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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

16/06/2023

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]

None

Universal Trial Number (UTN)

U1111-1181-4339

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

cirrhosis

liver fibrosis

Condition category

Condition code

Oral and Gastrointestinal

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]

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]

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]

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]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

9/01/2017

Actual

20/06/2018

Date of last participant enrolment

Anticipated

Actual

15/06/2022

Date of last data collection

Anticipated

Actual

1/08/2022

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Monash Medical Centre - Clayton campus - Clayton

Recruitment postcode(s) [1]

3168 - Clayton

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Monash Health

Address [1]

246 Clayton Road, Clayton Victoria 3168

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

National Health and Medical Research Council

Address [2]

GPO Box 1421
Canberra ACT 2601

Country [2]

Australia

Primary sponsor type

Hospital

Name

Monash Health

Address

246 Clayton Road, Clayton Victoria 3168

Country

Australia

Secondary sponsor category [1]

University

Name [1]

Monash University

Address [1]

Wellington Road, Clayton, 3800, Victoria

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Human Research Ethics Committee

Ethics committee address [1]

Monash Medical Centre
Level 2, I Block
246 Clayton Road
Clayton VIC 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/02/2016

Approval date [1]

08/08/2016

Ethics approval number [1]

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

Prof William Sievert

Address

Gastroenterology and Hepatology Unit
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168

Country

Australia

Phone

+613 9594 3177

Fax

+613 9594 6250

William.Sievert@monash.edu

Contact person for public queries

Name

William Sievert

Address

Gastroenterology and Hepatology Unit
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168

Country

Australia

Phone

+613 9594 3177

Fax

+613 9594 6250

William.Sievert@monash.edu

Contact person for scientific queries

Name

William Sievert

Address

Gastroenterology and Hepatology Unit
Monash Medical Centre
246 Clayton Road
Clayton VIC 3168

Country

Australia

Phone

+613 9594 3177

Fax

+613 9594 6250

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?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
981	Study protocol					370439-(Uploaded-09-01-2019-10-59-30)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	A pilot study evaluating the safety of intravenously administered human amnion epithelial cells for the treatment of hepatic fibrosis.	2017	https://dx.doi.org/10.3389/fphar.2017.00549
Dimensions AI	Concise Review: Fetal Membranes in Regenerative Medicine: New Tricks from an Old Dog?	2017	https://doi.org/10.1002/sctm.16-0447
Embase	Phase 1 trial of amnion cell therapy for ischemic stroke.	2018	https://dx.doi.org/10.3389/fneur.2018.00198
Dimensions AI	Crescentic Glomerulonephritis: Pathogenesis and Therapeutic Potential of Human Amniotic Stem Cells	2021	https://doi.org/10.3389/fphys.2021.724186
Dimensions AI	Amniotic fluid characteristics and its application in stem cell therapy: A review	2022	https://doi.org/10.18502/ijrm.v20i8.11752

N.B. These documents automatically identified may not have been verified by the study sponsor.

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