Remdesivir treatment for Long COVID in an initial clinical study

The aim of this study is to inform the design and delivery of a future definitive trial to compare the effectiveness of a 5-day treatment of Remdesivir with treatment as usual (TAU) for patients with LC. This feasibility study has the following objectives (please see Table 1: objectives and outcome measures):

Health related quality of life (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. 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.

Post COVID Functional Status Scale (PCFS, impact on daily life subscale of the LC Symptom Burden) will be assessed to monitor direct recovery and to assess functional sequelae. The PCFS will evaluate the ultimate consequences of COVID-19 on functional status and supplement other instruments that measure the 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).

Symptom Burden Questionnaire for Long COVID (LC symptom burden) (SBQ™-LC) is a patient-reported outcome (PRO) measure and multi-domain item bank that has been developed to measure symptom burden in adults with “post-acute sequelae of COVID-19" (PASC). The SBQ™-LC is composed of 17 independently functioning, unidimensional scales. Sixteen scales measure symptom burden (i.e. symptom presence, severity, or frequency) across different symptom “domains” and one scale measures symptom impact on daily life.

Fatigue Assessment Scale (FAS) is a 10-item scale evaluating symptoms of chronic fatigue. In contrast to other similar measures (e.g. the Multidimensional Fatigue Inventory), the FAS treats fatigue as a unidimensional construct and does not separate its measurement into different factors.

Modified Fatigue Impact Scale (MFIS) is a 20-item patient-reported scale designed to measure fatigue across five scales (general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue) [12]. The MFI-20 has been used to assess fatigue in patients with different respiratory conditions, including COPD, pulmonary fibrosis, and lung cancer.

Medical Research Council (MRC) Dyspnoea Scale is scale to grade how breathless a patient gets doing everyday activities; the scale contains 5 response options, ranging from “I only get breathless with strenuous exercise” to “I am too breathless to leave the house”.

Perceived Deficit Questionnaire (PDQ-5): The full-length PDQ consists of 20 items and provides a self-report measure of cognitive dysfunction. This instrument provides an assessment of several domains of cognitive functioning that are frequently affected in MS: attention, retrospective memory, prospective memory, and planning and organisation.

Generalised Anxiety Disorder (GAD-7) a seven-item diagnostic tool validated in both the primary care setting and the general population. The GAD-7 is a 7-item scale that reports scores from 0 to 3 on all the questions. It investigates how often the patient has been bothered by seven different symptoms of anxiety during the last two weeks with response options such as: “not at all”, “several days”, “more than half the days”, and “nearly daily” scored as 0, 1, 2, and 3, respectively. The scores of 5, 10, and 15 are taken as cut-off points for mild, moderate, and severe anxiety, respectively.

Modified De Paul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM) assesses symptom frequency and severity over a 6-month look back period, however, for the purposes of this study, it will be modified to assess over a 1-week look back period (in-line with Zimmerman et al.: Clinical Trials Identifier: 05595369). Frequency is rated on a 5-point Likert scale: 0 = none of the time, 1 = a little of the time, 2 = about half the time, 3 = most of the time, and 4 = all the time. Severity is also rated on a 5-point Likert scale: 0 = symptom not present, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe. Post-exertional malaise (PEM) will be deemed to be present if the participant reports having at least one moderate (rated severity ≥ 2) PEM symptom for a frequency rated ≥ 2.

This is a phase IV, open-label, single-arm, proof-of-concept study.

The Trial Management Group (TMG) will closely monitor recruitment performance at each site. The stages of the recruitment process are illustrated in Additional file 1.

Participants are required to attend the baseline visit within 1 month of their detailed screening. Participants will be sent their Patient Reported Outcome Measures (PROMs) by email 24 h before their baseline appointment to allow more time for them to complete them: EuroQol Group 5 Dimensions 5 Level (EQ-5D-5L) Post-COVID-19 Functional Status (PCFS) [13], Symptom Burden Questionnaire™ for Long Covid (SBQ™-LC) [14], Medical Research Council (MRC) Dyspnoea Scale [15], 5-item Perceived Deficits Questionnaire (PDQ-5) [16], Generalised Anxiety Disorder 7-item (GAD-7) [17], DSQ-PEM, Fatigue Assessment Scale (FAS) [18], and Modified Fatigue Impact Scale (MFIS) [11]. For those requiring paper questionnaire booklets, these will be handed to the participant at the preceding visit with instructions not to complete the questionnaires until 24 h before the baseline visit. A text will be sent to all participants to remind them about their baseline visit and to complete the required questionnaires 24-h beforehand.

In addition to returning the PROMs (if completed on paper), they are required to complete clinical tests for physical function, lung function, physiological function, and biomarker and inflammatory profiles. Participants will also be instructed on how to track their symptoms using an app (Visible) on their phone.

Seven days after their baseline visit, participants will attend a CPET on two consecutive days, which will be repeated post-intervention. They will receive an email and a text reminder 24 h before each CPET day. This will also include the PROMs: SBQ™-LC, FAS and MFIS to complete in advance to provide participants extra time to complete these. A text reminder of the appointments will also be sent.

On arrival at each session, pregnancy tests will be conducted with a urine dip.

Bloods will be taken and biomarkers and inflammatory profiles will be measured. Once patients are ready, they will progress with the CPET.

The 2-day CPET protocol has been specifically designed to determine impaired cardio-respiratory and muscular physiology in patients who are at risk of post-exertional malaise/post-exertional symptom exacerbation [21].The test uses a non-maximal design which allows for the detection of key ventilatory, cardiovascular and perfusion parameters to be observed whilst also imposing a strict inclusion/test termination criterion. The protocol also consists of different strata, and the chosen protocol is determined relative to a patient’s current ability to undertake functional tasks:

CPET will be performed/overseen by experienced and accredited clinical exercise physiologists. Tests will be used to determine peak oxygen uptake (V̇O2peak) and parameters representative of cardiovascular reserve [22]. CPETs will include continuous/regular monitoring of standard measurements, including inspired/expired air, ventilation profile, 12-lead electrocardiogram (ECG), blood pressure, blood lactate and blood gas tensions (where possible). The latter two measures have relevance to LC populations due to the established hypothesis of impaired mitochondrial function and abnormal aerobic contribution to exercise [23]. Blood samples will be obtained via capillary sampling (finger-prick). These measures are standard protocol as outlined by the British Association of Sport and Exercise Sciences (BASES) [24] and the American College of Sports Medicine (ACSM) [25]. Tests will be conducted using a standard bicycle ramp protocol following American Thoracic Society guidelines [26].

Key variables of interest include:

Exercise termination criteria:

Participants will be booked in for their pre-treatment PET/CT scan on Day 11 after baseline at one site.

All participants receive the antiviral medication Remdesivir via intravenous (IV) infusion over 5 consecutive days. It is licensed for use in patients with COVID-19 who have been admitted to the hospital with acute illness.

Patients receive five IV infusions. The first loading dose is infused over 60 min. Subsequent maintenance doses are infused over a 30-min period. Dosing schedules are guided by the SmPC and will be consistent for each participant.

Dosage modification: No dosage modifications are permitted.

Individual stopping criteria: If a participant develops clinical evidence of a significant adverse reaction during treatment administration, then the administration can be stopped at the direction of the treating clinician.

Remdesivir will be used outside of its licensed indication. For this trial, it is expected that all adverse events (AEs) that show a potential causal relationship with the IMP (known as adverse reactions [ARs]) are recorded. Other AEs of unexpected severity (in the opinion of and discussion with the PI), or which meet the criteria for a serious adverse event (SAE) should also be recorded. Investigators must seek further information on such adverse events and record details in the patient’s medical notes and on the eCRF. They should be recorded using the Common Terminology Criteria for Adverse Events (CTCAE terms) provided in the National Cancer Institute (NCI) CTCAE v5.0. Severity should be assessed using the NCI CTCAE v5.0 grading. The clinical course of each event should be followed until resolution or stabilisation.

All AEs and SAEs must be recorded from the time of written informed consent until the last study visit. Safety information will be reviewed for ongoing assessment during TMG and Trial Steering Committee (TSC) meetings as per the trial monitoring plan.

Each participant has the right to withdraw from the study at any time. The PIs may withdraw a participant from the study or withdraw aspects of the study (i.e. medication, exercise, or specific scans) if it is determined that the participant’s health is compromised by remaining in the study. All data collected from withdrawn participants will be included in the study report.

A PI may also decide to withdraw a participant from the study or reduce their participation at any time for any reason, including but not limited to:

The reason for withdrawal will be clearly stated (wherever possible) and recorded in the eCRF. If the participant is withdrawn due to an AE related to the study medication or trial assessments, the PI will arrange for a follow-up telephone call until the AE has resolved or stabilised.

If the participant is withdrawn from treatment only, all scheduled assessments will be carried out as planned, but no further study drug will be administered.

If the participant is fully withdrawn from the trial, any required safety checks will still need to be undertaken as planned (e.g. safety bloods at day 27). This will be explained to the participant fully by the research team member documenting the withdrawal.

A key aspect of this study is to inform progression to the main trial. The sample size is based on the feasibility outcomes of process assessments focused on the red, amber and green (RAG) system (Table 3) that tests against being in the RED zone (unacceptable outcome) based on an expectation of being in the GREEN zone (acceptable outcome) and on the sample size to give high power to reject being in the RED zone if the GREEN zone holds true, using the sample sizes provided in Table 1 in Lewis et al. [27]. Based on treatment fidelity (defined at completion of all 5 sessions), if we assume the upper boundary of the RED zone is 70% and the lower boundary of the GREEN zone is 85%, the sample size required for analysis for 90% power and 5% significance is n = 72.

In the two UK-based centres that will take part in this study, we expect a total of at least 120 patients that will be potentially eligible for the study from established LC clinics and a further 100 from an existing database of patients who have engaged in non-interventional research and have consented to be contacted about relevant research opportunities. Based on 220 potentially eligible participants, if at least 50% agree to participate ((i). GREEN zone), this is an indication that enough patients could be approached to participate in this study. Seventy-two patient-participants will be recruited over 12 months (5–6 per month).

