Study setting {9}
Patients will be assessed according to the eligibility criteria and recruited directly from Long COVID Clinics in the UK (Derbyshire Community Health Services, Sheffield Teaching Hospitals NHS Foundation Trust and Northumbria NHS Trust), the University of Illinois Post-COVID-19 Clinic, (Chicago, USA) and the Ramaiah Medical College Hospitals Post COVID Clinic (Bengaluru, India). Long COVID patients will be assessed according to the eligibility criteria and recruited following referral or contact with a long COVID clinic or having suspected or confirmed long COVID. Social media and targeted recruitment from established pages will be used to advertise the opportunity to engage with the trial for those in proximity. Inclusion and exclusion criteria is laid out below:
Study Sites
United Kingdom
In the UK, the study will be conducted at 3 sites: University of Derby, Derby; Advanced Wellbeing Research Centre, Sheffield, UK and Northumbria University, Newcastle. Patients will be recruited from the local NHS Hospitals Trust through the long covid clinic/hubs and through word of mouth and social media.
Ramaiah Medical College, Bengaluru, India
In India, the study will be conducted at the Centre for Rehabilitation, Ramaiah Memorial Hospital. Patients will be recruited through telephonic follow-up of patients discharged from the Ramaiah Medical College Hospitals as well as through their internal medicine, respiratory medicine and Post COVID Clinics.
University of Illnois, Chicago.
In the USA, study visits will be conducted at the University of Illinois’ Physical Therapy Faculty Practice, Chicago, IL, USA. Patients will be recruited from the University of Illinois Hospital through the pulmonology and cardiology clinics as well as through word of mouth and social media.
Eligibility criteria {10}
Inclusion/Exclusion Criteria: The risk of causing inadvertent harm can also be mitigated by implementing strict inclusion/exclusion criteria which include identifying and screening individuals who are at risk of a severe PEM/PESE reaction.
Eligibility criteria includes:
Inclusion:
≥ 18 years of age at the time of enrolment
Previously confirmed or suspected SARS-CoV-2 infection
Confirmed diagnosis of Long COVID by a Health Care Practitioner according to the *definition provided by the World Health Organisation for persistent symptoms following a confirmed SARS-CoV-2 infection.
Willing and able to provide informed consent, complete the surveys, and complete all planned clinical assessments, and return for scheduled study visits.
Has the use of a smart phone.
Evidence of persistent symptom profile relative to pre-COVID-19 status as derived from patient reported outcome measures.
* WHO define Long COVID as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation.
Exclusion criteria includes:
< 18 years of age
A diagnosis of a compromised immune system or function from a Healthcare Professional.
Currently engaged in a physical rehabilitation programme or intervention aimed to improve Long COVID symptom profile and/or functional status .
Recognised as a ‘severe risk’ of experiencing post-exertional malaise following engagement in physical tasks. Determined using the De Paul symptom questionnaire.
Lack of mental capacity to provide informed consent.
Unable to understand verbal English/have a hearing impairment that prevents adequate communication.*
Admitted to or received treatment from Intensive Care Units
Unconfirmed COVID-19 test diagnosis
Unable to understand verbal or written information in English
Achieving a grade 0 or 1 on the PCFS.
Unstable angina
Uncontrolled hypertension, that is, resting systolic blood pressure (SBP) > 180mmHg, or resting diastolic blood pressure (BP) (DBP) > 110mmHg
Orthostatic blood pressure drop of > 20 mmHg with symptoms
Significant aortic stenosis (aortic valve area 120 bpm)
Acute pericarditis or myocarditis
Decompensated HF
Third degree (complete) atrioventricular (AV) block without pacemaker
Recent embolism
Acute thrombophlebitis
Resting ST segment displacement (> 2 mm)
Uncontrolled diabetes mellitus
Severe orthopaedic conditions that would prohibit exercise
Other metabolic conditions, such as acute thyroiditis, hypokalaemia, hyperkalaemia or hypovolaemia (until adequately treated)
Severe grade 3 rejection (cardiac transplantation recipients)
Who will take informed consent? {26a}
Eligible patients will be identified at the designated PIC sites by individuals knowledgeable about the research. The researcher will introduce themselves to the patient and/or patient representatives and explain the nature of their visit to the patient. The researcher will proceed, if the patient agrees, to discuss the nature, objective, risks, and benefits of the proposed research. This will include the provision of written information regarding the research study, implications, expected outcomes, risks, and benefits. The patient will be allowed to ask questions throughout this process.
