitable patients via RDC clinic appointments RDC multidisciplinary team MDT lists or by RDC service evaluations supported where necessary by clinical informatics approaches eg structured query language searches or local research team
We estimate that each participating hospital will see approximately 20-50 new RDC patients per week thus we expect that we could recruit large numbers of patients from a small number of RDCs This estimation may evolve considering the number of participating sites as well as the evolving nature of how RDCs are utilised particularly given the impact of the COVID-19 pandemic on cancer diagnosis Recruitment will be consecutive in the order in which patients are seen within each respective RDC Allocation of participants to a particular sample typeassay will be pragmatic based on site geographycapability of the RDC at which the patient is recruited
Study Duration
The study will end when complete outcome or surveillance data is available for all participants or after 12 months following recruitment completion of clinical assessment of the last patient whichever occurs sooner This duration is necessary to ensure confirmation of diagnosis or stability after discharge and therefore ground truth It is expected that recruitment will complete within two years Patient data and samples will be stored for a total of ten years The ten-year duration of storage is necessary to allow us to utilise more advanced laboratory and data analysis techniques which may become available with evolving technology Newer approaches may require very large datasets and this timeframe would allow for a protocol amendment for expansion of our data and further research to be performed as the field evolves Upon completion of the study we will establish a research database for future work and will store patient data for a total of ten years
Assessment of imaging data quality and integrity and suitability of research specimens for laboratory analysis will be contemporaneous to patient recruitmentsample receipt and ongoing thereafter Analysis will typically be performed on patients with confirmed ground truth by biopsy or sufficient clinical surveillance if benign eg 12 months see above but scans performed after this period may be accessed if future relevant data become available
Enrolment and Consent
Patient enrolment into the study will occur once consent is taken and eligibility criteria is met A trial number will be allocated to each patient for the identification research samples
In most cases patients will donate a blood specimen on one visit Baseline Where recurrent visits to the hospital for surveillance CT scans are made over a longer period then up to 3 blood specimens will be collected in total with a minimum of 21 days between each research specimen collection or a treatment intervention This will allow the consideration of evolution of the biomarker signal in question as a determinant of cancer presence or absence using the logic that a given signal is likely to increase alongside tumour growth and therefore be easier to detect in comparison with samples from patients without malignancy
All participants are free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing further treatment The patient can request that any remaining samples donated are destroyed All members of the delegated research team will ensure that patient confidentiality is maintained in compliance with the UK Data Protection Act 2018 and General Data Protection Regulation
Patient Samples Acquisition and Processing
The laboratory manual will provide further details of the collection processing and storage of specimens
Study Oversite
A Trial Steering Group TSG will meet on a regular basis to provide overall study oversight and clinical or scientific steer - particularly for academicresearch considerations
In addition a Trial Management Group TMG will meet quarterly to discuss patient recruitment data collection data management data analysis reporting for adverse events and change management The minutes of these meetings will be made available and a rolling agenda will highlight any ongoing actions or concerns
In addition the trial management team will provide day-to-day support for trial administration including all rules and regulations concerning research studies in the UK This includes UK Policy Framework for Health and Social Care Research Data Protection Act 2018 and UK General Data Protection Regulations
Data Analysis and Statistical Considerations
Statistical guidance and study design oversight will be provided by RM-ICR guided by the CI and Lead StatisticianData Scientist and will be undertaken in partnership with academic partner institutions named in the protocol support from other academic centres Data sharing agreements will be in place in each case A full Data Analysis Plan will be assembled and ratified by the Trial Steering Group at its creation and on any subsequent amendment
Clinical Data analysis
The main analysis including clinical data values will be descriptive and will be focused to inform future prospective studies For continuous variables the mean and standard deviation will be presented together with the mean between-group difference and 95 confidence interval For binary outcomes the percentage and frequency of patients in the outcome category of interest will be presented When necessary intracluster correlation coefficients will be reported together with 95 confidence interval Where appropriate p-values will be presented
Baseline characteristics collected at the time of commencing the study will provide an overview of the study population both at the RDC and site level It is expected that patients may differ based on which RDC they are recruited at and described with summary statistics including the index of multiple deprivation score for the RDC postcode percentage of patients with comorbidities and the cancer type At the individual patient level variables can include gender age at baseline data collection individual Index of Multiple Deprivation IMD values baseline measures of all physiological measurements comorbidity Baseline characteristics will be summarised as the mean standard deviation and range for continuous approximately symmetric variables medians interquartile range and range for continuous skewed variables frequenciespercentages of patientsRDC in each category for categorical variables
Laboratory Data Analysis
Analysis of laboratory data will lie in the first instance with the clinical and scientific lead for each work package with further details provided in the laboratory manual and local laboratory protocols The assays will give a read out for each patient that will be assessed using receiver operating characteristic curve analysis against each endpoint Firstly this will be performed using a single biological parameter for cancer versus non-cancer or most likely cancer subtype and then in combination with other laboratory and clinical endpoints as a multiparametric signature for the same endpoints as outlined in the protocol
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 53826 | REGISTRY | None | None |
| 306766 | REGISTRY | IRAS Reference | None |