Cell therapy for acute liver injury trial
| ISRCTN | ISRCTN12637839 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12637839 |
| EudraCT/CTIS number | 2022-002584-29 |
| IRAS number | 1005258 |
| Secondary identifying numbers | AC22087, IRAS 1005258 |
- Submission date
- 20/12/2022
- Registration date
- 25/04/2023
- Last edited
- 11/03/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Injury, Occupational Diseases, Poisoning
Plain English Summary
Background and study aims
The aim of this clinical trial is to test the safety of a cell therapy for liver injury. Healthy people with no liver disease can develop sudden acute liver injury (ALI) which, in severe cases, can lead to a syndrome called acute liver failure (ALF). ALF is characterised by bleeding because the liver cannot make enough clotting factors, excessive pressure in the brain, kidney failure, and infection. ALF has no effective treatment other than liver transplantation, which has only limited use because of its associated complications, the expense to the health provider and the scarcity of donor's livers. Medicines are the most common cause of ALF in the Western world, especially paracetamol when taken in overdose. The only treatment for paracetamol overdose is called acetylcysteine, which is optimally effective only if treatment is started within around 8 hours of taking the tablets. For other causes of ALF, there are currently no specific treatments. Our new treatment is an infusion of cells called macrophages, which are large white blood cells that clear away damaged liver cells, and reduce inflammation, and, in mice with ALF have been shown to promote the regeneration of healthy liver tissue.
Who can participate?
Adults (16 years old and over) with ALI due to paracetamol overdose
What does the study involve?
All participants will receive a single infusion of macrophage blood cells. Patients will be included in cohorts with increasing doses. A group of independent experts will review the safety of each dose and decide whether or not the study can continue to the next higher dose. The researchers will carry out different tests before, during (Day 0) and after the infusion (on Days 1, 2, 7 and 30). These include routine checks of patients’ general well-being (temperature, blood pressure, breathing and pulse rate, blood oxygen levels), a tracing of the heart called an electrocardiogram (ECG), a physical exam and blood taking. We will also ask patients questions about their medical history, any other medications they take and any side effects they are experiencing.
What are the possible benefits and risks of participating?
The researchers do not know if patients will directly benefit from taking part in this trial. However, the information obtained from this study will help improve the treatment of people who require treatment in the future. This is a new treatment and the researchers do not yet know for certain what adverse effects, if any, it may have. However, different types of macrophages have been given to humans with other conditions in studies before. These studies did not show any severe adverse effects from the macrophage treatment. Patients will be monitored closely during treatment and will be given appropriate medication to treat any side effects that might occur. Rare, known side effects of cell therapies include the following symptoms:
1. Nausea, vomiting, chest tightness, skin flushes and a rise in blood pressure and/or temperature.
2. Very rarely may cause a drop in blood pressure, a change in heart rate, difficulty in breathing or an acute allergic reaction.
These side effects last only a short time and can be treated.
Where is the study run from?
The University of Edinburgh (UK)
When is the study starting and how long is it expected to run for?
December 2022 to November 2025
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
MAIL.Trial@ed.ac.uk (MAIL Trial Management Team, Edinburgh Clinical Trials Unit) (UK)
Contact information
Principal Investigator
Edinburgh Royal Infirmary
Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
| Phone | +44 (0)131 242 9214 |
|---|---|
| james.dear@ed.ac.uk |
Scientific
Edinburgh Royal Infirmary
Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
| Phone | +44 (0)131 242 9214 |
|---|---|
| james.dear@ed.ac.uk |
Public
Edinburgh Clinical Trials Unit
NINE Edinburgh BioQuarter
9 Little France Road
Edinburgh
EH16 4UX
United Kingdom
| Phone | None provided |
|---|---|
| MAIL.Trial@ed.ac.uk |
Study information
| Study design | Interventional randomized single-arm dose-escalation study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomized study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Macrophage Therapy For Acute Liver Injury (MAIL) trial: a phase I randomised, open-label, dose-escalation study to evaluate safety, tolerability, and activity of allogeneic alternatively activated macrophages (AAM) in patients with paracetamol-induced acute liver injury. |
| Study acronym | |
| Study hypothesis | There is currently no effective treatment for Acute Liver Failure (ALF) other than liver transplantation, which has limited use because of its associated complications, expense to the health provider and the scarcity of donor livers. Medicines are the most common cause of ALF in the Western world, especially paracetamol when taken in overdose. The only treatment for paracetamol overdose is called acetylcysteine, which prevents ALF only if treatment is started within around 8 hours of taking the tablets. For other causes of ALF there are currently no specific treatments. Previous research has shown that macrophages (large white blood cells which have the ability to “eat” dead cells) can help to reduce the damage and support regeneration of the liver. This study will test whether a new treatment for acute liver injury using macrophages is safe. The secondary objective of the trial is to determine whether there is any evidence that treatment with macrophages may improve the health of the injured liver. |
| Ethics approval(s) | Approved 08/03/2023, North East – York Research Ethics Committee (NHSBT Newcastle Blood Doner Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, UK; +44 (0)207 104 8079; york.rec@hra.nhs.uk) ref: 23/NE/0019 |
| Condition | Acute liver injury (paracetamol-induced) |
| Intervention | Participants will receive a single infusion of allogeneic alternatively activated macrophages (AAM). The first patient will be dosed with 10e6 macrophages; if there are no safety concerns, the highest dose in this trial will be up to 10e9 cells. Patients will be dosed in 5 cohorts with dose escalation decisions being guided by an independent Data Monitoring Committee. In dose cohorts 3-5, the dose of AAM will be randomised using a centralised online randomisation system. Participants will be followed-up for 30 days following the infusion. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Allogeneic alternatively-activated macrophages (AAM) |
| Primary outcome measure | Dose-limiting toxicity occurring within 30 days of infusion. DLT is defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and either meeting the NCI common terminology criteria that are CTCAE Grade 3 or 4 OR deemed by the independent Data Monitoring Committee (DMC) to be serious enough to prevent an increase in dose of treatment. All adverse events occurring in this study will be assessed against these criteria by an investigator and reviewed by the DMC within 30 days of dosing, assessed on days 1, 2, 3, 7 and 30. |
| Secondary outcome measures | Assessed on days 1, 2, 3, 7 and 30: 1. Safety: Adverse events of special interest (defined as: serious adverse events of transfusion reaction; macrophage activation syndrome; acute respiratory compromise) and all serious adverse events occuring within 30 days of infusion, clinical observations, clinical examination, electrocardiogram (ECG) and safety blood tests. 2. Activity measured by blood tests: 2.1. Pro-inflammatory – IL-6, TNF-alpha, IL-12, IL-8 (pg/mL). Anti-inflammatory - IL-10 (pg/mL). Assessed as change from baseline. 2.2. Liver injury – conventional markers of paracetamol-induced liver injury:ALT (U/L), INR, Lactate (mmol/L), Creatinine (μmol/L). Novel marker of paracetamol-induced liver injury: HMGB1 (ng/mL), GLDH (U/L), cytokeratin-18 (U/L) and miR-122 (copies/mL). Assessed as change from baseline. 3. Immunogenicity: Development of anti-HLA antibodies measured by blood test |
| Overall study start date | 15/12/2022 |
| Overall study end date | 30/11/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | 17 – 30 (The exact number of patients in this trial will be governed by the decisions of an independent Data Monitoring Committee.) |
| Participant inclusion criteria | 1. Serum ALT activity > 1000U/L at screening. 2. History of paracetamol overdose within 5 days of ALT>1000. Overdoses of paracetamol alone and mixed overdoses are eligible. 3. Other causes of ALT increase excluded based on previous investigations and trial screening. This will be documented in the patient’s medical notes. 4. Provision of written informed consent. 5. Adult male or female (16 yrs old or above). 6. Deemed safe for hospital discharge from a mental health perspective after full mental health assessment by a mental health professional. This will be documented in the patient’s medical notes. 7. Patients with child bearing potential must have a negative urine or serum pregnancy test at screening. If the patient is of child bearing potential, or is a male with a female partner with child bearing potential, the patient, and their partner(s), must agree to use a highly effective method of contraception throughout the trial period and for 90 days post study completion. |
| Participant exclusion criteria | 1. Patients who do not have the capacity to consent. 2. Any situation that in the Investigator’s opinion may interfere with optimal study participation such as alcohol or drug abuse, potential non-compliance or inability to co-operate. 3. Patients with known viral hepatitis infection or known COVID-19 infection. 4. Patients who are pregnant, or are planning on becoming pregnant during the study, or are breastfeeding and wish to continue breastfeeding. Patients of childbearing potential, or male patients with a female partner of childbearing potential, must agree to use a highly effective method of contraception as detailed above. 5. Patients who have previously participated in this study or another ATMP. 6. Potentially life-threatening liver injury with an immediate need for transplantation as documented in the patient’s medical notes. 7. Patients listed for any organ transplant. 8. Patients with stage 4 or 5 chronic kidney disease. 9. Any history of or suspected hypersensitivity to the cell product, excipients, or possible residual components used in manufacture. 10. Patients who are currently enrolled in another ATMP or Clinical Trial of an Investigational Medicinal Product (CTIMP). |
| Recruitment start date | 01/09/2023 |
| Recruitment end date | 31/05/2025 |
Locations
Countries of recruitment
- Scotland
- United Kingdom
Study participating centre
Old Dalkeith Road
Edinburgh
Lothian
EH16 4SA
United Kingdom
Sponsor information
Hospital/treatment centre
ACCORD
Queen's Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
Scotland
United Kingdom
| Phone | +44 (0)131 242 6226 |
|---|---|
| resgov@accord.scot | |
| Website | http://accord.scot/ |
"ROR" |
https://ror.org/03q82t418 |
University/education
Queen's Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
Scotland
United Kingdom
| Phone | +44 (0)131 242 9418 |
|---|---|
| resgov@accord.scot | |
| Website | http://accord.scot/ |
|
"ROR" |
https://ror.org/01x6s1m65 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/11/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | 1. Peer reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on website 5. Submission to regulatory authorities |
| IPD sharing plan | Consent will be sought from participants to permit sharing of anonymised data with funders and collaborators or published on publicly available resources as appropriate. Following publication of the primary MAIL Trial results, a de-identified individual participant data set will be prepared for sharing purposes. Access to de-identified data may be granted to other researchers upon reasonable request in line with ECTU policies at that time. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 26/07/2023 | No | No | ||
| Protocol article | 04/11/2024 | 11/03/2025 | Yes | No |
Editorial Notes
11/03/2025: Publication reference added. The recruitment start date was changed from 01/09/2023 to 31/05/2025.
05/09/2023: The recruitment start date was changed from 15/08/2023 to 01/09/2023.
12/07/2023: The following changes were made:
1. The recruitment start date was changed from 15/07/2023 to 15/08/2023.
2. Standard text was added to the participant information sheet field.
09/06/2023: The recruitment start date was changed from 01/06/2023 to 15/07/2023.
25/04/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 25/04/2023
20/12/2022: Trial's existence confirmed by NHS HRA.
