Clinical trial NCT03202498: Safety and Tolerability of Yaq-001 in Patients With Cirrhosis
Official title: Safety and Tolerability of Yaq-001 in Patients With Cirrhosis ("CARBALIVE-SAFETY")
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Liver Cirrhosis
Keywords: Cirrhosis, Liver
Fibrosis, Liver
Hepatic Cirrhosis
Liver Fibrosis
Lead sponsor: Yaqrit Ltd
Sponsor class: INDUSTRY
Collaborators: name: University College, London
name: University of Brighton
name: Institut d'Investigacions Biomèdiques August Pi i Sunyer
name: Azienda Ospedaliera di Padova
name: Hospital Universitari Vall d'Hebron Research Institute
name: IRCCS Azienda Ospedaliero-Universitaria di Bologna
name: University of Lisbon
name: Servicio Madrileño de Salud, Madrid, Spain
name: University of Bern
name: Assistance Publique - Hôpitaux de Paris
name: A2F Associates Limited
name: Alpha Bioresearch S.L.
First posted: 2017-06-28
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: DEVICE_FEASIBILITY

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Male and female patients
2. Age ≥ 18 years at screening
3. Clinical diagnosis of cirrhosis for any cause. Liver biopsy is not required
4. Cirrhotic patients with diuretic-responsive ascites and Child-Pugh score = 7-11 inclusive
5. Abstinence from alcohol for at least 4 weeks prior to screening

Exclusion Criteria:

1. Refusal or inability (lack of capacity) to give informed consent
2. Prohibited medication within 4 weeks before the start of the study treatment: all oral antibiotics, immunosuppressants, long acting benzodiazepines or barbiturates and antiviral medication
3. Change in dose of proton pump inhibitor therapy within 4 weeks before the start of the study treatment
4. Patients with once daily medications in which orocaecal transit time is greater than 10 hours
5. Patients requiring medication in which the dosing schedule is three times per day or greater
6. Antiviral therapy for hepatitis C within 3 months prior to screening
7. Hospital admission for liver-related indication for at least 4 weeks (except paracentesis)
8. BMI \> 35 or BMI \< 18
9. Clostridium Difficile diarrhoea within 4 weeks before the start of the study treatment
10. Uncontrolled infection (chronic viral hepatitis is not an exclusion criterion)
11. Human immunodeficiency virus
12. Presence of a transjugular intrahepatic portosystemic shunt (TIPSS)
13. Participation in any clinical study of an investigational medicinal product within 30 days of five half-lives of the investigational product, whichever is longer
14. 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.
15. 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.
16. Women of child bearing potential. Only postmenopausal women or with surgical sterilization will be included.

Primary outcomes:
measure: Assessment of reported and observed Serious Adverse Events
timeFrame: Day 1
measure: Assessment of treatment-related Serious Adverse Events
timeFrame: Day 1
measure: Assessment of withdrawals due to Adverse Events
timeFrame: Day 1
measure: Assessment of reported and observed Serious Adverse Events
timeFrame: Week 1
measure: Assessment of treatment-related Serious Adverse Events
timeFrame: Week 1
measure: Assessment of withdrawals due to Adverse Events
timeFrame: Week 1
measure: Assessment of reported and observed Serious Adverse Events
timeFrame: Week 4
measure: Assessment of treatment-related Serious Adverse Events
timeFrame: Week 4
measure: Assessment of withdrawals due to Adverse Events
timeFrame: Week 4
measure: Assessment of reported and observed Serious Adverse Events
timeFrame: Week 8
measure: Assessment of treatment-related Serious Adverse Events
timeFrame: Week 8
measure: Assessment of withdrawals due to Adverse Events
timeFrame: Week 8
measure: Assessment of reported and observed Adverse Events
timeFrame: Week 12
measure: Assessment of treatment-related Serious Adverse Events
timeFrame: Week 12
measure: Assessment of withdrawals due to Adverse Events
timeFrame: Week 12
Secondary outcomes:
measure: Assessment of changes in blood endotoxin activity
timeFrame: The EAA will be performed at randomization, 1-week, 4-week, 8-week and 12-week visits.
measure: Assessment of changes in organ function as per the CHILD-PUGH score
timeFrame: CHILD-PUGH scores will be calculated at screening, randomization, 1-week, 4-week, 8-week and 12-week visits.
measure: Assessment of changes in organ function as per the MELD score
timeFrame: MELD scores will be calculated at screening, randomization, 1-week, 4-week, 8-week and 12-week visits.
measure: Assessment of changes in nutritional status
timeFrame: Global assessment will be performed at randomization, 1-week, 4-week, 8-week and 12-week visits.
Other outcomes:
Locations:
city: Clichy
country: France
facility: Hospital Beaujon, Hepatology and Liver Intensive Care,
city: Bologna
country: Italy
facility: Policlinico S.Orsola Malpighi, Department of Medical and Surgical Sciences
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova, Hepatic Emergencies Unit
city: Lisbon
country: Portugal
facility: University Hospital of Santa Maria
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron, Liver Unit
city: Barcelona
country: Spain
facility: Hospital Clinic of Barcelona , Liver Unit,
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal, Department of Gastroenterology and Hepatology
city: Bern
country: Switzerland
facility: Inselspital Universitaet Bern, Department for Visceral Surgery and Medicine,
city: London
country: United Kingdom
facility: Royal Free Hospital, Institute of Liver and Digestive Disease
Study officials:
affiliation: Head, Liver Failure Group ILDH, Division of Medicine UCL Medical School Royal Free Campus Rowland Hill Street London NW32PF
name: Rajiv Jalan
role: STUDY_CHAIR
affiliation: Consultant, Liver Failure Group, ILDH, Division of Medicine UCL Medical School Royal Free Campus Rowland Hill Street London NW32PF
name: Jane Macnaughtan
role: STUDY_DIRECTOR
References: