A research trial to find out if tocilizumab helps adults with Long Covid feel better
| ISRCTN | ISRCTN46454974 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN46454974 |
| EudraCT/CTIS number | 2022-003211-29 |
| IRAS number | 1006298 |
| Secondary identifying numbers | 0862, IRAS 1006298, CPMS 60222 |
- Submission date
- 23/11/2022
- Registration date
- 18/01/2024
- Last edited
- 16/01/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
To date, over 1 million adults have been admitted into UK hospitals with COVID-19. Approximately only one in three people feel fully recovered 1 year after discharge. There are an estimated 2 million people living with Long Covid. Previous research has shown that proteins involved in inflammation are higher in adults who have the worst health outcomes. One of these proteins is called interleukin-6 (IL-6). Tocilizumab is a drug which lowers the levels of IL-6. The aim of this study is to test whether tocilizumab can help people with ‘inflammatory’ Long Covid feel better.
Who can participate?
People who do not feel fully recovered at least 3 months after COVID-19 and have ongoing whole-body inflammation measured by a commonly used blood marker
What does the study involve?
Participants will be put into two groups at random. One group will receive tocilizumab injections for 12 weeks and the other group will receive placebo injections (sterile solution without the drug). Injections will be weekly or fortnightly depending upon the participant’s weight. The main outcome is a questionnaire to assess how people feel related to their health. Other outcomes involve questionnaires to assess symptoms, physical and mental health, an assessment of brain fog, tests of physical performance and activity, and a breathing test. Blood and urine samples will be collected for detailed assessment. After consent and eligibility, there are three main research visits: at the start and end of the treatment period, and 12 weeks after the end of the treatment period. Any adverse events will be reported. Two optional sub-studies involve taking images/scans of the lungs and body organs, and more detailed breathing tests.
What are the possible benefits and risks of participating?
Tocilizumab is used across the world to treat other inflammatory conditions such as rheumatoid arthritis. It is given by an injection under the skin. Side effects from the medication include lowering the immune system and liver problems. Participants at high risk of these problems will be excluded. This trial is categorised as Type B = somewhat higher than the risk of standard medical care. The study is using tocilizumab out of current clinical indications and licensing. However, tocilizumab at the dose we are proposing is currently used safely in other long-term conditions where IL6 is raised and part of the underlying inflammatory pathway causing disease.
Current standard practice for Long COVID involves no medication specifically for the Long COVID disease process and specifically no anti-interleukin (IL) 6 agents. Therefore, any side effects of the medication are above the risk of standard medical care for Long COVID. There is no indication that patients with Long COVID would have a higher risk of side effects than other patient populations.
A comprehensive compilation of clinical and nonclinical data on tocilizumab is available in the Investigators Brochure. The main side effects are:
Very common (>10%): upper respiratory tract infections, injection site reaction
Common (10%-1%): cellulitis, oral herpes simplex, Herpes zoster, abdominal pain, mouth ulceration, gastritis, rash, pruritus, urticaria, headache, dizziness, increased hepatic transaminases, increased weight, hypertension, leucopenia, neutropenia, hypercholesterolemia, peripheral oedema, hypersensitivity reaction, cough, dyspnoea, conjunctivitis
Uncommon (<1%): diverticulitis, stomatitis, gastric ulcer, increased total bilirubin, hypertriglyceridemia, nephrolithiasis, hypothyroidism
The researchers will mitigate these as far as possible by excluding participants that would be high risk of side effects and by careful monitoring of potential side effects which can be measured through serial blood tests. The main side effects are neutropenia (a low type of white cell count), thrombocytopenia (low platelet count) and hepatitis (liver inflammation), therefore blood tests of neutrophils, platelets and liver function tests will be monitored every 4 weeks. Specific and clear dose adjustments are provided in the protocol based on the tocilizumab investigator brochure (IB).
There is no data to support the safety of tocilizumab during pregnancy to date and therefore for this trial the assumption is Tocilizumab is not safe during pregnancy and therefore any participant or participant’s spouse who is either pregnant or planning a pregnancy in the same timeframe would be excluded. Pregnancy tests (urine) will be performed at each visit. A serum pregnancy test will be performed at screening.
Where is the study run from?
University of Leicester (UK)
When is the study starting and how long is it expected to run for?
March 2023 to December 2025
Who is funding the study?
Genentech Roche (USA)
Who is the main contact?
1. Mrs Victoria Harris, phosp-i@leicester.ac.uk
2. Dr Rachael Evans, phosp-i@leicester.ac.uk
Contact information
Scientific
NIHR Leicester Biomedical Research Centre - Respiratory
Department of Infection, Immunity and Inflammation
Glenfield Hospital
Groby Road
Leicester
LE3 9QP
United Kingdom
| Phone | +44 (0)116 250 2670 |
|---|---|
| phosp-i@leicester.ac.uk |
Principal Investigator
Groby Road
Leicester
LE3 9QP
United Kingdom
| Phone | +44 (0)116 0300 030 1573 |
|---|---|
| phosp-i@leicester.ac.uk |
Study information
| Study design | Double-blind randomized placebo-controlled parallel-group trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A Phase IIa double-blind, randomized placebo-controlled trial of tocilizumab to investigate the effect on health-related quality of life in adults with Long COVID and persistent inflammation |
| Study acronym | PHOSP-I |
| Study hypothesis | Primary objective The primary objective is to compare the effect of 12 weeks of subcutaneous (s/c) tocilizumab versus 12 weeks of s/c placebo on health-related quality of life. Secondary objectives 1. To compare the effect of 12 weeks of s/c tocilizumab versus 12 weeks of s/c placebo on symptoms, mental health, physical performance, daily physical activity, cognitive impairment, multi-organ function and systemic inflammation. 2. To investigate the sustainability of any effect at 12 weeks after medication/placebo cessation on the primary and secondary outcome measures. Sub-study exploratory objectives: 1. To compare the effects of 12 weeks of tocilizumab versus 12 weeks of placebo on respiratory health using pulmonary function testing and computed tomography (CT) thoracic imaging. 2. To compare the effects of 12 weeks of tocilizumab versus 12 weeks of placebo on multi-organ health using magnetic resonance imaging. |
| Ethics approval(s) |
Approved 21/12/2023, West Midlands - Edgbaston Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 104 8155, +44 (0)207 104 8357; edgbaston.rec@hra.nhs.uk), ref: 23/WM/0234 |
| Condition | Long COVID |
| Intervention | Tocilizumab/placebo subcutaneously for 12 weeks Dosage: 162 mg subcutaneous injection. Frequency of administration: body weight <100 kg 162 mg fortnightly/body weight ≥100 kg 162 mg weekly for 12 weeks. Details of the randomisation process: Participants will be allocated to treatment groups using a mixed minimisation/randomisation procedure, designed to maintain balance with respect to: 1. Study site (1-15) 2. EQ5D-5L UI (<0.70 / ≥0.70) 3. CRP level (≤20 mg/L / >20 mg/L) 4. Participation in the MRI sub-study (Yes/No) 5. Acute admission/tocilizumab status (non-hospitalised/hospitalised, no tocilizumab/hospitalised, with tocilizumab) All patients included in the trial be assigned a unique trial number to identify the participant throughout the trial. Randomisation using a web-based randomisation system will be provided by Glasgow CTU. The research staff at sites will provide the trial ID number and minimisation information and, if eligible, the randomisation group will be allocated. Blinded new participant randomisation e-mail confirmations will be sent to the research nurse(s), investigator and pharmacy staff as required. In addition, the randomisation notification will be sent electronically to the Interactive Web Response System (IWRS) supplier, with details of the trial ID number and randomisation group to allow drug supply management at site. Information may be shared back to the Glasgow CTU server, from the IWRS system, to allow for cross-checking between systems. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Tocilizumab |
| Primary outcome measure | Health-related quality of life measured using Euroqol five-dimension five-level questionnaire – utility index assessed at baseline, after 12 weeks (+2 weeks) of IMP/Placebo and after a further 12 weeks (+2 weeks) after the end of the intervention period |
| Secondary outcome measures | Measured at baseline, after 12 weeks (+ 2 weeks) of IMP/Placebo and after a further 12 weeks (+2 weeks) after the end of the intervention period: 1. Symptoms measured using Symptom Questionnaires – fatigue and breathlessness (FACIT-Fatigue and Dyspnoea-12) 2. General and respiratory disease-specific health-related quality of health measured using EQ5D-5L Visual Analog Scale and St George’s Respiratory Questionnaire 3. Mental health measured using anxiety and depression questionnaires GAD-7 and PHQ-9 4. Physical performance measured using the Incremental Shuttle Walking Test, the Short Physical Performance Battery (SPPB) and hand grip strength 5. Daily physical activity measured using an accelerometer worn for 14 days 6. Cognitive impairment measured using Montreal Cognitive Assessment (MoCA) 7. Multi-organ function measured using blood biomarker levels (including full blood count, natriuretic peptides, kidney and liver function) spirometry, and urine and stool samples. 