Evaluation of Safety, Tolerability, and Efficacy of RTX001 Autologous Macrophages and Filgrastim in Patients with Decompensated Liver Cirrhosis
- Trial ID
- 2024-516288-10-00
- Protocol
- RTX001-002
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of RTX001 in participants with **liver cirrhosis** who have hepatic decompensation. This is clinically relevant as it aims to ensure that the treatment is safe for patients, minimizing potential adverse effects while assessing its feasibility for further clinical use.
Secondary objectives include:
- Evaluating the clinical efficacy of RTX001 in the Stabilised Group participants.
- Assessing changes in MELD scores from baseline to the end of the study in the Stabilised Group participants.
- Comparing and evaluating the characteristics and morbidities of the Stabilised Group participants after treatment.
Participants
The clinical trial involves a total of **16 participants** diagnosed with **liver cirrhosis**. The study population includes both male and female subjects, aged between **18 to 75 years**. Participants were selected based on specific criteria, including a confirmed diagnosis of liver cirrhosis through clinical, radiological, or histological evidence. The trial does not include a vulnerable population. Participants are required to have a history of hospitalization for a major hepatic decompensation event or medically refractory ascites. Lifestyle considerations include adherence to local contraceptive regulations and abstinence from alcohol above specified limits for those with alcohol-related liver disease. The trial aims to evaluate the safety and tolerability of RTX001 in stabilized group participants.
Plans and Procedures
The clinical trial is designed as an open-label, Phase 1/2, multicenter study to evaluate the **safety**, tolerability, and efficacy of RTX001 autologous macrophages in participants with **liver cirrhosis** who have experienced hepatic decompensation. The trial will involve a randomized, controlled methodology to ensure the reliability of the results. The estimated duration of the trial is from September 16, 2024, to August 29, 2028, allowing for comprehensive data collection and analysis over this period.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of liver cirrhosis, and recent hepatic decompensation events. The screening visit will also involve assessments to ensure no known contraindications to **filgrastim** or leukapheresis procedures. Following the screening, participants will attend regular follow-up visits to monitor the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), as well as changes from baseline in safety assessments. The end-of-study visit will conclude the participant's involvement, summarizing the overall safety and efficacy outcomes.
The expected length of participant involvement will vary depending on individual response and the occurrence of any adverse events. Conditions that may lead to early termination from the study include the development of severe adverse reactions or non-compliance with study procedures. The primary endpoints focus on the incidence and severity of TEAEs and SAEs, while secondary endpoints include the time-to, incidence, and severity of further hepatic decompensation events, mortality, and transplant-free survival. The study aims to provide valuable insights into the potential benefits and risks of RTX001 therapy in this patient population.
Treatment
The clinical trial involves the administration of **Neupogen 48 MU (0.96 mg/ml)**, a **solution for injection/infusion** containing the active substance **filgrastim**. This pharmaceutical product is provided in a pre-filled syringe and is manufactured by Amgen Europe B.V. The route of administration is via **intravenous infusion**. Filgrastim is a granulocyte colony-stimulating factor, which is a protein used to stimulate the production of white blood cells. The dosing schedule and frequency of administration are determined by the study protocol, and participant compliance is monitored throughout the trial.
Another treatment used in the study is **RTX001**, a **dispersion for infusion** developed by Resolution Therapeutics Ltd. RTX001 is a cell therapy product, classified as a structurally diverse substance, specifically involving genetically modified macrophages. The administration route for RTX001 is **intravenous**. The study aims to evaluate the safety and tolerability of RTX001 in participants with liver cirrhosis who have hepatic decompensation. The dosing regimen is outlined in the study protocol, and adherence to the treatment schedule is closely monitored.
Additionally, the trial includes the use of **Neupogen 30 MU (0.6 mg/ml)**, another **solution for injection/infusion** containing **filgrastim**. Similar to the 48 MU formulation, this product is also provided in a pre-filled syringe and is administered via **solution for infusion**. The manufacturer, Amgen Europe B.V., ensures the product's compliance with regulatory standards. The administration schedule is specified in the clinical trial protocol, and participant adherence is tracked to ensure accurate data collection.
Efficacy
Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints focus on the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), changes from baseline in safety assessments, and the incidence and severity of infusion reactions. These parameters will provide a comprehensive evaluation of the safety profile of RTX001 in participants with liver cirrhosis who have hepatic decompensation.
Secondary endpoints will include the time-to, incidence, and severity of a second portal hypertension-driven decompensating event, such as ascites, variceal haemorrhage, or hepatic encephalopathy, and/or jaundice. Additionally, the development of recurrent variceal bleeding, recurrent ascites, recurrent encephalopathy, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome-acute kidney injury (HRS-AKI) will be monitored. Other secondary measures include all hepatic decompensation events, new listings for liver transplantation, liver transplantation, mortality (both hepatic-related and all-cause), and transplant-free survival. Changes in the Model for End-Stage Liver Disease (MELD) score, including ΔMELD, ΔΔMELD, and MELD stabilization, will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be 18 to 75 years of age inclusive, at the time of signing the informed consent form (ICF)
- Participant confirms willingness/ability to comply with all study procedures.
- Diagnosis of liver cirrhosis based on at least one of: a. Clinical and radiological features that correlate with a diagnosis of cirrhosis. b. Transient elastography (Fibroscan®) >15 kPa. c. Previous liver biopsy confirming histological features of cirrhosis.
- Aetiology of liver disease of steatotic liver disease including MASLD or Met-ALD or ALD a. Participants with alcohol-related liver disease (ALD or Met-ALD) only if they are confirmed to not be drinking alcohol above Met-ALD limits defined in this protocol. (N.B. No more than 34% of the total treated participants in this protocol will be ALD [excludes Met-ALD]).
