Safety and Tolerability of Yaq-001 in Patients With Cirrhosis

Study Overview
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Brief Summary
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In patients with cirrhosis (scarring of the liver), bacterial fragments leak from the gut into the blood and cause harm. This study looks into a new way to lower the leakage of bacterial fragments into the blood. Yaq-001 is a new type of carbon that in previous laboratory studies has been shown to have the ability to bind these bacterial fragments and so confine them to the gut. The purpose of this clinical trial is to test the product Yaq-001 for the first time in patients with cirrhosis. This trial will assess if the treatment with Yaq-001 is safe, is well tolerated, and if it helps improve the overall health status of the cirrhotic patients. Candidate patients must be at least 18 years old and have a clinical diagnosis of cirrhosis for any cause. Only postmenopausal women or with surgical sterilisation are eligible. Additional inclusion and exclusion criteria of medical nature will be determined with the investigator at the screening visit, by means of standard care routines plus an additional test to assess the bowel transit time. Eligible patients will be randomly grouped to receive standard care treatment plus Yaq-001, or standard treatment plus placebo (non-active treatment). The use of placebo is necessary to better understand how safe and tolerable Yaq-001 really is. The treatment lasts for 12 weeks. During treatment, the patient will be visited by a study doctor 5 times. At all the visits the patients will undergo a routine physical examination, electrocardiogram, collection of blood and urine samples. On three occasions the patients will be asked to provide additional samples of blood, urine and stool for analysis outside the hospital. 56 patients from 9 hospitals in UK, France, Italy, Portugal, Spain and Switzerland will participate in this study.

Detailed Description
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First-in-human clinical investigation with Yaq-001. This is a multicentre, randomized, double blinded, placebo controlled trial to intended to evaluate safety and tolerability of oral administration of Yaq-001 therapy in two dosing cohorts. 56 cirrhotic patients with diuretic-responsive ascites will be enrolled. Patients will be randomized to two dosing cohorts. Cohort 1 (1:1 randomization) Standard medical treatment + Yaq-001 (4 g/ day) - n= 14. Standard medical treatment + placebo-control (placebo for 4 g of Yaq-001/ day) - n= 14. Cohort 2 (1:1 randomization) Standard medical treatment + Yaq-001 (8 g/ day) - n= 14. Standard medical treatment + placebo-control (placebo for 8 g of Yaq-001/ day) - n= 14. Study patients will be dosed daily with Yaq-001 (or an equivalent quantity of placebo) for 12 weeks. Assessments of DSMB will take place after 4 and 12 weeks. Investigational centres specialized in the management of patients with liver cirrhosis will participate in the study. For each patient, the study duration will be up to 17 weeks, including the screening (up to 4 weeks), treatment (12 weeks) and 7-day follow up period. The total study duration is estimated to be approximately 6 months from screening of first patient until study completion of the last patient. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 634579.

Official Title
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Safety and Tolerability of Yaq-001 in Patients With Cirrhosis (CARBALIVE-SAFETY)