Once patients have indicated their willingness to participate in the research, they will be invited to a session at their local site. Consent will be obtained by members of the research team and documented using the study consent form. Informed consent will be obtained before the participant undergoing any activities that are specifically for the study. All study documentation (i.e. participant information sheet, participant consent form) will be kept in the Trial Master File.
The right of the patient to refuse to participate in the study without giving any reason must be respected. Equally, the patient will be free to withdraw their consent to participate in the study without providing any reasons and without prejudicing his or her further treatment.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not Applicable, the consent for biological samples is within the informed consent documents outlined above.
Interventions
Explanation for the choice of comparators {6b}
Not Applicable for this study, no comparator arms.
Intervention description {11a}
Not Applicable for this study, all outcome measure protocols are shown in detail below.
Criteria for discontinuing or modifying allocated interventions {11b}
Each participant has the right to withdraw from the study at any time. Participants may be withdrawn from the study either at their request or at the discretion of the Chief Investigator. Participants will be made aware (via The Participant Information Sheet and Participant Consent Form) that withdrawing the data which has been collected cannot be erased and may still be used in the final data analysis and study dissemination (i.e. published journal). The Chief Investigator may withdraw a participant from the study at any time if they consider that the participant’s health is compromised by remaining in the study or the participant is not sufficiently cooperative. The reasons for any participant withdrawal will be recorded on the study completion form of the CRF. The data collected from withdrawn participants will be included in the study report.
Besides, the Chief Investigator may discontinue a participant from the study at any time if they consider it necessary for any reason including but not limited to:
-
Ineligibility (arising during study or retrospective having been overlooked at screening)
-
Significant protocol deviation
-
Significant non-compliance with study requirements
-
An AE which results in the inability to continue to comply with study procedures
-
Progression of illness that renders participants unable to comply with study procedures.
-
Consent is withdrawn
-
Lost to follow up
The reason for withdrawal will be clearly stated and recorded in the CRF.
If the participant is withdrawn due to an AE, the Chief Investigator will arrange for a follow-up telephone call until the AE has resolved or stabilised.
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
No concomitant interventions were permitted.
Provisions for post-trial care {30}
All participants will be contacted by the investigators at the end of their involvement to ascertain if any post-trial care is needed with follow up to a patient's general practitioners if necessary.
Outcomes {12}
Public Patient Involvement
This protocol has been reviewed as part of the PPI groups at Royal Derby Hospital, UK and Patient involvement in Research Group (PIRG) at the Advanced Wellbeing Research Centre, UK. Due to the sensitive nature of conducting CPET based research in populations where post exertional malaise is a common adverse event.
The protocol and supporting documentation have been reviewed by members of the research teams established Patient and Public Involvement group. Their feedback has shaped the design of the study processes. Ms. Lindsay Skipper will function as the trial’s public and patient involvement representative, and she is a Long COVID patient and a former Physiotherapist. Ms. Skipper has worked alongside the study team to ensure all the documentation and study processes are appropriate for patients with Long COVID. She has been extremely involved in ensuring that the study risks are identified and mitigated as much as possible. Ms. Skipper will be an active member of the TMG to ensure that the project maintains a patient and translatable approach.
Study progress will be discussed at the Patient and Public Involvement Group monthly meetings.
