Randomised study for immunosuppression regimen in liver transplantation
| ISRCTN | ISRCTN94834276 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN94834276 |
| Secondary identifying numbers | 3729 |
- 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
Scientific
Royal Free Hampstead NHS Trust
Pond Street
London
NW3 2QG
United Kingdom
| Phone | +44 (0)20 7433 0060 |
|---|---|
| Andrew.Burroughs@royalfree.nhs.uk |
Study information
| Study design | Randomised controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| 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 |
| Pharmaceutical study type(s) | |
| Phase | Not Specified |
| Drug / device / biological / vaccine name(s) | Tacrolimus, azathioprine, prednisolone |
| Primary outcome measure | 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 study start date | 01/01/2000 |
| Completion date | 01/06/2007 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 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
- England
- Ireland
- United Kingdom
Study participating centre
Royal Free Hampstead NHS Trust
London
NW3 2QG
United Kingdom
NW3 2QG
United Kingdom
Sponsor information
Royal Free Hampstead NHS Trust (UK)
Hospital/treatment centre
Hospital/treatment centre
Pond Street
Hampstead
London
NW3 2QG
England
United Kingdom
| klara.kalu@royalfree.nhs.uk | |
| Website | http://www.royalfree.nhs.uk/ |
"ROR" |
https://ror.org/04rtdp853 |
Funders
Funder type
Other
Investigator initiated and funded (UK)
No information available
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | 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 |