- Hospitalised as an inpatient for a recent major hepatic decompensation event including ascites, hepatic encephalopathy, variceal bleed, HRS-AKI or SBP, this being the only hospitalisation for an hepatic decompensation event hospitalisation within the last 6 months, and where recent is defined as within 6 weeks of hospital discharge OR
- Outpatient: Medically refractory ascites (ONLY), that recurs (i.e., second therapeutic LVP) within a 6-month period. Medically refractory ascites is defined by the repeated (≥2) need for LVP (i.e., therapeutic, not diagnostic) at least once per 8 weeks despite best medical attempts to control the ascites by sodium restriction and diuretic treatment, as confirmed by the Investigator. Onset is defined as the date of the second therapeutic LVP.
- Confirmatory PEth alcohol test <200 ng/ml
- MELD 3.0 score of 12-20 (inclusive) taken within 2 weeks of ‘qualifying’ decompensation event. If the participant qualifies as an outpatient then they must have a MELD 3.0 score of 12-20 (inclusive) at the time of the screening (Visit 1).
- No known contradictions to filgrastim or leukapheresis procedure.
- Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- Willing and able to give signed informed consent, and if applicable assent, as described in Section 8.1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria
- Liver cirrhosis due to: a. any viral hepatitidies b. autoimmune and cholestatic aetiologies including, but not limited to, primary biliary cholangitis and primary sclerosing cholangitis.
- Acute liver disease in the absence of underlying liver cirrhosis, including, but not limited to, drug induced liver injury.
- Any current organ failure requiring more than outpatient supportive care, and not associated with the participant’s qualifying hepatic decompensation event.
- Known splenomegaly ≥16 cm.
- Thrombocytopenia <50×109/L.
- Presence or suspicion of any of the following co-morbidities: a. History of liver transplantation or other organ transplant. b. ACLF. c. Sepsis (with positive microbial cultures) or as defined by the Principal Investigator, unless stable and is at least 4 weeks after having completed a full course of IV antibiotics. d. Known human immunodeficiency virus. e. Known syphilis. f. Known human T-lymphotropic virus 1. g. Pulmonary embolism. h. Hepatocellular carcinoma, or any active malignant disease within the last five years, (excluding non-melanoma skin cancer, cervical carcinoma in situ, superficial bladder cancer, benign polyps etc.). i. Co-hepatic morbidities e.g., portal vein thrombosis. j. Participants with hepatic hydrothorax are excluded unless it is a small hydrothorax, not clinically apparent, that is detected incidentally by radiologic evaluation that does not require clinical intervention. k. Chronic renal impairment (on dialysis) or unresolved AKI. l. Acute or chronic heart failure (New York Heart Association Grade III/IV). m. Porto-pulmonary hypertension. n. Severe chronic lung disease e.g., chronic obstructive pulmonary disease or interstitial lung disease where the forced expiratory volume in the first second (FEV1) is less than 50% and/or FEV1/forced vital capacity (FVC) is less than 60%. o. Hepatopulmonary syndrome. p. Previous or current treatment with long-term multiple infusions of albumin for therapeutic intent. [Use of albumin infusion at the time of large volume paracentesis for circulatory support is allowed.] q. Significant untreated/unstable psychiatric disease. r. Transjugular intrahepatic portosystemic shunt (TIPSS)
- As judged by the Investigator, any evidence of intercurrent illness that is either life threatening or of clinical significance such that it might limit compliance with study procedures.
- Current or planned use of immunomodulators or immunosuppressive medication; note: low doses of corticosteroids up to 10 mg per day prednisone or equivalent are permitted, or inhaled steroids to manage asthma.
- Received a gene or cell therapy at any time.
- Current or planned use of a live attenuated vaccines four weeks or fewer prior to enrolment (and for 3 months after the last administered dose of RTX001).
- Received any investigational product within the past 6 months, or five half-lives (whichever is longer) or participated in another investigational interventional study within 30 days prior to the screening visit.
- Participants with a known hypersensitivity to dimethyl sulfoxide (DMSO).
- Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.
- For female participants only – pregnant or breast-feeding or plans to become pregnant over the next year, or of childbearing potential and unwilling to comply with contraceptive requirements
- Alcohol misuse in the period between identification of the participant as potentially suitable for this study to Screening (Visit 1), defined as alcohol intake greater than three units/day for females and four units/day for males, or binge drinking (>14 units/day) as determined by the Investigator. N.B. One unit is equivalent to 14 g of alcohol: a half-pint (~240 mL) of beer, one glass (125 mL) of wine or one (25 mL) measure of spirits.
- Intake of non-medically supervised drugs of abuse that are judged (by the Investigator) to be a high risk to the participants acute health or which makes the participant likely to be non-compliant with follow-up.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 16 Sept 2024 | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RTX001 | Test | DISPERSION FOR INFUSION | INTRAVENOUS ADMINISTRATION | — | — | PRD11503615 |
Neupogen 30 MU (0,6 mg/ml) solución inyectable en jeringa precargada filgrastim | Other | SOLUCIÓN INYECTABLE EN JERINGA PRECARGADA | SOLUTION FOR INFUSION | — | — | PRD729930 |
Neupogen 48 MU (0,96 mg/ml) solución inyectable en jeringa precargada filgrastim | Other | SOLUCIÓN INYECTABLE EN JERINGA PRECARGADA | INTRAVENIOUS INFUSION | — | — | PRD7643932 |