Evaluating the Efficacy of Remdesivir for Long COVID Following a Confirmed COVID-19 Infection. (ERASE-LC)

• ClinicalTrials.gov Identifier: NCT05911906
• Recruitment Status: Not yet recruiting
• First Posted: June 22, 2023
• Last Update Posted: September 6, 2023
• Sponsor: University of Derby
• Collaborators: University of Exeter; Peninsula Clinical Trials Unit; University Hospitals of Derby and Burton NHS Foundation Trust
• Information provided by (Responsible Party): Mark Faghy, University of Derby

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
SARS-CoV-2 Infection; COVID-19	Drug: Remdesivir	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 98 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Two groups within the model.

One will receive remdesivir, the other group will not. Allocation to the treatment group to be randomised.

• Masking: None (Open Label)
• Masking Description: Open label.
• Primary Purpose: Basic Science
• Official Title: Evaluating the Safety and Feasibility of Remdesivir for the Improvement of Lung Function, Perfusion, and Symptom Profile in Long-covid Patients: a Pilot Randomised Controlled Trial.
• Estimated Study Start Date: January 1, 2024
• Estimated Primary Completion Date: January 1, 2025
• Estimated Study Completion Date: October 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Group; Remdesivir infusion delivered by IV.	Drug: Remdesivir; To be confirmed.; Other Name: Veklury
No Intervention: Non-treatment group; No intervention.

Outcome Measures

Primary Outcome Measures :

1. Observe changes in quality of life, functional status, and post-exertional symptoms. [ Time Frame: 53 days ]
   Health-related quality of life (EQ-5D-5L), & Symptom Burden Questionnaire for Long COVID.
2. Assess feasibility and acceptability of patients completing/engaging with all trial activities including a willingness to be randomised and receiving of 5 consecutive days of remdesivir intravenous infusion [ Time Frame: 53 days ]
   The proportion of patients excluded at screening, number of patients randomised, drop-out rates, patients who complete the study as per protocol, compliance with allocated treatment.
3. Collect safety data from all baseline tests and a 5-day course of remdesivir [ Time Frame: 53 days ]
   Total reported and severity of adverse/serious adverse events/reactions /SUSARs

Secondary Outcome Measures :

1. Observe changes in exercise tolerance and reduced post-exertional symptom exacerbation following incremental exercise [ Time Frame: 53 days ]
   Modified De Paul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM), symptom Burden Questionnaire for Long COVID
2. Functional Status [ Time Frame: 4 weeks ]
   Post COVID Functional Status Scale, Impact on daily life subscale of the Symptom Burden Questionnaire for Long COVID
3. Explore whole-body FDG uptake using PET/CT methods in patients with Long COVID. [ Time Frame: 53 days ]
   The standardised uptake volume (SUV) and Ki of 18FDG uptake observed during PET/CT scans.
4. Physical & Physiological function: [ Time Frame: 53 days ]
   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.
5. Functional Status [ Time Frame: 53 days ]
   Post-COVID Functional Status Scale, 6-minute walk test and timed up and go.
6. Cognitive Function [ Time Frame: 53 days ]
   Perceived Deficit Questionnaire (PDQ-5) and Montreal Cognitive Assessment 'Blind' version (MoCA-Blind)
7. Biochemical/inflammatory markers [ Time Frame: 4 weeks ]
   Full blood count, eGFR, LFTs, CRP, d-dimers, IL6, IL16, IL18, PCT, IFN-Y, TNF-A, VEGF-D, CRP, HLA-DP, and Vitamin D.
8. Emotional Status [ Time Frame: 53 days ]
   Generalised Anxiety Disorder (GAD-7)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.
• No treatment history of Remdesivir or anti-viral treatment
• Not engaged in any rehabilitation programme or intervention to improve Long COVID outcomes.
• 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.
• Not pregnant or attempting to become pregnant.
• eGFR>30mL/min
• Not currently taking or being prescribed chloroquine phosphate or hydroxychloroquine.

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.
• Engaged or previously engaged (<6 months) in a rehabilitation programme or intervention to improve Long COVID outcomes.
• Lack of mental capacity to provide informed consent.

Secondary Screening Criteria:

• No evidence of residual viral load derived by RNA and E-gene sequencing.
• 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/

Contacts and Locations

Contacts

Contact: Mark Faghy, PhD; 01332592109; m.faghy@derby.ac.uk

Contact: Ruth Ashton, PhD; 01332592109; R.Ashton@Derby.ac.uk

Locations

United Kingdom

University of Derby

Derby, United Kingdom, DE22 1GB

Contact: Mark A Faghy, PhD 01332592109 m.faghy@derby.ac.uk

Contact: Ruth Ashton, PhD 01332592109 R.Ashton@Derby.ac.uk

Principal Investigator: David Strain, MD

Sub-Investigator: Karen Knapp, PHD

Sub-Investigator: Hairil Razak, PhD

Sub-Investigator: Tom Bewick, MD

Sponsors and Collaborators

University of Derby

University of Exeter

Peninsula Clinical Trials Unit

University Hospitals of Derby and Burton NHS Foundation Trust

Investigators

• Study Chair: Victoria Allgar, PhD; Pen CTU

More Information

• Responsible Party: Mark Faghy, Associate Professor in Respiratory Physiology, University of Derby
• ClinicalTrials.gov Identifier: NCT05911906
• Other Study ID Numbers: UoD/ERASE-LC/23
• First Posted: June 22, 2023
• Last Update Posted: September 6, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: No plan to share IPD.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Mark Faghy, University of Derby:

Long COVID; Anti-virals; Remdesivir; Long COVID Symptoms

Additional relevant MeSH terms:

Remdesivir; Infections; COVID-19; Post-Acute COVID-19 Syndrome; Disease Attributes; Pathologic Processes; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents