Study to Test the Safety, Tolerability and Efficacy of Remdesivir for Long-COVID. (ERASE-LC)

Phase IIa Open-label Clinical Study of the Safety, Tolerability and Efficacy of Remdesivir for Long-COVID.

University of Exeter, Peninsula Clinical Trials Unit, University Hospitals of Derby and Burton NHS Foundation Trust

One in ten people following a COVID-19 infection develop ongoing symptoms which can last for months and even years. These symptoms affect people in different ways and have been demonstrated to broadly impact physical, mental and cognitive health. Currently, there are no treatments available to address the issues that patients experience but anti-viral medications have been suggested as being potentially effective. This pilot study will test how effective an existing anti-viral medication (Remdesivir) is at reducing the impact of Long COVID in patients.

Long COVID is defined as a prolonged constellation of symptoms that people experience at least 3 months following a probable or confirmed SARS CoV-2 infection that cannot be explained by an alternative diagnosis (WHO 2022). Whilst vaccines are up to 95% effective at reducing mortality and ITU admissions in SARS-CoV-2 patients (Creech et al 2021), at best, they reduce Long COVID by 40% (Al-Aly, 2022). Further, although the most recent Omicron variant is associated with a lower risk of hospitalisation and death, the risk of progression to long COVID remains the same as previous variants at approximately 10% of triple vaccinated people (Mahase et al, 2022, Office for National Statistics, 2022). The development of Long COVID is also not associated with the severity of acute COVID-19 infection and occurs in those that were asymptomatic or mild disease (Rivas-Vazquez et al 2022). A recent scoping review by Hayes et al (2021) reported over one hundred common patient complaints that are cyclical and prone to exacerbation. These symptoms significantly impact functional status, and quality of life and pose a significant burden for healthcare services and economic entities (e.g., employers). Recent data from the UK demonstrates that 668,000 patients are currently unable to complete their typical employment activities and 127,000 of these are healthcare workers, posing additional challenges to an already stretched healthcare system. Further, this does not appear to be self-resolving, indeed currently there are approximately 376,000 people who have had long Covid for more than 2 years, representing the impact of the first wave alone. A sustained post-viral maladaptive inflammatory profile has been indicated as a contributing factor in the severity and fluctuating state of Long COVID symptoms. Hybrid imaging that uses positron emission tomography and computed tomography (PET/CT) with Fluorodeoxyglucose (FDG) can identify inflammatory responses through the elevated glycolytic activity and cellular metabolism (Sollini et al, 2021). Increased uptake of FDG by inflammatory cells results from their expression of elevated levels of glucose transporters and hexokinase activity (Katal et al, 2021). Sollini et al (2021) explored the uptake of FDG in 13 patients >30 days post COVID recovery compared to the uptake in 26 oncology patients. Four long-covid patients showed lung abnormalities on CT with mild FDG uptake. Only one patient had a normal scan with no areas of increased uptake outside the expected areas of tracer accumulation but documented profound symptomology. A vascular binary pattern and diffuse bone marrow uptake of FDG in the long bones were reported in long COVID patients. A minority had also had uptake in the lung, mediastinal lymph nodes, soft tissue, gastrointestinal tract, and muscles. Significant changes were also found in the brain with hypometabolism. The novel insight provided from PET/CT scans that use FDG could provide increased knowledge about the efficacy of pharmacological interventions. Recent data indicates that >2 million people in the United Kingdom (ONS, 2022), and >144 million globally (Hanson et al, 2022) are suffering from Long COVID. Whilst restrictions and protective steps to reduce transmission continue to be relaxed, vaccine hesitancy and the threat of sustained transmission and the evolution of future variants of concern mean that long COVID diagnoses will create a challenge for health care systems for years to come (Markov et al, 2022). Systemic viral persistence has been detected via reverse transcription-polymerase chain reaction (RT-PCR) and within subgenomic RNA has been demonstrated beyond 10 days in non-immunocompromised individuals. (Davis et al 2022) and is considered a mechanism resulting in a prolonged and debilitating symptom profile (Tejerina et al 2022). Viral persistence is reported in other infectious diseases and can be treated effectively with a course of antiviral medications and has previously been shown to be effective in reducing the risk of progression to severe disease in high-risk patients early in SARS-CoV2 infection (Wang et al, 2021). Accordingly, there is an urgent need to investigate the efficacy of pharmacological interventions that can reduce Long COVID prevalence, and severity, improve patient outcomes and restore quality of life. The aetiology of long COVID, remains unknown, however viral persistence with associated inflammatory responses remains a favourite contender. This was recently bolstered by case reports of patients whos long COVID symptoms resolved after they were prescribed the anti-viral Paxlovid for secondary infections. Additionally, subgenomic RNA has been demonstrated beyond 10 days in non-immunocompromised individuals. (Davis et al 2022) and is considered a mechanism resulting in a prolonged and debilitating symptom profile (Tejerina et al 2022). Viral persistence with HHV6A and EBV is recognised in a subgroup of people with Myaglic Encephalomyelitis (chronic fatigue syndrome), and early trials suggest that these patients respond to the antiviral rintatolimod (Ampligen; Strayer et al 1995). Antivirals have been shown to be effective in reducing the risk of progression to severe disease in high-risk patients early in SARS-CoV2 infection (Wang et al, 2021), and in immunocompromised hospitalised patients with persistent viraemia. There is an urgent need to investigate the efficacy of pharmacological interventions that can reduce Long COVID prevalence, and severity, improve patient outcomes and restore quality of life.

