Condition category
Digestive System
Date applied
02/10/2017
Date assigned
07/11/2017
Last edited
07/11/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Primary sclerosing cholangitis is a chronic liver disease that causes the liver to decrease due to scars and inflammation (becoming swollen). Autoimmune hepatitis is an autoimmune disease (where the body attacks and damages its own tissue) of the liver that causes it to become inflamed. A therapy called mesenchymal stromal cells (MSC) could be a safe and effective treatment for these conditions. MSC are found in almost every part of the body. They are known to play a role in tissue repair, renewal and inflammation. When extracted, and used as treatment, they have been shown to reduce the body’s immune response when it is overactive and causing damage. This anti-inflammatory effect of MSC has been utilised in many clinical trials to treat conditions associated with inflammation such as graft versus host disease (GVHD) and Crohns disease with success. This study uses MSC derived and grown from human umbilical cords as they are readily accessible. The umbilical cords are ethically collected from mothers after childbirth. After collection, the MSC are purified and grown outside the body, before being infused directly into the body. The preparation of MSC we will use is called ORBCEL-C™. This is an 'off the shelf' product consisting of a purer and selected form of MSC. ORBCEL-C™ has not been used in a clinical trial previously however our fundamental laboratory studies have shown ORBCEL-C™ to be safe and effective in reducing liver inflammation. The aim of this study is to investigate whether patients with primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) can be safely and effectively treated with a therapy called mesenchymal stromal cells (MSC).

Who can participate?
Adults aged 18 to 70 years old with either PSC or AIH.

What does the study involve?
This study involves two stages. The first stage determines the highest safest dose to be evaluated in stage 2 by recording any side effects and reactions to the treatment. The second stage uses the dose determined in the first stage to examine the impact on the dose on the body. The treatment is the same in both stages. Participants are informed as to what dose they receive prior to starting teht treatment. Participants either receive 0.5 million cells, 1.0 million cells, or 2.5 million cells per kilogram of body weight. Participants receive a single intravenous infusion of ORBCEL-C™ through a needle in a vein in the arm, delivering the cells over 10-15 minutes. An infusion of saline is also given during the infusion. Participants are monitored for four hours after the infusion. Participants attend follow up visits where they undergo blood tests, scans and questionnaires to determine the treatment impact. Participants attend further follow up visits at six, nine, 12, 18 and 24 months. Blood tests are taken at every visit.

What are the possible benefits and risks of participating?
This study will assess whether the ORBCEL-C™ is safe and the effect in the activity of the liver and AIH. There are possible disadvantages and risks of the MSC infuson such as harm to unborn children and pregnancy. There are some mild side effects such as pain or itch at the injection site, high temperature, headache, foul/metallic taste in the mouth. There are few uncommon side effects such as tiredness and bad breath. A serious uncommon side effect is anaphylaxis.

Where is the study run from?
Stage 1 of the study takes place at the University Hospitals Birmingham, Queen Elizabeth Hospital (UK). Stage 2 of the study takes place at Queen Elizabeth Hospital (UK)., Nottingham University Hospital (UK), and the John Radcliffe Hospital (UK).

When is the study starting and how long is it expected to run for?
October 2017 to December 2020

Who is funding the study?
European Commission (EU)

Who is the main contact?
Miss Rebecca Storey
merlin@trials.bham.ac.uk

Trial website

http://fp7merlin.eu/

Contact information

Type

Public

Primary contact

Miss Rebecca Storey

ORCID ID

Contact details

MERLIN Trials office
Birmingham
B15 2TT
United Kingdom
+44 121 371 8118
merlin@trials.bham.ac.uk

Additional identifiers

EudraCT number

2016-000181-36

ClinicalTrials.gov number

Protocol/serial number

33534

Study information

Scientific title

An adaptive, single arm, multi-centre phase IIa multi-disease clinical trial investigating the safety and activity of the use of a single infusion of selected Mesenchymal Stromal Cells (MSC) to reduce liver inflammation in the treatment of patients with primary sclerosing cholangitis and autoimmune hepatitis

Acronym

Study hypothesis

This study seeks to investigate whether patients with primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) can be safely and effectively treated with a therapy called mesenchymal stromal cells (MSC).

