Acute liver injury (paracetamol-induced) Injury, Occupational Diseases, Poisoning
Conditions
Interventions
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 Monitor
Sponsors
NHS Lothian
Accord (United Kingdom)
Eligibility
Sex/Gender
All
Age
16 Years to 100 Years
Inclusion criteria
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.
Exclusion criteria
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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
England, Scotland, United Kingdom
Contacts
Public Contact. MAIL Trial Management Team
Outcome results
None listed