Baseline Clinical Data
Data collected will include demographics, the pre-admission symptoms, pre-admission therapy, preadmission exercise tolerance and performance status (retrospective assessment by the patient and/or representative 6 weeks preceding admission) level of educational attainment, past-medical history, time and route of admission, and in-hospital routine physiological observations (including heart rate, blood pressure, oxygen saturation, respiratory rate and temperature). Blood biomarkers that are part of clinical profiling such as C- Reactive Protein, total blood count, D-Dimers and IL-6 as well as exploratory markers for Long covid mechanisms including inflammatory responses and clotting factors. This will also be performed pre and post (30mins) exercise bouts.
Patient Reported Outcomes
Symptom profile will be measured twice at the baseline assessment (Day 0), to capture a) retrospective assessment by the patient of their symptom status at symptom onset (essentially their baseline symptoms), and b) their current symptom status at the point of testing. The EQ-5D-5L is routinely used in the assessment of the quality of life in respiratory research and is available in more than 130 languages (EQ-5D-5L). It comprises five dimensions (Previously 3): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has five levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Participants completed the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a self-report measure to assess sleep quality over 4 weeks, throughout the intervention. The measure consists of 19 individual items, with a 0–3 interval scale and creates 7 components that produce one global score. The PSQI is reliable and valid in the assessment of sleep problems. Fatigue is a common complaint in patients recovering from an acute respiratory infection and is not adequately captured in general quality of life or specific recovery questionnaires. Participants will also complete two separate measures of fatigue at Visit 1 and Visit 2); (A) the Fatigue Assessment Scale (FAS), a self-reported questionnaire validated to assess the presence and severity of fatigue; and (B) MFI-20. A 20-item self-reported questionnaire assessing fatigue across five aspects. The Medical Research Council (MRC) Dyspnoea Scale (MRC) is a measure to grade the effect of breathlessness on a person’s daily activities. The MRC is simple to administer and is a short 1–5 stage scale (1 item) and allows the person to state the extent to which their breathlessness affects their mobility. The post-COVID-19 Functional Status (PCFS) Scale was used to assess upon discharge from the hospital and during each face-to-face visit to monitor direct recovery and to assess functional sequelae. The PCFS will be used to evaluate the ultimate consequences of COVID-19 on functional status and supplement other instruments that measure quality of life, tiredness, or dyspnoea in the acute phase. The PCFS covers the full spectrum of functional outcomes and focuses on both limitations in usual duties/activities and changes in lifestyle in six scale grades. Briefly, grade 0 reflects the absence of any functional limitation, and the death of a patient is recorded in grade D. Upward of grade 1, symptoms, pain or anxiety are present to an increasing degree. This has no effect on activities for patients in grade 1, whereas a lower intensity of the activities is required for those in grade 2. Grade 3 accounts for the inability to perform certain activities forcing patients to structurally modify these. Finally, grade 4 is reserved for those patients with severe functional limitations requiring assistance with activities of daily living (ADL). The Montreal Cognitive Assessment (MoCA) will be conducted at Visit 1. To allow accurate interpretation, the highest educational level/attainment was captured during data collection.
Assessment of Functional Status
Two different assessments of lower extremity functional capacity will be conducted at each visit; these are (A) the 6-minute walk test (6MWT) and (B) the timed up-and-go test (TUG). The 6MWT is a standardized and widely used measure of functional status in individuals with chronic diseases such as chronic obstructive pulmonary disease, cystic fibrosis, congestive cardiac failure, peripheral vascular disease, and the elderly. It has been previously used to assess response to interventions and predict morbidity and mortality. Participants will be permitted a shortened practice attempt (1–2 minutes) at the beginning of each baseline assessment visit. This will not be recorded but performed to allow familiarization with the assessment and repeated at each visit for consistency. The TUG is reliable and reproducible and has been validated as a predictor of frailty and risk of falls in elderly adults. The TUG has several advantages over other measures, mainly its reproducibility and shorter assessment time. Its use in predicting functional status following pneumonia has not been assessed previously.
