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Trial registered on ANZCTR


Registration number
ACTRN12616000437460
Ethics application status
Approved
Date submitted
31/03/2016
Date registered
6/04/2016
Date last updated
9/01/2019
Date data sharing statement initially provided
9/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot study evaluating the safety of intravenously administered human amnion epithelial cells for the treatment of hepatic fibrosis
Scientific title
A pilot study evaluating the safety of intravenously administered human amnion epithelial cells for the treatment of hepatic fibrosis
Secondary ID [1] 288890 0
None
Universal Trial Number (UTN)
U1111-1181-4339
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cirrhosis 298195 0
liver fibrosis 298196 0
Condition category
Condition code
Oral and Gastrointestinal 298355 298355 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a pilot study to examine the safety of human amnion epithelial cells administered to patients with compensated cirrhosis. To determine whether patients have compensated cirrhosis and to avoid including patients with decompensated cirrhosis, the hepatic venous pressure gradient will be measured, which is the most accurate way to make this determination. Human amnion epithelial cells ( hAEC) are derived from the placenta, specifically the amnion epithelium that lines the sac in which the fetus develops, We have shown that hAEC have intrinsic immune modulating characteristics that can induce hepatic fibrosis regression and stimulate liver regeneration. We have developed a method to isolate the cells that is free of animal products and compliant for clinical use. Once isolated, the cells are frozen until ready for infusion, i.e. they do not undergo any further manipulation or expansion. Twelve patients in total will be studied. They will be divided into four cohorts and each cohort will include three patients. In Cohort 1, three patients will receive hAEC (500,000 cells/kg) as a single intravenous injection. If no serious adverse events (SAE) occur within 5 days, a further three patients will be enrolled in Cohort 2 and receive hAEC (1,000,000 cells/kg) as a single IV injection. If no SAE occur within 5 days, a further three patients will be enrolled in Cohort 3 and receive hAEC (1,000,000 cells/kg) as a single IV injection at 0 and 30 days. If no SAE occur within 5 days, a further three patients will be enrolled in Cohort 4 and receive hAEC (1,000,000 cells/kg) as a single IV injection at days 0, 30 and 60. The hAEC will be administered by peripheral intravenous infusion over 30 minutes at a concentration of 250,000 cells/ml. The number of cells infused and the number of infusions will be determined by the specific cohort. The cell infusions will be done by trained nurses in the Clinical Trial Centre of the Monash Health Translational Research Facility. Patients will be monitored for 24 hours after the infusion in the Clinical Trial Centre by nursing and medical personnel. .The CTC has direct access to Monash Medical Centre.
Intervention code [1] 294347 0
Treatment: Other
Comparator / control treatment
Four cohorts of three patients each will be assessed (12 patients in total). The first cohort will be given a single infusion of 500,000 cells/kg, the second cohort will be given a single infusion of 1,000,000 cells/kg, the third cohort will be given an infusion of 1,000,000 cells/kg on days 0 and 30, and the fourth cohort will be given an infusion of 1,000,000 cells/kg on days 0, 30 and 60.
Control group
Dose comparison

Outcomes
Primary outcome [1] 297830 0
The primary outcome of this first-in-man study is to determine the safety and tolerability of human amnion epithelial cells in patients with compensated cirrhosis. Safety will be determined by clinical assessment during the cell infusion with monitoring for 24 hours afterwards in the Clinical Trial Centre. Safety assessment for days 2 - 4 will be by telephone and on day 5 at a clinic visit. A further clinical assessment will occur 8 weeks after the infusion.
There is a possible risk of local and systemic side effects akin to those following blood transfusions. We will specifically assess for local skin reactions, anaphylaxis (acute deterioration of respiratory and cardiovascular parameters (trouble breathing, shortness of breath, changes in blood pressure or heart rhythms). We will also look for infection or features of cell rejection with changes in liver or kidney tests.
An independent group of experts will also evaluate our study (a data and safety monitoring board). These experts will review the data from each infusion and must give approval to enrol the next patient.
Timepoint [1] 297830 0
Patients will be assessed during cell administration then daily for 5 days. A further assessment will occur 8 weeks following cell administration. All patients will be followed at 6 monthly intervals for two years.
Secondary outcome [1] 322362 0
Secondary outcomes will include assessment of efficacy (reduction in liver fibrosis or regression of cirrhosis). These data will be used to inform phase 2 clinical trials. Several methods will be used for this assessment. The most accurate method of assessing the risk of developing serious complications of cirrhosis (ascites, variceal bleeding, death) is to measure the pressure in the veins entering the liver (the hepatic venous pressure gradient). This is done by a radiologist who places a catheter into a vein in the neck and guides it into the liver where the pressure is measured. The procedure is done with sedation and takes about 20 minutes. If the pressure measurement is lower after the cell infusion, this would indicate that the treatment is effective in treating cirrhosis. We will also use Fibroscan, a non-invasive test similar to an ultrasound, that estimates the amount of collagen (scar tissue) in the liver and also blood tests that estimate the amount of collagen.
Timepoint [1] 322362 0
Measurement of the hepatic venous pressure gradient will be done twice, once before the cells are infused and once at 8 weeks following the last cell infusion (this time varies according to the patient cohort). The Fibroscan and blood tests will be performed at baseline, on day 5 after each infusion and 8 weeks after the last infusion.

Eligibility
Key inclusion criteria
Adult female or male patients, age 18 years to 70 years

Liver disease due to non-alcoholic fatty liver disease, alcohol related liver disease (must be abstinent for at least 3 months), hepatitis C virus infection (treated or not treated), hepatitis B virus infection (on nucleoside analogues with normal ALT and HBV DNA viral load) or inactive phase, HIV co-infection with HCV/HBV with virological suppression >12 months, cryptogenic cirrhosis, haemochromatosis (on maintenance venesection)

Cirrhosis, defined as one of: liver biopsy confirming cirrhosis, transient elastography (Fibroscan) with a liver stiffness measurement (LSM) >12.5 kPa, FIB 4 >3.25, or clinical and radiological features that in the opinion of the investigator are consistent with a diagnosis of cirrhosis. Compensated cirrhosis will be defined as a hepatic venous pressure gradient between 6 - 10 mmHg.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded from the study if they have current or previous episodes of decompensated liver disease, including variceal haemorrhage, hepatic encephalopathy, ascites, are listed for liver transplantation, have primary biliary cholangitis, autoimmune hepatitis or other active autoimmune disease (IgG >2xULN), renal insufficiency (eGFR < 70mL/min/1.73m2), HIV infection (untreated or uncontrolled viraemia), HBV DNA >200 IU/mL, fulminant hepatitis (severe acute hepatitis withencephalopathy), primary sclerosing cholangitis, portal/hepatic vein thrombosis, significant comorbidity (chronic heart failure, COAD, pulmonary hypertension, diabetes or other in the investigator’s opinion), pregnancy, fibrotic liver disease other than cirrhosis (nodular regenerative hyperplasia), inability or unwillingness to provide informed consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Four cohorts of three patients each will be assessed (12 patients in total). The first cohort will be given a single infusion of 500,000 cells/kg, the second cohort will be given a single infusion of 1,000,000 cells/kg, the third cohort will be given an infusion of 1,000,000 cells/kg on days 0 and 30 and the fourth cohort will be given an infusion of 1,000,000 cells/kg on days 0, 30 and 60.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
There will be no formal statistical analysis of this phase I trial, but descriptive and inferential statistical analysis will be conducted to develop a sound statistical framework for later phase clinical trials of hAEC cell therapy

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5525 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 12995 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 293243 0
Hospital
Name [1] 293243 0
Monash Health
Address [1] 293243 0
246 Clayton Road, Clayton Victoria 3168
Country [1] 293243 0
Australia
Funding source category [2] 301590 0
Government body
Name [2] 301590 0
National Health and Medical Research Council
Address [2] 301590 0
GPO Box 1421
Canberra ACT 2601
Country [2] 301590 0
Australia
Primary sponsor type
Hospital
Name
Monash Health
Address
246 Clayton Road, Clayton Victoria 3168
Country
Australia
Secondary sponsor category [1] 292045 0
University
Name [1] 292045 0
Monash University
Address [1] 292045 0
Wellington Road, Clayton, 3800, Victoria
Country [1] 292045 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294721 0
Monash Human Research Ethics Committee
Ethics committee address [1] 294721 0
Monash Medical Centre
Level 2, I Block
246 Clayton Road
Clayton VIC 3168
Ethics committee country [1] 294721 0
Australia
Date submitted for ethics approval [1] 294721 0
04/02/2016
Approval date [1] 294721 0
08/08/2016
Ethics approval number [1] 294721 0

Summary
Brief summary
We propose a first-in-man clinical trial of human amnion epithelial cells (hAEC), a type of stem cell obtained from the placenta, The placenta is normally discarded after delivery so the use of hAEC does not pose any ethical issues. In laboratory studies we have shown that these cells can reduce liver fibrosis (scar tissue in the liver) and stimulate regeneration of liver cells.. Worldwide, cirrhosis is the sixth most common cause of death and liver transplantation remains the only chance for survival for some people with cirrhosis. In this study we will assess the safety and tolerability of giving hAEC to patients with stable liver cirrhosis. Our long-term goal is to develop hAEC as a clinically useful therapy to reduce the need for liver transplantation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64814 0
Prof William Sievert
Address 64814 0
Gastroenterology and Hepatology Unit
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168
Country 64814 0
Australia
Phone 64814 0
+613 9594 3177
Fax 64814 0
+613 9594 6250
Email 64814 0
William.Sievert@monash.edu
Contact person for public queries
Name 64815 0
Prof William Sievert
Address 64815 0
Gastroenterology and Hepatology Unit
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168
Country 64815 0
Australia
Phone 64815 0
+613 9594 3177
Fax 64815 0
+613 9594 6250
Email 64815 0
William.Sievert@monash.edu
Contact person for scientific queries
Name 64816 0
Prof William Sievert
Address 64816 0
Gastroenterology and Hepatology Unit
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168
Country 64816 0
Australia
Phone 64816 0
+613 9594 3177
Fax 64816 0
+613 9594 6250
Email 64816 0
William.Sievert@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Study protocol
De-identified individual participant data underlying published results
When will data be available (start and end dates)?
Study protocol currently available
Individual participant data available following publication (end date yet to be determined)
Available to whom?
Study protocol is published and available to anyone who wishes to access it
Individual participant data available on a case-by-case basis at the discretion of the Principal Investigator
Available for what types of analyses?
Related to an approved protocol
How or where can data be obtained?
Access subject to approvals by Principal Investigator
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 981 0
Study protocol
Citation [1] 981 0
Link [1] 981 0
Email [1] 981 0
Other [1] 981 0
Summary results
No Results