Ethics approval

South Central- Oxford A Research Ethics Committee, 22/03/2017, ref: 17/SC/0032

Study design

Non-randomised; Interventional; Design type: Treatment, Cellular

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Hepatology, Primary sub-specialty: Hepatology; UKCRC code/ Disease: Oral and Gastrointestinal/ Diseases of liver

Intervention

MERLIN is an adaptive, single arm, multi-centre, phase IIa multi-disease clinical trial. It is designed to:
1. Determine dose safety of ORBCEL-CTM
2. Evaluate treatment activity through assessment of biomarkers

This trial has two main stages:
1. Stage 1 determine the highest safe dose that can be administered by observing for occurrence of dose limiting toxicity (DLT).
2. Stage 2 will use the highest safe dose found in stage 1 to and further determine safety and activity outcomes of ORBCEL-CTM.

This study seeks to recruit two cohorts of patients; patients with primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Both cohorts are recruited from the UK only. Both diseases are related rare autoimmune liver diseases, and both are managed in the same clinic settings.

Dose Safety (Stage 1):
The Dose Safety component of the trial is identical in design and are conducted in parallel for both PSC and AIH cohorts. Participants are recruited in groups of three for this safety component. An identical approach to recruitment is undertaken in both the PSC and AIH cohorts.

As this is a first in man study, the first three patients in both the PSC and AIH cohorts are recruited to dose level A. The first patient in each cohort are recruited to dose level A and followed for the 14 day assessment period for DLT before the next two patients are recruited. Should one DLT be observed in the first three patients then a further three patients are treated at the current dose. If 2/3 DLTs are observed then this dose will be determined unsafe and no further higher dose will be assessed, de-escalation will occur if possible. Escalation occurs to a dose level higher (if possible) if there are no DLTs in the first three patients or less than two DLTs in six patients. The highest dose for which safety is determined will be taken forward to stage 2. An investigated dose level is determined to be safe for the purposes of expansion for stage 2 if we observe less than two DLTs in six patients or in the case of 0/3 DLTs at the highest dose level we will allow expansion to stage 2, with an early look after an additional 3 patients and if < 2 DLTs have been observed, that dose will be declared safe.

After a 28 day screening period, eligible participants receive a single infusion of ORBCEL C. All patients will then be followed up for 56 days for primary safety/ efficacy evaluation, and then followed up long term up to 22 months (720 days post infusion).

It is anticipated that recruitment for both cohorts will take between 18-24 months. An individual patient’s involvement spans 24 months including a 28 day screening period prior to MSC infusion.

Stage 2: Activity and Safety
For the primary outcome measure of change in ALP, co-primary analyses of examining
1. Change in ALP at day 28 from baseline and
2. Changes over multiple time-points before and after infusion (Visit 1 to Visit 8) will be conducted on the defined evaluable population.

Intervention type

Other

Phase

Phase II

Drug names

Primary outcome measures

For Both PSC and AIH patients:
Stage 1:
Highest safe single intravenous infusion dose of ORBCEL-CTM over a 14-day reporting period to take forward to Stage 2 of the clinical trial (study). All patients who have been recruited to and completed the 14-day reporting period in stage 1 will continue to be evaluated for outcomes as per Stage 2.

Stage 2:
Safety and tolerability of a single intravenous infusion of ORBCEL-CTM over the period of trial follow up (up to 56 days).

For PSC patients only:
Reduces serum alkaline phosphatase (ALP) in patients with PSC. This is a non-invasive biochemical surrogate of clinical outcomes in PSC

For AIH patients only:
Reduces serum alanine aminotransferase (ALT) in patients with AIH. This is a non-invasive biochemical surrogate marker of hepatic inflammatory activity and outcomes in AIH.

