Condition category
Digestive System
Date applied
09/07/2008
Date assigned
18/07/2008
Last edited
29/10/2013
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Prof Andrew Burroughs

ORCID ID

Contact details

Royal Free Hampstead NHS Trust
Pond Street
London
NW3 2QG
United Kingdom
+44 (0)20 7433 0060
Andrew.Burroughs@royalfree.nhs.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

3729

Study information

Scientific title

Randomised trial of monotherapy with tacrolimus versus triple therapy with tacrolimus azathioprine and steroids

Acronym

Study hypothesis

Hepatitis C virus (HCV)-induced cirrhosis is a leading indication for liver transplantation. There is universal and unavoidable graft re-infection, leading to cirrhosis in 20% after 5 years. Although immunosuppression influences severity of HCV recurrence, a particular regimen which conclusively results in less severe recurrence, is not known.

A recent meta-analysis demonstrated no difference between cyclosporin and tacrolimus, but tacrolimus based immunosuppression reduced graft loss compared to cyclosporin. Another meta-analysis suggests steroids may not be beneficial contrary to a recent study. A randomised study using only calcineurin inhibitor monotherapy (MT) showed both safety and effectiveness in terms of acute and chronic rejection rates, immune graft loss, graft function and patient and graft survival.

We designed a randomised study in liver transplant recipients with hepatitis C virus (HCV) cirrhosis assessing tacrolimus monotherapy (MT) versus tacrolimus, azathioprine and prednisolone triple therapy (TT), hypothesing that the monotherapy arm would have less immunosuppressive potency and, being without maintenance steroids, have less deleterious effects on recurrent HCV.

Ethics approval

Ethics approval received from the Ethics Committee of the Royal Free Hospital in 1999 (ref: 3729)

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Hepatitis C virus (HCV)-induced cirrhosis

Intervention

Tacrolimus (Prograf®, Fujisawa Ltd, Ireland) 0.1 mg/kg/day was given in two divided doses in both MT and TT groups starting within 6 hours from transplantation via a nasogastric tube. Azathioprine was given initially intravenously (iv) then orally 1 mg/kg/day, and methylprednisolone(16 mg/day iv) until oral intake was established, when 20 mg/day prednisolone was used. If poor renal and/or graft function was present tacrolimus dosing (which was evaluated every other day) was adjusted according to clinical progress and occurrence of adverse effects, maintaining a whole blood level of 5 - 14 ng/mL (aiming for 5 - 10 ng/mL) by microparticle enzyme immunoassay (ImxTacrolimus II, Abbott Laboratories, USA). Azathioprine was administered at the same dose unless neutropenia developed. Prednisolone was gradually tapered from 3 weeks onwards and then stopped between 3 and 6 months, according to each centre's practice.

Randomisation took place on arrival to the operating theatre. Each centre had a separate randomisation sequence. Follow-up stopped at death, re-transplantation, or end of January 2008.

Intervention type

Drug

Phase

Not Specified

Drug names

Tacrolimus, azathioprine, prednisolone

Primary outcome measures

The primary end-point was whichever of the following occurred first:
1. Progression of fibrosis, to Ishak stage 4, or
2. Graft failure requiring retransplantation or patient death, or
3. Treatment failure for immunological reasons, i.e., more than two histologically confirmed episodes of cellular rejection failing to respond to therapy

The primary endpoints were measured either in yearly intervals (biopsies) or whenever they occurred within the study period.

Secondary outcome measures

Secondary end-points included:
1. Patient survival
2. Acute cellular rejection early (less than 14 days) or not
3. Chronic rejection
4. Steroid resistant cellular rejection irrespective of further changes in immunosuppression
5. Recurrence of HCV, defined by Ishak inflammation score greater than or equal to 4
6. Withdrawal from the randomised allocation

The secondary endpoints were measured at yearly endpoints or whenever a clinical decompensation occurred.

Overall trial start date

01/01/2000

Overall trial end date

01/06/2007

Reason abandoned

Eligibility

Participant inclusion criteria

From January 2000 to June 2007, in three liver transplant centres, (Royal Free Hospital, Edinburgh Royal Infirmary and St Vincents Hospital, Dublin; all using the same donor pool) consecutive transplant recipients were randomised if they:
1. Had cirrhosis
2. Were hepatitis C virus ribonucleic acid (HCV RNA) positive in serum
3. Had previous histology confirming HCV-related disease
4. Had possible or confirmed/concomitant alcoholic aetiology or hepatocellular carcinoma (HCC)
5. Were older than 18 years, either sex
6. Had given informed written consent (at listing for transplantation)
7. Received a cadaveric liver transplant

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

110

Participant exclusion criteria

1. Retransplantation
2. Multi-organ, split or auxiliary transplants
3. Contraindications to tacrolimus or azathioprine
4. Refusal to participate

Recruitment start date

01/01/2000

Recruitment end date

01/06/2007

Locations

Countries of recruitment

Ireland, United Kingdom

Trial participating centre

Royal Free Hampstead NHS Trust
London
NW3 2QG
United Kingdom

Sponsor information

Organisation

Royal Free Hampstead NHS Trust (UK)

Sponsor details

Pond Street
Hampstead
London
NW3 2QG
United Kingdom
klara.kalu@royalfree.nhs.uk

Sponsor type

Hospital/treatment centre

Website

http://www.royalfree.nhs.uk/

Funders

Funder type

Other

Funder name

Investigator initiated and funded (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2006 results in: http://www.ncbi.nlm.nih.gov/pubmed/16623815
2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/24131637

Publication citations

  1. Results

    Samonakis DN, Mela M, Quaglia A, Triantos CK, Thalheimer U, Leandro G, Pesci A, Raimondo ML, Dhillon AP, Rolles K, Davidson BR, Patch DW, Burroughs AK, Rejection rates in a randomised trial of tacrolimus monotherapy versus triple therapy in liver transplant recipients with hepatitis C virus cirrhosis., Transpl Infect Dis, 2006, 8, 1, 3-12, doi: 10.1111/j.1399-3062.2006.00124.x.

  2. Results

    Manousou P, Cholongitas E, Samonakis D, Tsochatzis E, Corbani A, Dhillon AP, Davidson J, Rodríguez-Perálvarez M, Patch D, O'Beirne J, Thorburn D, Luong T, Rolles K, Davidson B, McCormick PA, Hayes P, Burroughs AK, Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes., Gut, 2014, 63, 6, 1005-1013, doi: 10.1136/gutjnl-2013-305606.

Additional files

Editorial Notes