Respiratory Muscle and Lung Function
Full lung function tests including FEV1, FVC, PEFR, flow-volume curves, Maximal Inspiratory (MIP) and Expiratory (MEP) Pressure will be conducted during the first visit. These spirometry measurements will be conducted by a suitably trained and experienced individual, proficient in the use of the specific equipment and according to published standards.
Cardiopulmonary Exercise Test (Sessions 2 and 3)
Participants will complete two identical CPET procedures which were separated by 24 hours, a common technique used to assess changes in functional capacity in clinical settings. Cardiopulmonary exercise testing will be performed to measure VO2 peak and other parameters representative of the cardiovascular reserve89. Tests will be conducted using a standard bicycle ramp protocol in accordance with the American Thoracic Society guidelines (12). In accordance with pilot data, individuals starting intensity will be stratified relative to performance on the 6MWT distance, Strata I: 6MWD < 400 (starting load of 10 watts; with subsequent increments of 5 watts), Strata II: 6MWD > 400 (starting load of 15w with subsequent increments of 5w. A stepwise incremental exercise test will be performed at a cadence of 60 revolutions per minute (rpm; ±10%). The exercise protocol will begin with a 3-minute rest period, followed by a stepwise incremental protocol, designed to achieve volitional exhaustion within 8–12 minutes of exercise onset. Heart rate and pulmonary gas exchange data will be measured continuously. Blood pressure and rating of perceived exertion (RPE; 6 to 20 scale) will be measured during the final 15-second period of each minute. Criteria for the assessment of a good participant effort included peak respiratory exchange ratio (RER) > 1.10, peak HR ≥ 85% predicted and RPE ≥ 18.3191. At the end of the exercise test, participants will complete a cooldown consisting of unloaded pedaling at 20rpm for 5–10 minutes. All data will be exported for offline analysis using Microsoft Excel (Washington, USA). Data will be analyzed over 30s averages to allow for differences in Gas analysis systems and monitor heart rate throughout the test and 10 minutes seated recovery.
Blood Pressure and ECG
Blood Pressure will be monitored every 30 seconds. Participants will be fitted with a 12-channel electrocardiography (ECG) device and a blood pressure cuff positioned over the brachial artery (. Measurements will be taken following 10 minutes of supine rest, during sit to stand task and monitored continuously throughout the CPET. Blood lactate concentration will be monitored through fingertip sampling at the end of each stage and 5-minute intervals for 30 minutes following volitional fatigue.
Pulmonary Gas Exchange Measures
Breath-by-breath pulmonary gas exchange data will be smoothed using a middle five of seven breath average. Key variables of interest include the first ventilatory threshold (VT1), the respiratory compensation point (RCP), peak oxygen consumption (V̇̇O2peak) and end-tidal CO2. V̇̇O2peak is defined as the mean V̇̇O2 over the last 30 seconds of the exercise test, adjusted for body mass (ml·kg − 1·min − 1). VT1 will be determined by using the V-slope method to identify the deflection point in the relationship between V̇̇CO2 and V̇̇O2 – indicating a disproportionate rise in CO2 production due to increasing anaerobic glycolytic activity (13). VT1 was confirmed using the nadir of the ventilatory equivalent (VE) for V̇̇O2 (VE/V̇̇O2). The RCP will be determined using the V-slope method to identify the deflection point in the relationship between VE and V̇̇CO2 – which marks the onset of hyperventilation caused by excessive blood lactate accumulation. The RCP will be confirmed using the nadir of VE/V̇̇CO2. The VT1 and the RCP will be confirmed by two researchers at each site. Where agreement is not reached, a third researcher at a separate site was approached to adjudicate. End-tidal CO2 is the partial pressure of CO2 measured at the end of each breath.
Test Termination Criteria
Standard test termination criteria were adopted throughout each test to ensure patient well-being and safety as guided by the American College of Sports Medicine. Exercise termination criteria included chest pain suggestive of ischaemia, fall in systolic blood pressure > 20 mmHg from the highest value during exercise, > 225 mmHg systolic blood pressure, > 130 mmHg diastolic blood pressure, hypotension (< 100 mmHg systolic), severe desaturation: SpO2 ≤ 80% when accompanied by symptoms of severe hypoxaemia, sudden pallor, loss of coordination, mental confusion, dizziness or faintness, signs of respiratory failure.
Sub-sample Follow-up Assessments (UK only)
Using a custom developed application alongside commercially available heart rate monitoring devices, participants will be asked to provide accelerometery (asked through the participants phone), heart rate variability (iHeart) and a subjective wellness score for each day following baseline and CPET investigations each for a period of 3 days (14). This custom developed software has been developed at the Advanced Wellbeing Research Centre to provide objective and subjective assessment of fatigue in people suffering with long covid and has successfully been piloted with over 200 individuals. Where smartphone data is not possible, individuals will be asked to wear an accelerometer and subjectively report their wellness through patient diary.
Participant timeline {13}
Participants attended a total of three face-to-face visits occurring over two weeks. The details of which can be found below. Study baseline will be conducted 7–10 days post baseline measures to ensure no symptoms of post exertional malaise and/or excessive fatigue from baseline assessments for patient safety.
Sample size {14}
A minimum of 150 patients with a positive COVID-19 infection will be recruited, Sample size estimations are based on previous work by the CI and PI. A prospective power analysis was conducted using G*Power. To achieve a large effect size with an alpha level of 0.05, with an effect size of 0.35, a minimum of 120 participants are required to demonstrate changes in functional status (measured via VO2 peak, ventilationary threshold and gas exchange threshold). To account for potential, drop out and loss to follow up we have inflated this number by 20% (30 patients)
Recruitment {15}
Patients will be assessed according to the eligibility criteria and recruited directly from Long COVID Clinics in the UK (Derbyshire Community Health Services, Sheffield Teaching Hospitals NHS Foundation Trust and Northumbria NHS Trust), the University of Illinois Post-COVID-19 Clinic, (Chicago, USA) and the Ramaiah Medical College Hospitals Post COVID Clinic (Bengaluru, India). Long COVID patients will be assessed according to the eligibility criteria and recruited following referral or contact with a long COVID clinic or having suspected or confirmed long COVID. Social media and targeted recruitment from established pages will be used to advertise the opportunity to engage with the trial for those in proximity.
Assignment of interventions: allocation
Sequence generation {16a}
No Randomisation will be done as part of this study.
Concealment mechanism {16b}
No concealment will be done as part of this study.
Implementation {16c}
This is observational study so not applicable.
Assignment of interventions: Blinding
Who will be blinded {17a}
Not Applicable for this study.
Procedure for unblinding if needed {17b}
Not Applicable for this study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
This information can be found in the section above.
Plans to promote participant retention and complete follow-up {18b}
Participants will be actively recruited through NHS services as well as social media. Researchers will maintain regular contact with participants once they have begun the study to ensure participant retention, this includes arranging travel and accommodation where applicable and chaperoning. Where outcome data cannot be collected this will be noted in the case report form for each individual and included within the dataset where applicable. When removed from the dataset this will be indicated in the report, for example if a participant doesn’t return for day 2 CPET, data from day 1 will be included and highlighted.
Data management {19}
All investigators and study site staff will comply with the requirements of the Data Protection Act 2018 with regards to the collection, storage, processing, and disclosure of personal information and will uphold the Act’s core principles. This includes a trial independent monitor which will carry out the monitoring of the study data as an on-going activity.
GDPR - Collecting Personal Data
Researchers will be collecting data from participants in this study. This data has been specifically chosen to achieve the aforementioned aims and study outcomes and in the public interest of enhancing clinical understanding academic research. No information that is not directly associated with the research questions will be collected.
This is the legal basis on which we are collecting your data and while this allows us to use your data, it also means we have obligations towards you to:
-
Not seek more information from you than what is essential and necessary for the study;
-
Make sure that you are not identified by the data by anonymising it using ID codes;
-
Use your anonymised data only for the purposes of this study and for any relevant publications that arise from it;
-
Store data safely in password-protected databases to which only the named researchers have access;
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Not keep your information for longer than is necessary (usually for seven years);
-
Safely destroy your data by shredding or permanently deleting them.
-
Researchers on the project with access to the data are supervised by highly qualified and experienced staff and have been very careful to ensure the security of your data.
The study was approved for its ethical standards by Health Research Authority (IRAS 313936) and the University of Derby Human Sciences Research Ethics Committee.
Data Retention
Study records will be stored for 15 years according to the Research & Innovation Office SOP for archiving, in a secure off-site storage. Direct access to source documents and data will be granted to authorised representatives from the sponsor, host institution and the regulatory authorities to permit trial-related monitoring, audits, inspections and reviews.
The study database will be kept on Microsoft Excel© 2016 and hosted on the University of Derby internal server. The server and database are protected by several measures including anti-virus and anti-spyware applications, firewalls, encryption technology and permissions. Data will be entered onto the paper CRF and retained and stored securely until the study end date, at which point the CRFs will be sent securely to the coordinating centre for entry onto the electronic study database. The data will be securely stored in line with ICH-GCP standards and data protection principles. The data stored will be checked for missing or unusual values and for consistency within participants over time. If any problems are identified, the appropriate CRFs will be reviewed in discussion with relevant local site personnel and queried for confirmation or correction as required until resolution.
The Chief and Principal Investigators, sponsor, and authorised staff will have access to participants’ data. The Chief Investigator and/or Principal Investigators will facilitate access to study records for monitoring, audits, and regulatory inspections.
In compliance with the ICH/GCP guidelines, regulations and following the University Hospitals NHS Trust Code of Research Conduct and Research Ethics the Chief Investigator will maintain all records and documents regarding the conduct of the study. These will be retained for at least 15 years (or for longer if required). If the Chief Investigator is no longer able to maintain the data records, an alternative person will be nominated to take over this responsibility.
The Trial Master File and Trial documents held by the Chief Investigator on behalf of the Sponsor shall be finally archived by the sponsor local NHS Trust. This archive shall include all study databases and associated meta-data encryption codes.
Confidentiality {27}
Staff involved in the study will ensure that all participants’ confidentiality is maintained. The participants will be identified only by initials and surname (for purposes of address on the telephone), and a unique patient study identification number on the CRF and central electronic database. All documents will be stored securely and only accessible by staff involved in the study and authorised personnel. The study will comply with the Data Protection Act (in the UK) and with local legal requirements alongside the principles of ICH-GCP (worldwide); in line with this, all data will be anonymised as soon as it is practical to do so. The fully anonymised study data will be stored for at least five years following the closure of the study and thereafter disposed of in line with regulatory requirements. No participant will be individually identified in any subsequent publications relating to this study.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
In-line with the outlined biomarkers participants will have serum samples taken for the measurement of inflammatory and metabolic biomarkers, including full blood count (to determine neutrophil leukocyte ratio (NLR) and the polymorph lymphocyte ratio (PLR), C-reactive protein (CRP), ferritin, d-dimers, ferritin, Amylase and Interleukin 6. For exploratory research including fibrin amyloid microclots (109). Samples will be stored at -80oC until analysis.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Statistical analysis will be performed by a statistician at the University of Derby and conducted using SPSS version 26. This study is a prospective observational cohort study, designed to identify suitable tools and measures across different domains for assessing patient recovery from COVID-19. Descriptive statistics will be calculated for all outcomes of interest. These will be presented as proportions and means with standard deviations or medians with interquartile ranges, depending on the distribution of data. Within group differences will be compared using parametric (students t-test) and non-parametric (Mann-Whitney U, Chi square) tests, depending on normality of distribution.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Sub-group analyses will take place for the cohorts using the smartphone application to quantify changes in PESE/PEM symptoms and how this is influencing patient report outcome measures and symptom severity.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Any deviations from the protocol or non-adherence will be recorded in the CRF. For missing data, the individuals’ variables will be shown in the final work with number of data points. Where data is missing for comparison (i.e. first CPET completed but not second) then participants data will be removed from statistical analysis.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The full protocol is available at clinicaltrials.gov for the study. Data from the study will be placed in University of Derby Data Repository where it can be accessed upon reasonable request to the chief investigator.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The protocol and supporting documentation have been reviewed by members of the research teams established Patient and Public Involvement group. Their feedback has shaped the design of the study processes. Ms. Lindsay Skipper will function as the trial’s public and patient involvement representative, and she is a Long COVID patient and a former Physiotherapist. Ms. Skipper has worked alongside the study team to ensure all the documentation and study processes are appropriate for patients with Long COVID. She has been extremely involved in ensuring that the study risks are identified and mitigated as much as possible. Ms. Skipper will be an active member of the TMG to ensure that the project maintains a patient and translatable approach.