Secondary outcome measures

Stage 2
1. Single intravenous infusion of ORBCEL-CTM elicits a change over the duration of the study after treatment in patients with PSC and AIH:
1.1. Liver biochemistry and function, immunoglobulin G concentrations (in AIH patients) and composite risk scores
1.2. Non-invasive clinical markers of fibrosis
1.3. Patient quality of life (QoL)
1.4. Severity of co-existent IBD in patients with PSC.
2. Further exploratory research objectives of the trial determine whether MSC infusion modulates the immune response by measuring whether treatment elicits a change in patients with PSC and AIH:
2.1. Markers of immune activation including immunoglobulin values and C-reactive protein concentration
2.2. Markers of biliary injury including total bile acid levels
2.3. Circulating inflammatory cells profile this includes phenotypic expression of T regulatory cells (Tregs) a common mechanistic primary endpoint
2.4. Endothelial cell activation markers such as VAP-1 and ICAM1

Overall trial start date

31/10/2017

Overall trial end date

31/12/2020

Reason abandoned

Eligibility

Participant inclusion criteria

Patients with PSC
1. Age ≥ 18 , ≤70 years old at visit 1 (screening)
2. Diagnosis of PSC at visit 1 (screening) as evidenced clinically by:
2.1. Chronic biochemical cholestasis (elevated serum alkaline phosphatase (ALP) above the upper limit of normal (ULN) and/or gamma-glutamyl transpeptidase (GGT) above the ULN) > 6 months duration AND
2.2. Radiological AND /OR histological evidence of clinically documented PSC
3. Serum ALP) ≥ 1.5 ULN at visit 1 (screening)
4. Serum ALP value at Visit 2 within +/- 25% of ALP value at Visit 1 as per the formula below:
5. At visit 2, it should be confirmed that a patient does not meet any of the exclusion criteria

Patients with AIH
1. Age ≥ 18, ≤70 years old at visit 1 (screening)
2. Established pre-existing clinical diagnosis of AIH confirmed by clinical expert review consistent with the simplified IAIHG criteria (http://www.mdcalc.com/simplified-scoring-autoimmune-hepatitis-aih/) and must include history of a liver biopsy reported compatible with AIH
3. Active AIH defined by ALT ≥ 1.5 ULN.
4. Serum ALT must be above ≥ 1.5 ULN at both screening (visit 1) and visit 2
5. At visit 2, it should be confirmed that a patient does not meet any of the exclusion criteria
6. Patients must be on standard-of-care AIH treatment for ≥ 24 weeks –this includes any AIH therapy except biologics
7. Stable doses of immunosuppression for a minimum period of 4 weeks at the time of screening, and no planned change in immunosuppression for the course of the trial

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 56; UK Sample Size: 56

Participant exclusion criteria

Generic exclusion criteria that will apply to both patients with PSC and AIH:
1. Refusal or lacks capacity to give informed consent to participate in trial
2. Patient who is unable to participate in follow up assessment
3. Participation actively, or within 5 half-lives, of another interventional clinical trial
4. Known hypersensitivity to the investigational product or any of its formulation excipients
5. Evidence of active malignancy (within 3 years of visit 1 (screening)), other than non-melanomatous skin cancer and cervical dysplasia in situ
6. Major surgical procedure within 30 days at visit 1 (screening)
7. Prior organ transplantation
8. Active harmful alcohol consumption as evaluated and documented by the investigator
9. Creatinine > 133 μmol/L or being treated with renal replacement therapy at the time of Visit 1 (screening)
10. AST or ALT > 10 x ULN
11. ALP > 10 x ULN
12. Platelets < 50 x 10^9/L
13. Total Bilirubin > 2 x ULN
14. INR > 1.3 (in the absence of concomitant use of Warfarin or equivalent anti-coagulant therapy)
15. Albumin < 35 g/litre
16. Haemoglobin < 10 g/dl
17. Past or present evidence of decompensated chronic liver disease:
17.1. Radiological or clinical evidence of ascites
17.2. Hepatic encephalopathy
17.3. Endoscopic evidence for portal hypertensive bleeding
18. Any active treatment with biologic therapy (monoclonal antibodies)
19. Clinically severe cardiovascular disease as evaluated by the Investigator
20. Pregnancy or breast-feeding
21. Women of childbearing age who are unwilling to practice effective contraception 22. Non-vasectomised men, sexually active with women of child-bearing age, who are not willing to practice effective contraception (condom with spermicide) for the duration of the trial up to 90 days after the trial drug is administered
23. Patients with a history of hepatitis C (present or past infection), known positivity for antibody to HIV or any evidence of current or past hepatitis B infection
24. Presence of an acute/chronic infection or illness that, at the discretion of the Investigator, might compromise the patient’s health and safety in the trial
25. Receipt of live vaccination within six weeks prior to visit 1 (screening)