8. Systemic inflammation measured using a blood test for C-reactive protein 9. Frailty and activities of daily living measured using Fried’s frailty criteria and Nottingham Activities of Daily Living Scale Exploratory outcomes: Respiratory health substudy: Pulmonary pathophysiology assessed by CT thorax and full pulmonary function tests at baseline and after 12 weeks (+4 weeks) after IMP/Placebo: 1. Pulmonary pathology on CT thoracic imaging such as ground-glass opacities, interstitial abnormalities, established pulmonary fibrosis, or small airways disease suggestive of ongoing post-COVID pulmonary changes 2. Pulmonary function tests include spirometry, transfer factor, residual volume and total lung capacity Multi-organ health substudy: MRI markers of multi-organ inflammation evaluated by describing the presence or absence of multiorgan abnormality (defined as MRI abnormalities involving two or more organs including the lungs) at baseline and after 12 weeks (+4 weeks) after IMP/Placebo: 1. The composite score based on relative difference in myocardial extracellular volume, myocardial T1, liver cT1, renal T1, and lung parenchymal signal intensity heterogeneity index post-treatment will be used. Exploratory objectives using the bioresource: 1. Inflammatory profile measured using blood (up to 100 ml) and urine (up to 100 ml) samples obtained at up to four time points: baseline, after 8 weeks (+/-2 weeks) of treatment/placebo, end of treatment/placebo at 12 weeks (+2 weeks) and 12 weeks (+2 weeks) after treatment/placebo 2. A subset of serum, plasma, whole blood, cells and urine samples will be subject to multi-omic assays to analyse the effect of treatment vs placebo on putative inflammatory biomarkers in the blood and urine, and their association with outcomes. This may include, but is not limited to, measurement of proteins, gene expression (mRNA), metabolites, cell populations and lipids related to the inflammatory response and other biological processes (for example, tissue damage and repair). 3. DNA will be analysed using either genome-wide microarray or next-generation sequencing (targeted, whole exome or whole genome) approaches to identify whether specific genetic variants, or combinations thereof, are associated with treatment response and outcomes 4. Stool samples will be collected for virus detection and other analyses at baseline, end of treatment/placebo at 12 weeks and 12 weeks after treatment/placebo. |
| Overall study start date | 11/03/2023 |
| Overall study end date | 31/07/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 80 Years |
| Sex | Both |
| Target number of participants | 152 |
| Participant inclusion criteria | 1. Age ≥18 years old and ≤80 years old 2. Clinical diagnosis of COVID-19 at least 3 months prior to consent. Patient-reported positive test is acceptable 3. Patient does not feel fully recovered at recruitment after COVID-19 (response no or unsure to “do you feel fully recovered from your COVID-19”) 4. CRP >5 mg/L persistently raised after contracting COVID-19 and prior to randomisation 5. Euroqol EQ5D-5L utility index ≤0.90 units prior to randomisation 6. Reasonable understanding of the English language assessed by the research team (i.e. able to understand the risks of taking part in the trial and complete the measurements including the patient-reported outcome measures) |
| Participant exclusion criteria | Current exclusion criteria as of 16/01/2025: 1. Other comorbidity indicating survival at one year from consent is unlikely 2. Active malignancy or on treatment for malignancy 3. Unable or unwilling to provide written consent 4. Inability to comply with protocol-directed procedures and assessments 5. Current immunosuppression therapy including oral corticosteroids 6. Prior use of the trial drug within 3 months of consent (including intra-venous Tocilizumab for acute COVID). 3 months is five-half lives of tocilizumab 7. Involvement in other trials involving an IMP either concurrently or within four months of consent - to allow washout. This includes medications prescribed for acute COVID studies. 8. Previous adverse event to tocilizumab, either a severe allergic reaction or deranged liver function tests 9. Hepatic transaminases greater than three times the upper limit of normal 10. Low neutrophil (below 2 x 109/L) or low platelet levels (below 100 x 10e3/μL) 11. Signs of active infection 12. Receipt of live vaccine within 3 months or planning a live vaccine during the trial period. Most COVID vaccines are not live. 13. Pregnancy or breastfeeding, or planning a pregnancy during the trial period or unable or unwilling to meet the contraception criteria (see below) 14. Latent TB: to be excluded with IGRA testing and if positive exclude and refer for treatment as per national guidelines. 15. New diagnosis or on treatment for HIV 16. Past history of diverticulitis 17. Significant alcohol or substance misuse 18. History of clinically significant hypersensitivity reaction or significantly deranged liver function tests with other medication 19. Hepatitis B 20. Exclude Hepatitis C if untreated: on testing antibody positive and detectable viral load. If antibody positive, but viral load negative compatible with previous infection only participant can be included. 21. Supervised exercise rehabilitation programme including exercise training, or other rehabilitation therapy for example fatigue management or breathing retraining lasting for a minimum of 4 sessions within three months of consent or planned to occur during the trial period 22. New medication for Long Covid symptoms started within six weeks of consent 23. No new weight management medication to start within three months of consent or during the trial period, for example glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors _____ Previous exclusion criteria: 1. Other comorbidity indicating survival at one year from consent is unlikely 2. Active malignancy or on treatment for malignancy 3. Unable or unwilling to provide written consent 4. Inability to comply with protocol-directed procedures and assessments 5. Current immunosuppression therapy including oral corticosteroids 6. Prior use of the trial drug within 3 months of consent (including intra-venous Tocilizumab for acute COVID). 3 months is five-half lives of tocilizumab 7. Involvement in other trials involving an IMP either concurrently or within four months of consent - to allow washout. This includes medications prescribed for acute COVID studies. 8. Previous adverse event to tocilizumab, either a severe allergic reaction or deranged liver function tests 9. Hepatic transaminases greater than three times the upper limit of normal 10. Low neutrophil (below 2 x 109/L) or low platelet levels (below 100 x 10e3/μL) 11. Signs of active infection 12. Receipt of live vaccine within 3 months or planning a live vaccine during the trial period. Most COVID vaccines are not live. 13. Pregnancy or breastfeeding, or planning a pregnancy during the trial period or unable or unwilling to meet the contraception criteria (see below) 14. Latent TB: to be excluded with IGRA testing and if positive exclude and refer for treatment as per national guidelines. 15. New diagnosis or on treatment for HIV 16. Past history of diverticulitis 17. Significant alcohol or substance misuse 18. History of clinically significant hypersensitivity reaction or significantly deranged liver function tests with other medication 19. Hepatitis B 20. Exclude Hepatitis C if untreated: on testing antibody positive and detectable viral load. If antibody positive, but viral load negative compatible with previous infection only participant can be included. 21. Supervised exercise rehabilitation programme within three months of consent or planned to occur during the trial period |
| Recruitment start date | 01/02/2024 |
| Recruitment end date | 31/08/2025 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Groby Road
Leicester
LE1 5WW
United Kingdom
London
SE1 7EH
United Kingdom
London
SE5 9RS
United Kingdom
4th Floor
170 Tottenham Court Road
London
W1T 7HA
United Kingdom
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Herries Road
Sheffield
S5 7AU
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Glasgow
G4 0SF
United Kingdom
Southmoor Road
Wythenshawe
Manchester
M23 9LT
United Kingdom
Stott Lane
Eccles
Salford
M6 8HD
United Kingdom
Sponsor information
University/education
Groby Road
Leicester
LE3 9QP
England
United Kingdom
| Phone | +44 (0)116 252 2522 |
|---|---|
| RGOSponsor@le.ac.uk | |
| Website | http://www.le.ac.uk/ |
"ROR" |
https://ror.org/04h699437 |
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 30/06/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Conference presentation 3. Publication on website 4. Submission to regulatory authorities |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date Research data will be shared with bona fide researchers in different organisations, including those in other countries or in commercial organisations. Access to data will be managed through the Trial Management Group (TMG) and formal application requests will be submitted to the TMG by researchers requesting data. Once permission has been granted by the TMG data will be released to collaborators. Data will be labelled with a unique study number in place of any identifiable data (pseudonymised). Contractual agreements will be put in place prior to any sharing of data. Some trial data (anonymised questionnaire data) will be suitable for sharing for research. |
Editorial Notes
16/01/2025: The following changes were made to the trial record:
1. The exclusion criteria were changed.
2. The study participating centres were added.
3. The intention to publish date was changed from 31/12/2025 to 30/06/2026.
10/12/2024: The following changes were made:
1. The overall study end date was changed from 31/12/2025 to 31/07/2026.
2. The recruitment end date was changed from 31/12/2024 to 31/08/2025.
04/03/2024: The overall study start date was changed from 23/01/2023 to 11/03/2023.
07/02/2024: Internal review.
22/12/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 22/12/2023.
23/11/2022: Trial's existence confirmed by the HRA.