Study progress will be discussed at the Patient and Public Involvement Group monthly meetings. Their input will have significant impact on the future trial also.
Trial Steering Committee (TSC)
The trial steering committee will oversee and supervise the progress of the trial and ensure that it is being conducted according to ICH-GCP and the applicable regulations. The TSC is an independent body that includes mostly members who are not involved with the running of the trial. TSC meetings will be held according to the monitoring plan and will be detailed in an agreed TSC Charter.
Patient and Public Representatives (PPI)
Patient, public involvement and engagement (PPIE) representatives have been involved in the design and final review of the protocol as well as other aspects of trial design, including reviewing documentation. They will retain a pertinent role in the TMG and TSC and will attend and be involved in meetings to allow input into the ongoing management and delivery of the trial.
Composition of the data monitoring committee, its role and reporting structure {21a}
The DMC for the study will comprise of the centre leads for each recruitment centre, its role is to check data accuracy and completeness, this will report to the CI and be independent from the funder.
Adverse event reporting and harms {22}
Definition of Adverse Event (AE)
Any untoward medical occurrence in a clinical study where participants are administered a medicinal product, which does not necessarily have to have a causal relationship with participation in this study.
An AE includes:
-
Exacerbation of pre-existing illness
-
Increase in frequency or intensity of a pre-existing episodic event or condition
-
Condition detected or diagnosed after study intervention even though it may have been present before the start of the study
-
Continuous persistent disease or symptoms present at baseline that worsens following the start of the study
An AE does not include:
-
Medical or surgical procedure (e.g. surgery, tooth extraction) but the condition that leads to the procedure is an AE
-
Pre-existing disease or conditions present or detected at the start of the study that did not worsen
-
Situations where an untoward medical occurrence has occurred (e.g. hospitalisations for cosmetic elective surgery)
-
Disease or disorder being studied, or sign or symptom associated with the disease or disorder unless more severe than expected for the participant’s condition
-
Overdose of concurrent medication without any signs or symptoms
Non-serious AEs
All such events, whether expected or not, should be recorded.
Abnormal Baseline Findings
Abnormal findings that are deemed to be a clinically significant abnormality may be reported as an AE, according to the judgement of the Chief Investigator taking into account any associated clinical symptoms/signs from the below measures during pre; mid and post time frame.
Reporting Procedures for All AEs
Aim: to describe adverse events relating to study and the reporting process
Adverse event (AE) and Serious Adverse Event (SAE) will use the local NHS Trust reporting procedures but reported to the University of Derby Research and Knowledge Exchange Office as soon as possible.
All AEs should be reported on the CRF. Any questions concerning adverse event reporting should be directed to the Chief Investigator in the first instance. Participants will be asked to report AE’s and SAE’s during all follow up sessions. All participants will be provided with contact details for a trial phone, where they can communicate AE/SAE throughout the study and will be operated during working hours (Monday to Friday 9 − 5). Outside of these working hours, participants are encouraged to leave a voicemail and the study team will contact them back as soon as possible during working hours.
The following information will be recorded: description, date of onset and end date and severity. Follow-up information should be provided, as necessary. AEs considered related to the study as judged by a medically qualified investigator (Tom Bewick, CI) or the sponsor will be followed until resolution or the event is considered stable. All related AEs that result in a participant’s withdrawal from the study or are present at the end of the study, should be followed up until a satisfactory resolution occurs. It will be to the responsibility of the Chief Investigator’s clinical judgement whether an AE is of sufficient severity to warrant removal from the study. The relationship of AEs to the study will be assessed by a medically qualified investigator. All such events, whether expected or not will be recorded.
Definition of Serious Adverse Event (SAE)
Any untoward and unexpected medical occurrence or effect that:
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Results in death
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Is life-threatening – refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe
-
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation
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Results in persistent or significant disability or incapacity
-
Is a congenital anomaly or birth defect
An SAE form will be completed and forwarded to the sponsor or delegated representative within 24 hours. However, relapse and death and hospitalisations for elective treatment of a pre-existing condition do not need reporting as SAEs. All SAEs should be reported to the study sponsor local Research Ethics Committee where in the opinion of the Chief Investigator, the event was:
-
‘Related’, i.e. resulted from the administration of any of the research procedures; and
-
‘Unexpected’, i.e. an event that is not listed in the protocol as an expected occurrence
Reporting Procedures for All SAEs
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief Investigator becoming aware of the event, using the ‘COREC SAE’ form for non-CTIMP studies. Local investigators should report any SAEs as required by their Local Research Ethics Committee and/or Research & Development Office. Fatal or life-threatening SAEs must be reported within 7 days which will be reported to the Competent Authorities MHRA and the Research Ethics Committee.
The intensity of the AE will initially be assessed according to the following definitions:
-
Mild: An event easily tolerated by the participant, causing minimal discomfort, and not interfering with everyday activities
-
Moderate: An event sufficiently discomforting to interfere with everyday activities
-
Severe: An event that prevents everyday activities
All AE and SAE Reporting documentation (i.e. NHS National Patient Safety Agency, National Research Ethics Service, Report of Adverse Event (AE) and Serious Adverse Event) physical copies of these will be kept in the Trial Master File.
Frequency and plans for auditing trial conduct {23}
Not applicable.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any protocol amendments will be communicated and approved by local and NHS ethics committees as well as amendments filed on clinicaltrials.gov.
Dissemination plans {31a}
All data arising from this study will be owned by the named academics from the University of Derby. On completion of the study, the data will be analysed and reported into a final study report. The full study report will be accessible via the Chief Investigator.
There shall be no publication or dissemination of the conclusions of the study, including all or any part of the results of the study, without the prior written consent of the Chief Investigator and the Sponsor, such consent not to be unreasonably withheld or delayed. There shall be no publication or other dissemination of the conclusions of the study until the Sponsor has approved the conclusions of the study.
There are no plans to notify the participants of the outcome of the study. Participants may specifically request results from the PI; this information would be provided after study results have been published. The study protocol, full study report, anonymised participant-level dataset, and statistical code for generating the results will not be made publicly available.
Manuscripts resulting from the research will be conceived, written, and published at the discretion of the Chief Investigator, in conjunction with the Principal Investigator and other members of the research team as appropriate. This activity will be independent of the Research Funder, who will not have any control over the content or results of any publications. It is anticipated that the research will lead to publications in subject-specific international peer-reviewed journals and presentations at international conferences.
Authorship eligibility guidelines and any intended use of professional writers
Authorship will be determined by the research team on the final study report and subsequent publications, following the International Committee of Medical Journal Editors guidance for authorship of manuscripts submitted for publication. Professional writers will not be employed.