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Device: 4g Yaq-001
* Other: 4g Placebo
* Device: 8g Yaq-001
* Other: 8g Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients Age ≥ 18 years at screening Clinical diagnosis of cirrhosis for any cause. Liver biopsy is not required Cirrhotic patients with diuretic-responsive ascites and Child-Pugh score = 7-11 inclusive Abstinence from alcohol for at least 4 weeks prior to screening Exclusion Criteria: Refusal or inability (lack of capacity) to give informed consent Prohibited medication within 4 weeks before the start of the study treatment: all oral antibiotics, immunosuppressants, long acting benzodiazepines or barbiturates and antiviral medication Change in dose of proton pump inhibitor therapy within 4 weeks before the start of the study treatment Patients with once daily medications in which orocaecal transit time is greater than 10 hours Patients requiring medication in which the dosing schedule is three times per day or greater Antiviral therapy for hepatitis C within 3 months prior to screening Hospital admission for liver-related indication for at least 4 weeks (except paracentesis) BMI > 35 or BMI < 18 Clostridium Difficile diarrhoea within 4 weeks before the start of the study treatment Uncontrolled infection (chronic viral hepatitis is not an exclusion criterion) Human immunodeficiency virus Presence of a transjugular intrahepatic portosystemic shunt (TIPSS) Participation in any clinical study of an investigational medicinal product within 30 days of five half-lives of the investigational product, whichever is longer Presence of clinically relevant cardiovascular, pulmonary, gastro-intestinal, renal, hepatic, metabolic, haematological, neurological, psychiatric, systemic, ocular, gynaecologic or any acute infection disease or signs of acute illness that, in the opinion of the investigator, might compromise the patient's safe participation in the trial and/or results in a WHO performance status of 2 or more. Presence of the history of cancer within the past 5 years with exception of hepatocellular carcinoma within Milan criteria, adequately treated localised basal cell carcinoma of the skin, in situ cervical carcinoma or solid malignancy surgical excised in total without recurrence for five years. Women of child bearing potential. Only postmenopausal women or with surgical sterilization will be included.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Device Feasibility
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Cohort 1 (1:1 randomization): Standard medical treatment + Yaq-001 (4 g/ day) - n= 14. Standard medical treatment + placebo-control (placebo for 4 g of Yaq-001/ day) - n= 14. Cohort 2 (1:1 randomization): Standard medical treatment + Yaq-001 (8 g/ day) - n= 14. Standard medical treatment + placebo-control (placebo for 8 g of Yaq-001/ day) - n= 14.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (4g Yaq-001)<br>Standard medical treatment + Yaq-001 (4 g/ day) | Device: 4g Yaq-001<br>* Study patients will be dosed daily with 4g of product Yaq-001 for a period of 12 weeks. The product will be provided as beads packed in individual sachets intended each for one oral administration. For each patient, the study duration will be up to 17 weeks, including the screening (up to 4 weeks), treatment (12 weeks) and 7-day follow up period.<br>|
| Placebo Comparator: Cohort 1 (4g Placebo)<br>Standard medical treatment + placebo-control (placebo for 4 g of Yaq-001/ day) | Other: 4g Placebo<br>* Study patients will be dosed daily with a quantity of placebo equivalent to 4g of product Yaq-001 for a period of 12 weeks. The product will be provided as beads packed in individual sachets intended each for one oral administration. For each patient, the study duration will be up to 17 weeks, including the screening (up to 4 weeks), treatment (12 weeks) and 7-day follow up period.<br>|
| Experimental: Cohort 2 (8g Yaq-001)<br>Standard medical treatment + Yaq-001 (8 g/ day) | Device: 8g Yaq-001<br>* Study patients will be dosed daily with 8g of product Yaq-001 for a period of 12 weeks. The product will be provided as beads packed in individual sachets intended each for one oral administration. For each patient, the study duration will be up to 17 weeks, including the screening (up to 4 weeks), treatment (12 weeks) and 7-day follow up period.<br>|
| Placebo Comparator: Cohort 2 (8g Placebo)<br>Standard medical treatment + placebo-control (placebo for 8 g of Yaq-001/ day) | Other: 8g Placebo<br>* Study patients will be dosed daily with a quantity of placebo equivalent to 8g of product Yaq-001 for a period of 12 weeks. The product will be provided as beads packed in individual sachets intended each for one oral administration. For each patient, the study duration will be up to 17 weeks, including the screening (up to 4 weeks), treatment (12 weeks) and 7-day follow up period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of reported and observed Serious Adverse Events | The percentage of patients experiencing SAEs will be tabulated by arm. | Day 1 | 
| Assessment of treatment-related Serious Adverse Events | The percentage of patients experiencing device-related SAEs will be tabulated by arm. | Day 1 | 
| Assessment of withdrawals due to Adverse Events | The percentage of patients who withdraw due to an AE will be tabulated by arm. | Day 1 | 
| Assessment of reported and observed Serious Adverse Events | The percentage of patients experiencing SAEs will be tabulated by arm. | Week 1 | 
| Assessment of treatment-related Serious Adverse Events | The percentage of patients experiencing device-related SAEs will be tabulated by arm. | Week 1 | 
| Assessment of withdrawals due to Adverse Events | The percentage of patients who withdraw due to an AE will be tabulated by arm. | Week 1 | 
| Assessment of reported and observed Serious Adverse Events | The percentage of patients experiencing SAEs will be tabulated by arm. | Week 4 | 
| Assessment of treatment-related Serious Adverse Events | The percentage of patients experiencing device-related SAEs will be tabulated by arm. | Week 4 | 
| Assessment of withdrawals due to Adverse Events | The percentage of patients who withdraw due to an AE will be tabulated by arm. | Week 4 | 
| Assessment of reported and observed Serious Adverse Events | The percentage of patients experiencing SAEs will be tabulated by arm. | Week 8 | 
| Assessment of treatment-related Serious Adverse Events | The percentage of patients experiencing device-related SAEs will be tabulated by arm. | Week 8 | 
| Assessment of withdrawals due to Adverse Events | The percentage of patients who withdraw due to an AE will be tabulated by arm | Week 8 | 
| Assessment of reported and observed Adverse Events | The percentage of patients experiencing SAEs will be tabulated by arm. | Week 12 | 
| Assessment of treatment-related Serious Adverse Events | The percentage of patients experiencing device-related SAEs will be tabulated by arm. | Week 12 | 
| Assessment of withdrawals due to Adverse Events | The percentage of patients who withdraw due to an AE will be tabulated by arm. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of changes in blood endotoxin activity | The changes from baseline in blood endotoxin activity, measured by the EAA, will be used as device-related performance indicator. | The EAA will be performed at randomization, 1-week, 4-week, 8-week and 12-week visits. | 
| Assessment of changes in organ function as per the CHILD-PUGH score | Changes from baseline in kidney, liver, brain, intestinal and immune functions will be assessed by means of the CHILD-PUGH score. | CHILD-PUGH scores will be calculated at screening, randomization, 1-week, 4-week, 8-week and 12-week visits. | 
| Assessment of changes in organ function as per the MELD score | Changes from baseline in kidney, liver, brain, intestinal and immune functions will be assessed by means of the MELD score. | MELD scores will be calculated at screening, randomization, 1-week, 4-week, 8-week and 12-week visits. | 
| Assessment of changes in nutritional status | Changes from baseline in nutritional status be assessed by means of the global assessment score (RFH-GA); | Global assessment will be performed at randomization, 1-week, 4-week, 8-week and 12-week visits. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cirrhosis, Liver, Fibrosis, Liver, Hepatic Cirrhosis, Liver Fibrosis