Randomised study for immunosuppression regimen in liver transplantation

ISRCTN	ISRCTN94834276
DOI	https://doi.org/10.1186/ISRCTN94834276
Protocol serial number	3729
Sponsor	Royal Free Hampstead NHS Trust (UK)
Funder	Investigator initiated and funded (UK)

Submission date: 09/07/2008
Registration date: 18/07/2008
Last edited: 29/10/2013

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Digestive System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Andrew Burroughs
Scientific

Royal Free Hampstead NHS Trust
Pond Street
London
NW3 2QG
United Kingdom

Phone	+44 (0)20 7433 0060
Email	Andrew.Burroughs@royalfree.nhs.uk

Study information

Primary study design	Interventional
Study design	Randomised controlled trial
Secondary study design	Randomised controlled trial
Scientific title	Randomised trial of monotherapy with tacrolimus versus triple therapy with tacrolimus azathioprine and steroids
Study objectives	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(s)	Ethics approval received from the Ethics Committee of the Royal Free Hospital in 1999 (ref: 3729)
Health condition(s) or problem(s) studied	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 / device / biological / vaccine name(s)	Tacrolimus, azathioprine, prednisolone
Primary outcome measure(s)	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.
Key secondary outcome measure(s)	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.
Completion date	01/06/2007

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	110
Key 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
Key exclusion criteria	1. Retransplantation 2. Multi-organ, split or auxiliary transplants 3. Contraindications to tacrolimus or azathioprine 4. Refusal to participate
Date of first enrolment	01/01/2000
Date of final enrolment	01/06/2007

Locations

Countries of recruitment

United Kingdom
England
Ireland

Study participating centre

Royal Free Hampstead NHS Trust

London
NW3 2QG
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/03/2006		Yes	No
Results article	results	01/06/2014		Yes	No