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
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
-
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.
-
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.