A detailed statistical analysis plan (SAP) will be drafted by the trial statisticians and approved by an independent statistician on the TSC before the database lock. The study will be reported following the relevant CONSORT2010 statement extension to pilot and feasibility trials [28].

Baseline characteristics of participants will be summarised descriptively. Loss to follow-up after baseline will be summarised visually via a CONSORT style flow diagram. Baseline characteristics will be subjectively examined to assess potential differences between participants who withdraw, discontinue, and complete the trial. The study process will be descriptively summarised (with 95% confidence intervals). This will include recruitment and retention rates. The proportion of patients who did not meet eligibility criteria will be looked at. Adherence and compliance rates will be examined.

Safety outcome measures with reporting as per the clinical trial of investigational medical product (CTIMP) protocol (Medicines and Healthcare products Regulatory Agency (MHRA) guidelines) will be descriptively summarised.

In general, the use of hypothesis tests is not appropriate for a feasibility study, as the study has not been powered to address these, and the use of estimates with confidence intervals is preferred to obtain signals of efficacy. Secondary outcome analyses should be considered as hypothesis-generating rather than providing firm conclusions. Key continuous secondary outcomes will be descriptively summarised and analysed using a paired-sample t-test approach to calculate the unadjusted change in scores and the 95% confidence interval using normal linear mixed-effects repeated-measures models. The changes between baseline and each of the follow-up time points will be modelled on time point, with adjustment for baseline and recruitment site.

The end of the trial is defined as the last visit of the last participant or the completion of any follow-up and data collection process, and all queries.

PenCTU will oversee the management of data for the ERASE-LC trial. Participant screening and outcome data will be entered into REDCap, a web-based data capture system [29], by authorised personnel from participating sites. Access to REDCap is regulated using usernames, encrypted passwords, and two-factor authentication. The system maintains an electronic audit trail and hosts in-built validation mechanisms to ensure data integrity and security, including validation checks at the point of data entry.

To ensure data quality and completeness, the PenCTU data team will regularly monitor the data using validated R scripts [30]. Details of these monitoring and validation activities are outlined in the data management plan (DMP), available upon request. The monitoring process includes post-entry validation checks, completeness of critical data items, surveillance of safety and withdrawal reports, and audit trail monitoring. The data manager will provide ongoing reports to the TMG regarding data quality and completeness throughout the trial.

No direct identifiers will be shared with the trial statisticians, and access to directly identifiable information within the data capture system will be restricted to only users who require access. The trial adheres to relevant data protection legislation, including compliance with the Health Research Authority’s (HRA) GDPR.

Data from the ERASE-LC trial will be retained and accessible for fifteen years post-study completion.

After the trial has been reported, the anonymised individual participant data that underlie the results will be available on request from the CI and Sponsor, along with supplementary files as required (e.g. data dictionaries, blank data collection forms, analysis code). Data will be shared with (or access to the data will be provided to) requestors whose proposed use of the data has been approved by the CI and Sponsor, under an appropriate data sharing agreement. It will not be possible to identify participants personally from any information shared.

The results of this trial will be submitted to peer-reviewed journals for publication as soon as data analysis is completed. Participants will not be identified in any publications. PPIE representatives involved in the trial will support the dissemination of the information into the public domain and to the participants involved in the trial, in an appropriate manner. The findings will be presented at national and international conferences.

Social media: findings will be disseminated and publicised through links with organisations with a large social media presence.

The Sponsor for this study, the University of Derby, assumes overall responsibility for the initiation and management of the trial. The Sponsor and Funder are not directly involved in trial design, conduct, data analysis and interpretation, manuscript writing, and dissemination of results.

The CI (Chief Investigator) and co-applicants designed the trial with support from the PenCTU. The PenCTU has been allocated tasks associated with the overall trial and data management, including monitoring. The TMG will meet monthly to review trial progress and ensure appropriate trial management. The TSC will meet every 6–7 months per an agreed set of terms of reference to review the trial’s progress and any serious adverse events and will report to the Sponsor. A Data Monitoring Committee (DMC) was not convened as the study is low-risk and non-randomised.

The protocol and supporting documentation have been reviewed by members of the research teams established Patient and Public Involvement (PPI) group. Their feedback has shaped the design of the study processes. One PPI representative (Ms. Skipper) is a co-applicant and is an active member of the TMG to ensure that the project maintains a patient and translatable approach. Ms. Skipper is an LC patient, a former physiotherapist and has worked alongside the study team to ensure the documentation and study processes are appropriate for patients with LC. They have been extremely involved in ensuring that the study risks are identified and mitigated as much as possible. These include:

The aim is to develop a study where patients feel safe and willing to participate.

Study progress will be discussed at the PPI Group monthly meetings. Their input will also have a significant impact on the future definitive trial.

Approval has been obtained from the UK Health Research Authority (HRA), the Medicines and Healthcare products Regulatory Agency (MHRA) and the South Central – Oxford B Research Ethics Committee (REC). All patients have provided informed consent to participate in the study.

Not applicable. There is no patient data or identifiers in this publication; therefore, consent is not required.

The authors declare they have no competing interests.

Not applicable.