The proportion of patients excluded at screening, drop-out rates, patients who complete the study as per protocol, compliance with allocated treatment.

Determine the clinical safety and tolerance parameters of the use of Remdesivir in the treatment of patients with Long Covid.

Post COVID Functional Status Scale, Impact on daily life subscale of the Symptom Burden Questionnaire for Long COVID

Impact on daily life subscale of the Symptom Burden Questionnaire for Long COVID, & DSQ-PEM. Fatigue Assessment Scale (FAS), Medical Research Council (MRC) Dyspnoea Scale. Maximum inspiratory and expiratory mouth pressure, lung function, blood pressure, oxygen saturation, breathing rate, and resting heart rate, rate of perceived exertion and oxygen saturation.

Perceived Deficit Questionnaire (PDQ-5) and Montreal Cognitive Assessment 'Blind' version (MoCA-Blind)

Full blood count, eGFR, LFTs, CRP, d-dimers, IL6, IL16, IL18, PCT, IFN-Y, TNF-A, VEGF-D, CRP, HLA-DP, and Vitamin D.

Primary Inclusion Criteria: ≥18 years of age at the time of enrolment Previously confirmed SARS-CoV-2 infection via PCR and/or lateral flow test. Confirmed or suspected diagnosis of Long COVID according to the definition provided by the World Health Organisation and subsequent referral to an established Long COVID clinic for persistent symptoms following a confirmed SARS-CoV-2 infection. Evidence of persistent symptom profile relative to pre-COVID-19 status as derived from patient reported outcome measures. Willing and able to provide informed consent, complete the surveys, and complete all planned clinical assessments, and return for scheduled study visits≥18 years of age at the time of enrolment Willing and able to provide informed consent, complete the surveys, and complete all planned clinical assessments, and return for scheduled study visits. Secondary Screening Criteria (diagnostic testing): Evidence of residual viral load derived by RNA and E-gene sequencing. eGFR < 30 mL/min Exclusion Criteria: Evidence of treatment history of Remdesivir or any other anti-viral medication. Confirmed compromised immune system/function. No evidence of persistent symptom profile and severity consistent with Long COVID. Currently Engaged or previously engaged in a rehabilitation programme or intervention to improve Long COVID outcomes. 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. Participation in another clinical drug trials within the last 3 months Secondary Screening Criteria (diagnostic testing): Currently pregnant, breastfeeding or attempting to get pregnant (i.e., not using effective methods of contraception). History of Hepatic or Renal Impairment (eGFR (<30ml/min) and LFTs ALT>x5 ULN). Currently taking medications known to have an interaction with Remdesivir (e.g., chloroquine phosphate or hydroxychloroquine) as defined by British National Formulary (BNF) information on the selection, prescribing, dispensing and administration of medicines: https://bnf.nice.org.uk/interactions/remdesivir/