Exclusion criteria specific to patients with PSC:
1. Documented alternative aetiology for sclerosing cholangitis (i.e. secondary sclerosing cholangitis)
2. A dominant (as determined by Investigator) alternative chronic or active liver injury other than PSC at the time of visit 1 (screening); Patients with possible overlap syndrome with AIH are excluded from the PSC cohort if the Investigator considers AIH as the dominant liver injury
3. UDCA use within 8 weeks of the first screening visit (if a patient was taking UDCA a washout period of at least 8 weeks prior to the first screening is required)
4. ALP > 10 x ULN
5. Evidence of cholangitis within 90 days of visit 1 (screening)
5.1. Documented evidence of cholangitis by physician
5.2. Need for any antibiotics for presumed cholangitis
6. Any patient taking prophylactic antibiotics to combat recurrent cholangitis
7. Presence of percutaneous biliary drain, or internal biliary stent
8. Diagnosed hepatocellular carcinoma or cholangiocarcinoma or high clinical suspicion thereof
9. Dominant stricture clinically suspicious of cholangiocarcinoma (as determined by Investigator)

Exclusion criteria for those with IBD:
1. Unstable disease as evidenced by:
1.1. Documented clinically significant flare within 90 days of enrolment requiring any marked intensification of therapy from baseline maintenance (maintenance therapy = thiopurines, 5-aminosalicylates, or oral prednisolone < 10mg/day; biologics therapy is an exclusion criteria; see section 5.2
1.2. Requirement for daily prednisolone > 10mg
1.3. Mayo Clinic Score > = 2 AND clinician assessment of active disease requiring up-titration of treatment; last colonoscopy within last year used for endoscopic component
2. Any colonoscopic evidence of clinically significant dysplasia at last colonoscopy
3. Patients who have not had their routine colonoscopy within 24 months prior to planned MSC infusion and are unwilling to have their annual colonoscopy examination as per standard care prior to study visit 3 (treatment)

Exclusion criteria specific to patients with AIH:
1. A dominant (as determined by Investigator) alternative chronic or active liver injury other than AIH at the time of visit 1 (screening); Patients with possible overlap syndrome with PSC are excluded from the AIH cohort if the Investigator considers PSC as the dominant liver injury
2. AST or ALT > 10 x ULN
3. Patients on a prednisolone dose of > 20 mg at the time of screening
4. Treatment with biologic therapy within 24 weeks of the time of screening
5. Patients with a history of poor compliance with medication
6. Diagnosed hepatocellular carcinoma or cholangiocarcinoma or high clinical suspicion there

Recruitment start date

31/12/2017

Recruitment end date

31/12/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University Hospital Birmingham
Queen Elizabeth Hospital Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Nottingham University Hospital
Queens Medical Centre
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

John Radcliffe Hospital
Oxford Radcliffe Hospitals NHS Trust
Oxford
OX3 9DU
United Kingdom

Sponsor information

Organisation

University of Birmingham

Sponsor details

MERLIN Trials office
Birmingham
B15 2TT
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

European Commission

Alternative name(s)

EC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date

Intention to publish date

31/12/2021

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes